RARE DISEASE
Huntington disease
Huntington disease
Huntington disease
Synonyms: Huntington chorea
Synonyms: Huntington chorea
Synonyms: Huntington chorea
Drug discovery
78
drugs
With orphan designations
Overview
Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HTT gene, leading to progressive motor dysfunction (e.g., chorea, rigidity), cognitive decline, and psychiatric symptoms. Onset typically occurs in mid-adulthood (30–50 years), with juvenile forms (<20 years) presenting severe parkinsonism. Diagnosis is confirmed by genetic testing. While incurable, symptom management includes pharmacotherapy, multidisciplinary care, and emerging disease-modifying therapies targeting mutant huntingtin protein (mHTT) reduction [1][5][9][13].
Burden
Life expectancy: 10–30 years post-onset; juvenile HD progresses faster [9][13].
High morbidity: Loss of independence, dysphagia, dementia, and suicide rates 4–8× higher than general population [9][13][16].
Economic/psychosocial strain: Full-time care required in advanced stages; significant caregiver burden [17][20].
Therapies
Symptomatic control: Chorea managed with VMAT2 inhibitors (tetrabenazine, deutetrabenazine), antipsychotics (olanzapine), and anti-glutamatergics (amantadine, riluzole) [3][9][19].
Supportive care: Physical/occupational therapy, psychiatric interventions, and caregiver support [1][17].
Emerging therapies: Antisense oligonucleotides (ASOs, e.g., RG6042 in Phase 3), RNA interference, and CRISPR-based gene editing to reduce mHTT [7][11][15].
Categories: rare genetic diseases, rare neurological diseases, rare ophthalmic disorders
Research Papers
4,753 drug discovery papers about Huntington disease, with 2 first-in-class and 50 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
4,753 drug discovery papers about Huntington disease, with 2 first-in-class and 50 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-14 | Real-world treatment patterns and outcomes of deutetrabenazine in patients with chorea associated with Huntington disease: A retrospective chart review study.
IntroductionReal-world evidence of deutetrabenazine (DTBZ) treatment for Huntington disease (HD)-associated chorea is limited.MethodsThis is a non-interventional, retrospective chart review study from a Huntington's Disease Society of America clinical practice at the University of Alabama at Birmingham (UAB). Patients had a diagnosis of HD-associated chorea, DTBZ initiation (4/2017-12/2021), ≥2 visits at UAB, and ≥3 months of chorea-related care records post DTBZ initiation. The last Unified HD Rating Scale-Total Maximal Chorea (TMC) score within 3 months prior to DTBZ initiation and first after reaching the last stable dose during follow-up were analyzed.ResultsAmong 80 eligible patient charts, mean (SD) age was 52.1 (12.6) years and 45 (56.3%) were female. Fifty patients had pre- and post-DTBZ TMC scores and reached a stable dose, including 30 with no prior tetrabenazine (TBZ) or DTBZ exposure, 8 with prior TBZ exposure with a switch to DTBZ after a gap, and 9 with prior TBZ exposure with a switch to DTBZ without a gap. Mean (SD) TMC score decreased (i.e., improved) by 3.7 (4.5), 7.8 (2.8), and 2.1 (4.2), respectively. Overall, 27 (33.8%) patients had ≥1 adverse event recorded between DTBZ initiation and the first visit with a TMC score after reaching their last stable DTBZ dose or DTBZ discontinuation for those without a stable dose.DiscussionThis real-world study describes improvements in TMC scores among patients with HD-associated chorea treated with DTBZ, regardless of prior treatment. The observed safety profile supports the known safety profile of DTBZ in this population.
2026-08-09 | Molecular insights of peroxisome proliferator-activated receptor-γ signalling in amyotrophic lateral sclerosis and Huntington's disease.
Progressive neuronal loss is a hallmark of neurodegenerative diseases like Huntingtons disease (HD) and Amyotrophic lateral sclerosis (ALS) which are caused by convergent mechanisms such as oxidative stress, mitochondrial dysfunction, neuroinflammation, impaired autophagy and dysregulated cell death pathways. Both conditions share significant disruptions in metabolic and inflammatory signalling despite having different genetic origins and clinical manifestations; underscoring the necessity of pathway-oriented treatment approaches. In the central nervous system, peroxisome proliferator-activated receptor-γ (PPAR-γ), a ligand-activated nuclear receptor has become an important regulator of inflammation, redox homeostasis, mitochondrial biogenesis and cellular stress responses. After giving a thorough overview of PPAR-γ structure activation and transcriptional regulation and the PGC-1α-mediated mitochondrial biogenesis axis, this chapter delves deeply into its interactions with major signalling pathways such as NF-κB, Wnt/β-catenin Nrf2/ARE and the autophagy-apoptosis networks. With a focus on experimental data showing PPAR-γ signaling's neuroprotective, anti-inflammatory, antioxidant and metabolic regulatory roles the pathophysiology of ALS and HD is critically investigated. Lastly the need for improved biomarkers, tailored multi-target strategies and selective modulators is highlighted in the discussion of current therapeutic limitations and translational difficulties.
2026-08-05 | Cholesterol nose-to-brain delivery as a possible therapeutic strategy in Huntington's disease.
Huntington's disease (HD) is a genetically dominant neurodegenerative disorder characterized by several pathological mechanisms, including the disruption of brain cholesterol homeostasis. In several HD animal models, brain cholesterol biosynthesis and levels are reduced. Since circulating cholesterol cannot reach the brain, providing exogenous cholesterol has been shown to improve HD phenotypes. However, the methods used for cholesterol delivery were invasive and not easily transferable to clinical practice. Cholesterol-enriched liposomes were developed by using freeze-and-thaw methods and were administered to R6/2 mice through a single or repeated intranasal administrations. Deuterated-cholesterol was used to discriminate exogenous from endogenous cholesterol. Exogenous cholesterol accumulation and distribution, as well as the levels of cholesterol precursors and metabolites, were measured using mass spectrometry. Behavioral tests, real-time PCR analysis, and immunostaining of mutant HTT (muHTT) aggregates were performed to verify the therapeutic effects of liposomes. Plasma neurofilament levels were measured by Simoa-Quanterix assay. We developed and characterized freeze-and-thaw liposomes. Then, we demonstrate that the exogenous cholesterol can spread throughout the entire brain following intranasal administration of cholesterol-enriched liposomes. Furthermore, repeated intranasal treatments with liposomes result in a full restoration of cognitive decline, and delayed the onset of coordination and motor impairment as well as the loss of muscular strength in the early stages of the disease. Cholesterol supplementation also reduced the plasma level of neurofilament light chain and promoted the clearance of muHTT aggregates. The findings support the effectiveness of cholesterol supplementation as a therapeutic strategy for HD and indicate the translational potential of nose-to-brain cholesterol delivery.
2026-07-20 | From glycemic control to neuroprotection: alogliptin as a repurposed candidate for Huntington's disease.
Huntington's disease (HD) is a progressive, autosomal dominant neurodegenerative disorder characterized by motor dysfunction, cognitive decline, and psychiatric disturbances, for which no disease-modifying therapies are currently available. Emerging evidence implicates metabolic impairment, mitochondrial dysfunction, oxidative stress, and neuroinflammation as central contributors to HD pathogenesis, thereby highlighting novel avenues for therapeutic intervention beyond conventional strategies. In this context, drug repurposing has gained considerable attention as an efficient approach to accelerate therapeutic development. Alogliptin has multiple complementary mechanisms of action that exert neuroprotective effects through inhibition of DPP-4 to boost endogenous incretin signaling (especially GLP-1), inhibition of inflammatory pathways, inhibition of oxidative stress, preservation of mitochondrial function, and modulation of neuronal survival signaling. The review summarizes existing data on the contribution of the incretin signaling to neuroprotection and critically analyzes the mechanism through which alogliptin might regulate important pathological events in HD, such as apoptosis, oxidative stress, and neuroinflammation. Additionally, preclinical results and pharmacological properties in favor of its translational potential are presented, as well as the reflection on its clinical usage and additional research perspectives. Even though direct evidence in HD is not extensive, the overlap of metabolic and neurodegenerative pathways offers a strong argument to study. This review identifies alogliptin as a potent repurposable agent and the necessity to conduct specific experimental and clinical research to determine its effectiveness in refining symptoms and changing the disease course in HD. This narrative review critically evaluates the available experimental evidence supporting the repurposing potential of Alogliptin for HD.
2026-07-17 | Mutant Huntingtin disrupts neurogenic and astroglial programs via the EZH2-Let-7g-LIN28 axis with rescue by epigenetic modulators.
The molecular mechanisms by which mutant huntingtin (mHTT) drives pathogenesis in Huntington's disease (HD) remain incompletely defined. Here we show that neurogenesis is disrupted at multiple stages of lineage progression in both rodent and human neural stem cell (NSC) models of HD. We identify a previously unrecognized phenotype characterized by aberrant expansion of early multipotent progenitors coupled to a profound defect in astrogliogenesis, whereby HD astrocytes fail to express glial fibrillary acidic protein (GFAP). Mechanistically, this defect arises from dysregulation of an epigenetic regulatory axis involving EZH2 and LIN28 upregulation together with reduced expression of the mature let-7g microRNA. Epigenetic pharmacological interventions, targeting this pathway at distinct nodes-through EZH2 modulation, let-7g restoration, or LIN28 inhibition-rescued astroglial differentiation in human HD cells and improved motor function in a Drosophila HD model. Our findings suggest that mHTT might trigger a dual-phase astroglial failure: an early developmental impairment followed by a collapse of regenerative gliogenesis. This bimodal mechanism proposes astrocytic dysfunction as a central driver of HD pathogenesis. Finally, we identify a panel of clinically relevant epigenetic compounds that, by converging on distinct targets within this axis, hold promise for stage-spanning therapeutic strategies capable of modifying disease trajectory.
cell therapies
2026-04-12 | Stem cells enhance mitochondrial function in experimental Huntington's disease.
Huntington's disease (HD) is a neurodegenerative disorder caused by cytosine-adenine-guanine (CAG) triplet expansion in the HTT gene, producing a mutant Huntingtin protein that impairs mitochondrial dynamics by reducing fusion and increasing fission. Mesenchymal stem cells (MSCs) have shown potential therapeutic effects by sharing functional mitochondria and other secretomes. In this study, quinolinic acid-lesioned neuro-2a (QA-N2a) cells and glutamatergic neurons with 50 CAG repeats (HD neurons) were co-cultured with human umbilical cord-derived MSCs for 5 hours. For QA-N2a cells, immunocytochemistry (ICC) was performed to demonstrate the change in GABA and Substance P before and after co-culture. For HD neurons, ICC was conducted to identify mitochondrial proteins, while Western blot was employed to evaluate proteins related to inflammation and mitochondrial function. As a result, co-culture with MSC significantly restored the expression of GABA and Substance P, which diminished after QA exposure. In HD neurons co-cultured with MSCs, an increase in mitochondrial abundance was observed, with significantly higher intensity and dendritic distribution of mitochondria compared to control cells. Western blot analysis confirmed this increase and showed a rising trend in ATP5a levels. MSCs also promoted mitochondrial fusion, indicated by higher levels of Mitofusin 2 (MFN2) and Mitochondrial Dynamin Like GTPase (OPA1), and a trend of reduction in the fission marker Dynamin-Related Protein (DRP1). Additionally, the co-culture led to a decreased trend in neuroinflammation markers IL-6, TNF-α, MMP9, and p-NFkB. Collectively, this study demonstrates that MSCs alleviate HD pathology by restoring the mitochondria activity and potentially suppressing inflammation in two different HD in vitro models.
2026-03-18 | Human iPSC-derived exosomes for amelioration of Huntington's disease through mitochondrial, synaptic, and anti-apoptotic mechanisms.
Huntington's disease (HD) is driven by expanded CAG repeats in the huntingtin gene, resulting in mutant huntingtin (mHtt) aggregation, mitochondrial dysfunction, neuronal loss, and neuroinflammation. Although stem cell-based therapies provide potent regenerative, anti-inflammatory, and neuroprotective effects, their clinical translation remains constrained by tumorigenicity and poor engraftment efficiency. Therefore, we investigated whether exosomes derived from human induced pluripotent stem cells (iPSC-exo) could serve as a safe, cell-free therapeutic approach by leveraging their paracrine mechanisms. iPSC-exo were isolated from iPSC-conditioned medium and characterized by nanoparticle tracking analysis, Western blotting, and ExoView assays, confirming exosomal size (∼100 nm) and expression of canonical markers (CD63, CD81, ALIX, HSP70/90). Treatment of HD neural stem cells with iPSC-exo significantly reduced mHtt aggregation, as shown by EM48 immunostaining and Western blot analysis. iPSC-exo also restored mitochondrial membrane potential, improved mitochondrial morphology, and upregulated CREB while suppressing c-Jun expression, indicating enhanced mitochondrial and stress resilience. Furthermore, iPSC-exo promoted neurite outgrowth and synaptic maturation, reflected by increased MAP2 and PSD95 levels and reduced Tuj1 expression, signifying neuronal progression toward a mature phenotype. Western blot analysis revealed downregulation of BAX, cleaved caspase-3, NF-κB, and JNK, alongside upregulation of BCL-2 and TrkB, demonstrating suppression of apoptosis and inflammation with concurrent activation of survival pathways. These multifaceted effects collectively alleviated mHtt aggregation, as confirmed by EM48 immunostaining and Western blot analysis. Together, our findings demonstrate that iPSC-exo mitigate HD pathology by improving mitochondrial function, neuronal differentiation, and anti-apoptotic signaling, thereby reducing mHtt accumulation.
2026-02-26 | Clinical-Grade Human Induced Pluripotent Stem Cell-Derived Neural Precursor Cells Restore Motor Function and Preserve Striatal Integrity in a Quinolinic Acid-Lesioned Rat Model of Huntington's Disease.
Huntington's disease (HD) is an inherited neurodegenerative disease characterised by progressive degeneration of GABAergic medium spiny neurons (MSNs) in the striatum. Neural precursor cells (NPCs) derived from human induced pluripotent stem cells (iPSCs) have been considered as a promising and scalable source for neuronal replacement and circuit restoration. In this study, we investigated the therapeutic effects of a clinical-grade, human leukocyte antigen (HLA)-homozygous iPSC line (YZWJ-s513) differentiated into NPCs (s513-NPCs) in a quinolinic acid (QA)-lesioned rat model of HD. Following intrastriatal transplantation, s513-NPCs not only survived for 12 weeks but also differentiated into neurons, astrocytes, and oligodendrocytes, while generating new DARPP32+ GABAergic MSNs. Specifically, graft-derived neurons projected to the host globus pallidus, indicating structural integration into the striato-pallidal pathways. Additionally, NPC-transplanted rats exhibited significant motor recovery across multiple tasks for up to 12 weeks, accompanied by reduced striatal atrophy and ventricular enlargement. Histological findings also revealed attenuated astrogliosis and microgliosis, along with a shift toward an anti-inflammatory milieu. Collectively, these results demonstrate that transplantation of clinical-grade, HLA-homozygous iPSC-derived NPCs can provide both neuronal replacement and modulation of the diseased microenvironment, supporting their potential as a regenerative therapy for HD. Key quality attributes and release criteria supporting the clinical-grade characterisation of the cell product used in vivo are summarised in Table S1.
2025-11-05 | A phase I, open-label study of intravenous human dental pulp stem cells (NestaCell®) at two dose levels in patients with Huntington's disease.
Huntington's disease (HD) is a progressive neurodegenerative disorder with no approved disease-modifying therapies. Human dental pulp stem cells (hDPSCs) offer potential therapeutic benefits due to their neurogenic, neurotrophic, and immunomodulatory properties. This prospective, open-label, single-centre, first-in-human clinical trial evaluated the safety, tolerability, and preliminary efficacy of intravenous hDPSC in patients with HD. Six male patients with HD received intravenous infusions of hDPSCs in two dosage cohorts: three patients received 1 million cells/kg, and three received 2 million cells/kg. The treatment protocol consisted of cycles of three infusions at monthly intervals followed by subsequent administration cycles every six months, as per a protocol amendment based on the initial favourable safety outcomes. The total number of infusions ranged from 4 to 26 over the five years. During the first year, all patients underwent intensive multiparametric monitoring in an intensive care unit (ICU) for 48 h after each infusion. No adverse events occurred during the 48-h ICU monitoring or within 15 days post-infusion. Of 41 treatment-emergent adverse events (TEAEs) reported during follow-up, 35 were judged unrelated to the hDPSCs, mainly reflecting disease progression or incidental findings. Six treatment-emergent adverse events (TEAEs) were considered treatment-related, involving transient changes in hair pigmentation or regrowth. One patient discontinued due to a serious adverse event-lung cancer arising from a pre-existing pulmonary nodule identified at enrolment. Genetic analysis of the excised tumour showed no evidence of investigational product engraftment, supporting its non-tumorigenic nature. The same patient experienced a severe depressive episode lasting approximately 93 days; the relationship to treatment was considered uncertain. Minor, clinically insignificant fluctuations in CD4/CD8 lymphocyte counts and cytokine levels were observed. Preliminary efficacy analyses indicated potential stabilisation of disease progression, particularly in the Unified Huntington's Disease Rating Scale (UHDRS), Total Motor Score (TMS) and Total Functional Capacity (TFC). hDPSCs infusions were well tolerated and exhibited a favourable safety profile, even with prolonged exposure and follow-up. These findings support the continued clinical development and warrant further investigation in more extensive trials to assess therapeutic efficacy in Huntington's disease. This study was registered on April 4, 2016, at ClinicalTrials.gov (identifier: NCT02728115; https://clinicaltrials.gov/study/NCT02728115 ).
2025-10-31 | The Evolving Landscape of Stem Cell Therapies for Huntington's Disease.
Huntington's disease (HD) is a fatal, inherited neurodegenerative disorder marked by the progressive and selective loss of spiny projection neurons (SPNs), resulting in a characteristic triad of motor, cognitive, and psychiatric symptoms. Despite ongoing research, no disease-modifying treatments are available, and existing therapies are limited to symptomatic relief. Stem cell-based approaches represent a promising avenue to restore striatal circuitry by replacing lost neurons and/or delivering trophic support to preserve the remaining neural tissue.In this review, we present a critical analysis of past and current clinical trials exploring cell-based therapies for HD. Early studies using human fetal tissue were hindered by sample heterogeneity and inconsistent outcomes, ultimately limiting their clinical applicability. More recent trials have shifted focus toward mesenchymal stem cells (MSCs), which are valued for their neuroprotective secretome but are not suitable for neuronal replacement. To address these limitations, human pluripotent stem cells (hPSCs) have emerged as a renewable and scalable source for the development of advanced therapy medicinal products (ATMPs). In vitro differentiation protocols mimic key developmental signaling pathways to generate striatal-like neural progenitor cells (NPCs). We review the cellular composition of these hPSC-derived ATMPs and summarize findings from preclinical transplantation studies, including data on graft survival, neuronal maturation, synaptic integration, and functional recovery. In addition, we discuss other emerging strategies such as direct neuronal reprogramming. Finally, we examine the major challenges that remain-such as ensuring graft safety, consistency, and regulatory compliance-and highlight the importance of international collaboration to overcome these barriers and accelerate clinical translation.
proteins
2026-07-07 | CDKN1A protects medium spiny neurons from Huntington's disease pathology.
Huntington's disease (HD) arises from abnormal expansion of CAG trinucleotide repeats within the HTT gene, leading to mutant huntingtin (mHTT) aggregation, progressive loss of striatal medium spiny neurons (MSNs), and progressive neurodegeneration. While the genetic cause is established, the mechanisms that confer selective MSN vulnerability, particularly those linked to aging, remain unclear. We employed a combination of miR-9/9*-124-driven reprogramming and MSN-specific transcription factors to generate patient-derived MSNs from fibroblasts of symptomatic HD patients (HD-MSNs), pre-symptomatic mutation carriers (pre-HD-MSNs), and healthy controls, preserving donor age signatures. Multi-omics analysis integrating RNA-seq and ATAC-seq revealed reduced CDKN1A expression and promoter accessibility in HD-MSNs compared with pre-HD-MSNs. Overexpression of CDKN1A in HD-MSNs alleviated HD pathologies, including DNA double-strand breaks, oxidative DNA damage, and mHTT aggregates, while improving neuronal survival and autophagy-associated activity. Conversely, knockdown of CDKN1A in pre-HD-MSNs elicited opposite effects, revealing a CDKN1A-dependent survival mechanism in HD. Together, these findings suggest that reduced CDKN1A expression may contribute to HD-associated MSN vulnerability and is associated with altered DNA damage responses and autophagy-related processes in HD-MSNs. Our study identifies CDKN1A as a potential modulator of neuronal resilience in HD.
2026-06-27 | Mutant huntingtin in the extracellular matrix: A new perspective on Huntington's disease pathology.
Huntington's disease (HD) is a monogenic neurodegenerative disorder characterized by extensive brain pathology. While its underlying cause has been attributed to intracellular mutant huntingtin (mHTT), growing evidence reveals that mHTT is also present, and biologically active, outside cells. Detected in cerebrospinal fluid, plasma, and brain tissue, extracellular mHTT can induce toxicity and spread between cells. This commentary explores a challenging, yet the largely overlooked possibility that the extracellular matrix (ECM) - a dynamic and highly structured network surrounding neurons and glia - may shape how mHTT aggregates form, accumulate and propagate in the brain. Drawing on parallels with other proteinopathies, we examine how ECM components could create a microenvironment that favors mHTT accumulation and pathogenicity. While direct evidence remains limited, we argue that the ECM may play a more active role in HD than previously recognized. This perspective invites a rethinking of HD pathology and may help guide the development of therapies that extend beyond targeting intracellular mHTT.
2026-05-29 | SQSTM1/p62 UFMylation Enhances Autophagic Clearance of Pathogenic Mutant Huntingtin.
Ubiquitin-fold modifier 1 (UFM1) covalently modifies protein substrates (UFMylation) and alters their biological functions. Genetic screening disclosed that enzymes in the UFMylation system play critical roles in regulating autophagy. However, it is still elusive which protein is UFMylated and how this modification modulates autophagy. Here, our quantitative proteomics and biochemical experiments identify SQSTM1/p62 as a UFMylation substrate and discover its two major UFMylation sites, K420 and K435. Mutating them to Arg (p622KR) completely abolishes the effect of p62 on autophagic activity. Fusion of UFM1ΔC4 to p622KR (p622KR-UFM1ΔC4) restores the p62-mediated pathogenic autophagic degradation in primary cortical neurons and Huntington's disease mouse striatum. Mechanistically, p62 UFMylation enhances its interaction with LC3, augments autophagic flux, and eliminates pathogenic mutant huntingtin. Collectively, this work discovers a new post-translational modification, UFMylation, on p62 and establishes this modification as a key regulator of autophagy that promotes the clearance of mutant huntingtin, offering a potential target for therapeutic intervention.
2026-04-08 | Distinct autophagy impairment mechanisms of huntingtin aggregates with different polyQ lengths.
Huntington's disease (HD) is characterized by the aggregation of mutant huntingtin (mHTT) containing elongated polyglutamine (polyQ) tracts. mHTT aggregates that fail to be cleared by autophagy cause neurotoxicity. While the polyQ length in patients with HD ranges from 40 to over 90 repeats, how these varying polyQ lengths affect autophagy impairment remains unclear. Using polyQ aggregation sensors based on bimolecular fluorescence complementation (BiFC), we uncovered distinct autophagy impairment mechanisms: PolyQ103 aggregates evade recognition by autophagy receptor SQSTM1/p62, whereas polyQ43 condensates are recognized by SQSTM1/p62, but their bulky association prevents complete autophagosome formation. Interestingly, overexpression of optineurin (Optn), another autophagy receptor, preferentially binds to polyQ103 aggregates but not polyQ43 condensates, improving cell survival. K63-ubiquitination on polyQ103 aggregates serves as a critical determinant for Optn recruitment via its UBAN domain. These findings reveal polyQ length-dependent pathological mechanisms underlying autophagy impairment of mHTT aggregates, suggesting potential therapeutic strategies for patients with longer polyQ sequences.
2026-04-03 | Modest rescue of RBFOX1 splicing function attenuates Huntington's disease features.
BACKGROUND: RNA mis-splicing underlies a growing number of neurological disorders and, consequently, splicing correction therapies have been developed for some monogenic forms, like spinal muscular atrophy or neuronal ceroid lipofuscinosis. In Huntington’s disease (HD), alternative splicing alteration emerged as a molecular mechanism in view of individually reported mis-splicing events in neurodegeneration-linked genes such as HTT itself, MAPT and TAF1. Later, more systematic genome-wide RNA-seq analyses of HD brains revealed mis-splicing signatures involving additional neurodegeneration-linked genes. Individual correction of each of the potentially pathogenic mis-spliced genes would be unapproachable. However, the identification of upstream pivotal splicing factors altered in HD may be useful to design pleiotropic therapeutic strategies. We previously performed motif-enrichment analyses of the sequences flanking exons that are mis-spliced in HD and identified RBFOX splicing factors as underlying candidates. METHODS: We performed RT-PCR and Western blot analyses of RBFOX in post-mortem brain samples from HD patients and mice. We generated transgenic mouse lines overexpressing RBFOX1 in forebrain neurons and performed RNA-seq to analyze its impact on HD-associated mis-splicing. In addition, we combined HD mice with RBFOX1-overexpressing mice to verify correction of Rbfox1 levels and mis-splicing of RBFOX target genes, and performed histopathological and motor behavioral analyses. RESULTS: We observed that decreased expression of Rbfox1 in striatum of HD mice at early stages of disease progression correlates with a reduction of Rbfox1 immunostaining particularly in the nucleus. This prompted us to generate transgenic mouse lines overexpressing the nuclear isoform of RBFOX1. The overexpression of RBFOX1 in this new transgenic mouse line induced widespread alternative splicing changes that significantly overlapped with genes mis-spliced in brains of both HD patients and mouse models. We found that moderate neuronal RBFOX1 overexpression in HD mice results in correction of several HD-associated mis-splicing events and in attenuation of neurodegeneration and motor symptoms. CONCLUSIONS: These results demonstrate that the observed decrease of RBFOX1 levels in brains of HD patients and mice contributes to HD pathogenesis and suggest therapeutic potential of RBFOX-increasing strategies for HD.
oligonucleotides
2026-08-12 | Blocking somatic repeat expansion and lowering huntingtin by RNAi synergize to attenuate Huntington's disease pathogenesis in mice.
Huntington's disease (HD) is a progressive neurodegenerative disorder with no approved therapies. Despite multiple clinical trials, huntingtin (HTT)-lowering strategies have yet to show meaningful clinical benefit. Both somatic expansion and toxic HTT species are key molecular drivers of HD, yet therapeutic strategies targeting these pathways have never been directly compared or evaluated in combination. Using therapeutic divalent siRNAs, we assessed the long-term impact of silencing MutS homolog 3 (MSH3), a critical regulator of somatic expansion, HTT, or both in Q111 HD mice (>110 CAGs), which develop robust expansion, mutant HTT inclusions, and transcriptional dysregulation by 12 months. Long-term MSH3 silencing blocked somatic expansion, reduced inclusions, and normalized gene expression. HTT silencing alone had a limited effect, whereas combined MSH3/HTT targeting synergistically eliminated inclusions and restored transcriptomic profiles. Parallel treatment in wild-type mice showed no toxicity, supporting the safety of long-term intervention. These findings position somatic expansion as a promising therapeutic target and demonstrate the potential of RNAi-based cosilencing of MSH3 and HTT as a disease-modifying strategy for HD.
2026-06-27 | Anle138b ameliorates pathological phenotypes in mouse and cellular models of Huntington's disease.
Huntington's disease (HD) is a hereditary movement disorder caused by a CAG repeat expansion in the huntingtin gene. HD is characterized by deposition of mutant huntingtin (mHTT) aggregates, and by severe neurodegeneration of the basal ganglia and neocortex. No cure is currently available, and new treatment options are urgently needed. Here, we show that the oligomer modifying molecule anle138b (INN: emrusolmin) improves multiple disease phenotypes in cell culture and in two mouse models of HD. Application of anle138b reduced mHTT aggregate formation and ameliorated neurotoxicity in primary neurons. Oral administration of anle138b delayed deposition of mHTT inclusions, reduced brain atrophy, mitigated neuroinflammation and transcriptional alterations, improved motor function and extended life span in HD mice. Downregulation of striatal markers and synapse loss in striatal spiny projection neurons were also partially rescued. No adverse effects of anle138b were observed in wildtype animals. Moreover, anle138b markedly decreased mHTT aggregation in human neural precursor cells differentiated from HD patient-derived induced pluripotent stem cells (iPSCs). Altogether these results illustrate the potential of anle138b as a disease-modifying treatment for HD.
2026-06-10 | Which HTT transcript to lower?
Huntington's disease (HD) RNA therapeutics have focused on lowering canonical huntingtin (HTT), yet clinical benefit remains uncertain. Papadopoulou et al. and Bragg et al. suggest that HTT1a-engaging strategies can produce stronger molecular rescue than full-length HTT lowering that spares HTT1a, highlighting transcript-species coverage as a key variable in HTT-lowering pharmacology.
2026-06-06 | Huntington Disease: A Comprehensive Overview of Molecular Genetics, Clinical Pathophysiology, Management and Emerging Therapies
Huntington disease (HD) is a relentlessly progressive, autosomal dominant neurodegenerative disorder caused by an expanded CAG trinucleotide repeat in the HTT gene on chromosome 4p16.3. This mutation translates into an aberrant polyglutamine tract within the huntingtin protein, conferring toxic gain-of-function and dominant-negative loss-of-function effects that preferentially devastate the striatal medium spiny neurons. Clinically, HD manifests in mid-adulthood with a characteristic triad of choreiform motor disturbances, progressive cognitive decline (subcortical dementia), and a spectrum of psychiatric and behavioral abnormalities including apathy, depression, irritability, and psychosis. Juvenile-onset HD (Westphal variant) presents before age 20 with rigidity, bradykinesia, seizures, and rapid cognitive deterioration. Diagnosis rests upon characteristic clinical findings in the context of a positive family history and is confirmed by targeted CAG repeat analysis. While no disease-modifying therapy currently exists, symptomatic management employs VMAT2 inhibitors and antipsychotics for chorea, antidepressants and behavioral interventions for psychiatric symptoms, and comprehensive supportive care including physical, occupational, speech, and nutritional therapy. Disease progression spans 15 to 20 years, with death typically resulting from aspiration pneumonia or suicide. Emerging therapies—including gene silencing (antisense oligonucleotides, RNA interference), cell transplantation, and small molecules targeting excitotoxicity, mitochondrial dysfunction, and protein aggregation—are under active investigation. Optimal patient outcomes require an interprofessional team approach integrating neurology, genetic counseling, nursing, pharmacy, rehabilitation therapies, and social work, with emphasis on early advance care planning and caregiver support.
2026-03-18 | Lowering the HTT1a transcript as an effective therapy for Huntington's disease in a knockin mouse model.
Lowering huntingtin (HTT) transcript levels has been a major focus of therapeutic development for Huntington's disease (HD), but which transcript should be lowered? HD is caused by a CAG repeat expansion in exon 1 of the HTT gene, and the rate of somatic expansion of this CAG repeat throughout life drives the age of onset and rate of disease progression. As the CAG repeat expands, the extent to which the HTT mRNA is alternatively processed to generate the HTT1a transcript and highly aggregation-prone and pathogenic HTT1a protein increases. Several HTT-lowering modalities have entered clinical trials that target either both HTT and HTT1a together or full-length HTT alone. We have developed siRNAs that target the Htt1a mouse transcript (634/486) and used these, together with a potent Htt-targeting siRNA (10150), to compare the efficacy of lowering either full-length Htt or Htt1a. zQ175 and wild-type mice were treated with 10150 or 634/486 alongside control groups at 2 months of age and euthanized at 6 months, at 2 months and again at 6 months and euthanized at 10 months, or at 6 months and euthanized at 10 months. The siRNA potency and durability were most effective in the hippocampus. Although both strategies showed benefits, despite the greater potency of 10150, targeting Htt1a was more effective at delaying HTT aggregation and transcriptional dysregulation than targeting full-length Htt. These data support HTT-lowering strategies that are designed to target the HTT1a transcript, either alone or together with lowering full-length HTT.
other
2026-07-24 | IL17A disrupts autophagy-lysosomal function and lysosome reformation through the GSK3B-TFE3 signaling pathway in Huntington disease.
Huntington disease (HD) is a progressive neurodegenerative disease caused by an expanded CAG repeat in the HTT (huntingtin) gene, leading to the accumulation of mutant HTT (mHTT). IL17A (interleukin 17A), a proinflammatory cytokine primarily secreted by Th17 and γδ T cells, has been implicated in immune-mediated neurodegeneration. However, the role of IL17A in the pathogenesis of HD remains poorly understood. Here, we identify IL17A as a critical pathogenic factor in HD that promotes neuroinflammation, mHTT aggregation, and autophagy-lysosomal dysfunction. IL17A disrupts autophagic flux by downregulating CTSB and CTSD, inducing SQSTM1/p62 and MAP1LC3B-II/LC3-II accumulation, and impairing lysosomal reformation. Mechanistically, IL17A suppresses lysosomal biogenesis by inhibiting the nuclear translocation of TFE3. This regulation occurs via a novel GSK3B/GSK-3β-TFE3 signaling pathway. Therapeutic neutralization of IL17A with a monoclonal antibody (IL17A mAb) ameliorates disease phenotypes in R6/2 HD mice, improving motor performance, extending survival, and reducing gliosis. IL17A mAb also attenuates mHTT aggregation and enhances neuroprotective signaling, as evidenced by increased expression of DLG4/PSD-95, phosphorylated CREB1, and BDNF. Moreover, IL17A mAb restores autophagy-lysosomal function by facilitating the clearance of protein aggregates and upregulating lysosomal enzymes and biogenesis markers, including CTSB, CTSD, PIP5K1A, and LAMP2. These findings establish IL17A as a key modulator of HD pathophysiology and highlight IL17A inhibition as a promising therapeutic strategy for targeting autophagy-lysosomal dysfunction in HD.
2026-07-13 | CRISPR-Cas9-based therapies for Huntington's disease and Friedreich's ataxia: mechanisms, advances, and future perspectives.
Huntington's disease (HD) and Friedreich's ataxia (FRDA) are progressive inherited neurodegenerative disorders caused by trinucleotide repeat expansions but characterized by distinct pathogenic mechanisms. HD arises from a coding-region CAG expansion in the HTT gene that produces toxic gain-of-function effects of mutant huntingtin (mHTT), whereas FRDA results primarily from intronic GAA repeat expansion in FXN, leading to epigenetic repression and frataxin deficiency. The emergence of CRISPR-based genome engineering has created new opportunities to address these diseases at their genetic origin. This review examines current CRISPR therapeutic strategies for HD and FRDA, including allele-specific editing, transcriptional suppression, repeat excision, epigenetic reactivation, and emerging precision editing approaches such as base editing and prime editing. We compare the molecular rationale, preclinical outcomes, and translational limitations associated with each approach while highlighting how disease architecture influences therapeutic design. Although preclinical studies demonstrate promising restoration of cellular phenotypes and functional improvement, significant barriers remain. Efficient delivery to the central nervous system and cardiac tissue, control of editing duration, immune responses, off-target activity, and emerging concerns regarding on-target genomic instability continue to limit clinical translation. Recent advances in delivery engineering, non-viral systems, and programmable editing platforms suggest that future therapeutic success will depend on integrating disease-specific biology with increasingly precise and controllable genome engineering technologies. Ethical and regulatory concerns remain substantial, particularly regarding informed consent in the context of cognitive decline and the irreversibility of genomic modification.
2026-06-26 | Childhood to Adult Neurodevelopment in Gene-Expanded Huntington's Disease (ChANGE-HD): A prospective longitudinal neurodevelopmental study of Huntington's disease.
Although adult Huntington's disease (HD) studies have significantly advanced our understanding of the course of degeneration, they may underrepresent critical neurodevelopmental aspects of the disease. Significant gaps remain in understanding how mutant huntingtin affects early neurodevelopment, its long-term impact, as well as potential implications for treatment outcomes. The Childhood to Adult Neurodevelopment in Gene-Expanded Huntington's Disease (ChANGE-HD; NCT01951588) study aims to evaluate brain structure and function in premanifest, at-risk children and young adults, and explore HD's developmental origins. Here, we introduce the ChANGE-HD study, which will investigate and integrate the neurodevelopmental and neurodegenerative aspects of HD. The ChANGE-HD study is a prospective, seven-year multi-site observational study with an accelerated longitudinal design, where participants are not bound to a fixed schedule across multiple visits. Four hundred and fifty participants aged 6-30 years who are at risk for HD will be recruited and asked to return for multiple visits (if possible). At each visit, cognitive, motor, behavioral, blood/saliva, and MRI data are collected. Alongside ChANGE-HD, we are also recruiting individuals for the juvenile-onset HD (JOHD) study to investigate the neuropathology of this rarer form of HD. ChANGE-HD represents the first prospective multi-site study to systematically document brain structure and function during the premanifest phase of HD in children and young adults. Data collection is ongoing with first results anticipated in 2026-2027. The ChANGE-HD approach is likely to provide novel physiological insights and guide the development of therapeutic strategies tailored to both the developmental and degenerative phases of the disease.
2026-06-11 | Recognizing repeat expansion disorders in clinical practice.
Repeat expansion disorders are caused by unstable DNA sequences that exceed pathogenic thresholds, disrupting normal gene function. These conditions often affect the nervous system, but may involve multiple organs, with presentations ranging from subtle cognitive or motor changes to overt neuromuscular or neurodevelopmental syndromes. Early symptoms can mimic common conditions, making clinical suspicion, family history, and awareness of intergenerational patterns essential. Molecular features, including repeat size, sequence, location and stability, determine disease severity and variability. Nurse practitioners are well positioned to recognize early signs, make early referrals to genetics, and support families with education, anticipatory guidance, and coordination of follow-up care. Case examples include Huntington disease, fragile X syndrome, and myotonic dystrophy and illustrate clinical heterogeneity, premutation effects, and genetic anticipation. Early recognition and referral remain crucial, particularly as emerging gene-targeted therapies may offer potential disease-modifying options.
2026-06-03 | Friend or foe? Glial-vascular interactions in health and neurodegenerative disease.
Dysfunction of glial and vascular cells is increasingly recognized as a central feature of neurodegenerative diseases. Growing evidence points to disruptions in glial-vascular interactions, which are critical for maintaining the functions of the neurogliovascular unit throughout the lifespan, as key contributors to disease initiation and progression. However, the mechanisms governing this complex intercellular crosstalk and its potential role in disease pathogenesis remain incompletely understood. In this review, we summarize the current understanding of glial-vascular communication across health and disease, with a particular focus on Alzheimer disease, stroke, cerebral small vessel disease, Parkinson disease, Huntington disease, and multiple sclerosis. We highlight emerging cellular and molecular interactions of interest, outline major gaps in our understanding, and discuss innovative tools, including transcriptomics, which are reshaping the study of neurogliovascular dynamics. A central unresolved question is whether glial and/or vascular dysfunction represents the primary initiating event across neurodegenerative diseases, or whether these processes emerge in parallel through shared upstream drivers. Unraveling these interactions may ultimately reveal novel therapeutic opportunities for a broad range of neurodegenerative conditions. SIGNIFICANCE STATEMENT: Neurogliovascular unit interactions are fundamental to brain homeostasis, yet the molecular basis of this crosstalk and its disruption in neurodegeneration remains poorly understood. This review provides the first comprehensive synthesis of molecular mechanisms governing the Neurogliovascular unit interface across physiological and pathological conditions, integrating evidence from related disorders. By consolidating key signaling pathways, disease-associated alterations, and emerging experimental approaches, this review offers a unifying framework to guide biomarker development and therapeutic targeting.
small molecules
2026-08-14 | Real-world treatment patterns and outcomes of deutetrabenazine in patients with chorea associated with Huntington disease: A retrospective chart review study.
IntroductionReal-world evidence of deutetrabenazine (DTBZ) treatment for Huntington disease (HD)-associated chorea is limited.MethodsThis is a non-interventional, retrospective chart review study from a Huntington's Disease Society of America clinical practice at the University of Alabama at Birmingham (UAB). Patients had a diagnosis of HD-associated chorea, DTBZ initiation (4/2017-12/2021), ≥2 visits at UAB, and ≥3 months of chorea-related care records post DTBZ initiation. The last Unified HD Rating Scale-Total Maximal Chorea (TMC) score within 3 months prior to DTBZ initiation and first after reaching the last stable dose during follow-up were analyzed.ResultsAmong 80 eligible patient charts, mean (SD) age was 52.1 (12.6) years and 45 (56.3%) were female. Fifty patients had pre- and post-DTBZ TMC scores and reached a stable dose, including 30 with no prior tetrabenazine (TBZ) or DTBZ exposure, 8 with prior TBZ exposure with a switch to DTBZ after a gap, and 9 with prior TBZ exposure with a switch to DTBZ without a gap. Mean (SD) TMC score decreased (i.e., improved) by 3.7 (4.5), 7.8 (2.8), and 2.1 (4.2), respectively. Overall, 27 (33.8%) patients had ≥1 adverse event recorded between DTBZ initiation and the first visit with a TMC score after reaching their last stable DTBZ dose or DTBZ discontinuation for those without a stable dose.DiscussionThis real-world study describes improvements in TMC scores among patients with HD-associated chorea treated with DTBZ, regardless of prior treatment. The observed safety profile supports the known safety profile of DTBZ in this population.
2026-08-09 | Molecular insights of peroxisome proliferator-activated receptor-γ signalling in amyotrophic lateral sclerosis and Huntington's disease.
Progressive neuronal loss is a hallmark of neurodegenerative diseases like Huntingtons disease (HD) and Amyotrophic lateral sclerosis (ALS) which are caused by convergent mechanisms such as oxidative stress, mitochondrial dysfunction, neuroinflammation, impaired autophagy and dysregulated cell death pathways. Both conditions share significant disruptions in metabolic and inflammatory signalling despite having different genetic origins and clinical manifestations; underscoring the necessity of pathway-oriented treatment approaches. In the central nervous system, peroxisome proliferator-activated receptor-γ (PPAR-γ), a ligand-activated nuclear receptor has become an important regulator of inflammation, redox homeostasis, mitochondrial biogenesis and cellular stress responses. After giving a thorough overview of PPAR-γ structure activation and transcriptional regulation and the PGC-1α-mediated mitochondrial biogenesis axis, this chapter delves deeply into its interactions with major signalling pathways such as NF-κB, Wnt/β-catenin Nrf2/ARE and the autophagy-apoptosis networks. With a focus on experimental data showing PPAR-γ signaling's neuroprotective, anti-inflammatory, antioxidant and metabolic regulatory roles the pathophysiology of ALS and HD is critically investigated. Lastly the need for improved biomarkers, tailored multi-target strategies and selective modulators is highlighted in the discussion of current therapeutic limitations and translational difficulties.
2026-08-05 | Cholesterol nose-to-brain delivery as a possible therapeutic strategy in Huntington's disease.
Huntington's disease (HD) is a genetically dominant neurodegenerative disorder characterized by several pathological mechanisms, including the disruption of brain cholesterol homeostasis. In several HD animal models, brain cholesterol biosynthesis and levels are reduced. Since circulating cholesterol cannot reach the brain, providing exogenous cholesterol has been shown to improve HD phenotypes. However, the methods used for cholesterol delivery were invasive and not easily transferable to clinical practice. Cholesterol-enriched liposomes were developed by using freeze-and-thaw methods and were administered to R6/2 mice through a single or repeated intranasal administrations. Deuterated-cholesterol was used to discriminate exogenous from endogenous cholesterol. Exogenous cholesterol accumulation and distribution, as well as the levels of cholesterol precursors and metabolites, were measured using mass spectrometry. Behavioral tests, real-time PCR analysis, and immunostaining of mutant HTT (muHTT) aggregates were performed to verify the therapeutic effects of liposomes. Plasma neurofilament levels were measured by Simoa-Quanterix assay. We developed and characterized freeze-and-thaw liposomes. Then, we demonstrate that the exogenous cholesterol can spread throughout the entire brain following intranasal administration of cholesterol-enriched liposomes. Furthermore, repeated intranasal treatments with liposomes result in a full restoration of cognitive decline, and delayed the onset of coordination and motor impairment as well as the loss of muscular strength in the early stages of the disease. Cholesterol supplementation also reduced the plasma level of neurofilament light chain and promoted the clearance of muHTT aggregates. The findings support the effectiveness of cholesterol supplementation as a therapeutic strategy for HD and indicate the translational potential of nose-to-brain cholesterol delivery.
2026-07-20 | From glycemic control to neuroprotection: alogliptin as a repurposed candidate for Huntington's disease.
Huntington's disease (HD) is a progressive, autosomal dominant neurodegenerative disorder characterized by motor dysfunction, cognitive decline, and psychiatric disturbances, for which no disease-modifying therapies are currently available. Emerging evidence implicates metabolic impairment, mitochondrial dysfunction, oxidative stress, and neuroinflammation as central contributors to HD pathogenesis, thereby highlighting novel avenues for therapeutic intervention beyond conventional strategies. In this context, drug repurposing has gained considerable attention as an efficient approach to accelerate therapeutic development. Alogliptin has multiple complementary mechanisms of action that exert neuroprotective effects through inhibition of DPP-4 to boost endogenous incretin signaling (especially GLP-1), inhibition of inflammatory pathways, inhibition of oxidative stress, preservation of mitochondrial function, and modulation of neuronal survival signaling. The review summarizes existing data on the contribution of the incretin signaling to neuroprotection and critically analyzes the mechanism through which alogliptin might regulate important pathological events in HD, such as apoptosis, oxidative stress, and neuroinflammation. Additionally, preclinical results and pharmacological properties in favor of its translational potential are presented, as well as the reflection on its clinical usage and additional research perspectives. Even though direct evidence in HD is not extensive, the overlap of metabolic and neurodegenerative pathways offers a strong argument to study. This review identifies alogliptin as a potent repurposable agent and the necessity to conduct specific experimental and clinical research to determine its effectiveness in refining symptoms and changing the disease course in HD. This narrative review critically evaluates the available experimental evidence supporting the repurposing potential of Alogliptin for HD.
2026-07-17 | Mutant Huntingtin disrupts neurogenic and astroglial programs via the EZH2-Let-7g-LIN28 axis with rescue by epigenetic modulators.
The molecular mechanisms by which mutant huntingtin (mHTT) drives pathogenesis in Huntington's disease (HD) remain incompletely defined. Here we show that neurogenesis is disrupted at multiple stages of lineage progression in both rodent and human neural stem cell (NSC) models of HD. We identify a previously unrecognized phenotype characterized by aberrant expansion of early multipotent progenitors coupled to a profound defect in astrogliogenesis, whereby HD astrocytes fail to express glial fibrillary acidic protein (GFAP). Mechanistically, this defect arises from dysregulation of an epigenetic regulatory axis involving EZH2 and LIN28 upregulation together with reduced expression of the mature let-7g microRNA. Epigenetic pharmacological interventions, targeting this pathway at distinct nodes-through EZH2 modulation, let-7g restoration, or LIN28 inhibition-rescued astroglial differentiation in human HD cells and improved motor function in a Drosophila HD model. Our findings suggest that mHTT might trigger a dual-phase astroglial failure: an early developmental impairment followed by a collapse of regenerative gliogenesis. This bimodal mechanism proposes astrocytic dysfunction as a central driver of HD pathogenesis. Finally, we identify a panel of clinically relevant epigenetic compounds that, by converging on distinct targets within this axis, hold promise for stage-spanning therapeutic strategies capable of modifying disease trajectory.
cell therapies
2026-04-12 | Stem cells enhance mitochondrial function in experimental Huntington's disease.
Huntington's disease (HD) is a neurodegenerative disorder caused by cytosine-adenine-guanine (CAG) triplet expansion in the HTT gene, producing a mutant Huntingtin protein that impairs mitochondrial dynamics by reducing fusion and increasing fission. Mesenchymal stem cells (MSCs) have shown potential therapeutic effects by sharing functional mitochondria and other secretomes. In this study, quinolinic acid-lesioned neuro-2a (QA-N2a) cells and glutamatergic neurons with 50 CAG repeats (HD neurons) were co-cultured with human umbilical cord-derived MSCs for 5 hours. For QA-N2a cells, immunocytochemistry (ICC) was performed to demonstrate the change in GABA and Substance P before and after co-culture. For HD neurons, ICC was conducted to identify mitochondrial proteins, while Western blot was employed to evaluate proteins related to inflammation and mitochondrial function. As a result, co-culture with MSC significantly restored the expression of GABA and Substance P, which diminished after QA exposure. In HD neurons co-cultured with MSCs, an increase in mitochondrial abundance was observed, with significantly higher intensity and dendritic distribution of mitochondria compared to control cells. Western blot analysis confirmed this increase and showed a rising trend in ATP5a levels. MSCs also promoted mitochondrial fusion, indicated by higher levels of Mitofusin 2 (MFN2) and Mitochondrial Dynamin Like GTPase (OPA1), and a trend of reduction in the fission marker Dynamin-Related Protein (DRP1). Additionally, the co-culture led to a decreased trend in neuroinflammation markers IL-6, TNF-α, MMP9, and p-NFkB. Collectively, this study demonstrates that MSCs alleviate HD pathology by restoring the mitochondria activity and potentially suppressing inflammation in two different HD in vitro models.
2026-03-18 | Human iPSC-derived exosomes for amelioration of Huntington's disease through mitochondrial, synaptic, and anti-apoptotic mechanisms.
Huntington's disease (HD) is driven by expanded CAG repeats in the huntingtin gene, resulting in mutant huntingtin (mHtt) aggregation, mitochondrial dysfunction, neuronal loss, and neuroinflammation. Although stem cell-based therapies provide potent regenerative, anti-inflammatory, and neuroprotective effects, their clinical translation remains constrained by tumorigenicity and poor engraftment efficiency. Therefore, we investigated whether exosomes derived from human induced pluripotent stem cells (iPSC-exo) could serve as a safe, cell-free therapeutic approach by leveraging their paracrine mechanisms. iPSC-exo were isolated from iPSC-conditioned medium and characterized by nanoparticle tracking analysis, Western blotting, and ExoView assays, confirming exosomal size (∼100 nm) and expression of canonical markers (CD63, CD81, ALIX, HSP70/90). Treatment of HD neural stem cells with iPSC-exo significantly reduced mHtt aggregation, as shown by EM48 immunostaining and Western blot analysis. iPSC-exo also restored mitochondrial membrane potential, improved mitochondrial morphology, and upregulated CREB while suppressing c-Jun expression, indicating enhanced mitochondrial and stress resilience. Furthermore, iPSC-exo promoted neurite outgrowth and synaptic maturation, reflected by increased MAP2 and PSD95 levels and reduced Tuj1 expression, signifying neuronal progression toward a mature phenotype. Western blot analysis revealed downregulation of BAX, cleaved caspase-3, NF-κB, and JNK, alongside upregulation of BCL-2 and TrkB, demonstrating suppression of apoptosis and inflammation with concurrent activation of survival pathways. These multifaceted effects collectively alleviated mHtt aggregation, as confirmed by EM48 immunostaining and Western blot analysis. Together, our findings demonstrate that iPSC-exo mitigate HD pathology by improving mitochondrial function, neuronal differentiation, and anti-apoptotic signaling, thereby reducing mHtt accumulation.
2026-02-26 | Clinical-Grade Human Induced Pluripotent Stem Cell-Derived Neural Precursor Cells Restore Motor Function and Preserve Striatal Integrity in a Quinolinic Acid-Lesioned Rat Model of Huntington's Disease.
Huntington's disease (HD) is an inherited neurodegenerative disease characterised by progressive degeneration of GABAergic medium spiny neurons (MSNs) in the striatum. Neural precursor cells (NPCs) derived from human induced pluripotent stem cells (iPSCs) have been considered as a promising and scalable source for neuronal replacement and circuit restoration. In this study, we investigated the therapeutic effects of a clinical-grade, human leukocyte antigen (HLA)-homozygous iPSC line (YZWJ-s513) differentiated into NPCs (s513-NPCs) in a quinolinic acid (QA)-lesioned rat model of HD. Following intrastriatal transplantation, s513-NPCs not only survived for 12 weeks but also differentiated into neurons, astrocytes, and oligodendrocytes, while generating new DARPP32+ GABAergic MSNs. Specifically, graft-derived neurons projected to the host globus pallidus, indicating structural integration into the striato-pallidal pathways. Additionally, NPC-transplanted rats exhibited significant motor recovery across multiple tasks for up to 12 weeks, accompanied by reduced striatal atrophy and ventricular enlargement. Histological findings also revealed attenuated astrogliosis and microgliosis, along with a shift toward an anti-inflammatory milieu. Collectively, these results demonstrate that transplantation of clinical-grade, HLA-homozygous iPSC-derived NPCs can provide both neuronal replacement and modulation of the diseased microenvironment, supporting their potential as a regenerative therapy for HD. Key quality attributes and release criteria supporting the clinical-grade characterisation of the cell product used in vivo are summarised in Table S1.
2025-11-05 | A phase I, open-label study of intravenous human dental pulp stem cells (NestaCell®) at two dose levels in patients with Huntington's disease.
Huntington's disease (HD) is a progressive neurodegenerative disorder with no approved disease-modifying therapies. Human dental pulp stem cells (hDPSCs) offer potential therapeutic benefits due to their neurogenic, neurotrophic, and immunomodulatory properties. This prospective, open-label, single-centre, first-in-human clinical trial evaluated the safety, tolerability, and preliminary efficacy of intravenous hDPSC in patients with HD. Six male patients with HD received intravenous infusions of hDPSCs in two dosage cohorts: three patients received 1 million cells/kg, and three received 2 million cells/kg. The treatment protocol consisted of cycles of three infusions at monthly intervals followed by subsequent administration cycles every six months, as per a protocol amendment based on the initial favourable safety outcomes. The total number of infusions ranged from 4 to 26 over the five years. During the first year, all patients underwent intensive multiparametric monitoring in an intensive care unit (ICU) for 48 h after each infusion. No adverse events occurred during the 48-h ICU monitoring or within 15 days post-infusion. Of 41 treatment-emergent adverse events (TEAEs) reported during follow-up, 35 were judged unrelated to the hDPSCs, mainly reflecting disease progression or incidental findings. Six treatment-emergent adverse events (TEAEs) were considered treatment-related, involving transient changes in hair pigmentation or regrowth. One patient discontinued due to a serious adverse event-lung cancer arising from a pre-existing pulmonary nodule identified at enrolment. Genetic analysis of the excised tumour showed no evidence of investigational product engraftment, supporting its non-tumorigenic nature. The same patient experienced a severe depressive episode lasting approximately 93 days; the relationship to treatment was considered uncertain. Minor, clinically insignificant fluctuations in CD4/CD8 lymphocyte counts and cytokine levels were observed. Preliminary efficacy analyses indicated potential stabilisation of disease progression, particularly in the Unified Huntington's Disease Rating Scale (UHDRS), Total Motor Score (TMS) and Total Functional Capacity (TFC). hDPSCs infusions were well tolerated and exhibited a favourable safety profile, even with prolonged exposure and follow-up. These findings support the continued clinical development and warrant further investigation in more extensive trials to assess therapeutic efficacy in Huntington's disease. This study was registered on April 4, 2016, at ClinicalTrials.gov (identifier: NCT02728115; https://clinicaltrials.gov/study/NCT02728115 ).
2025-10-31 | The Evolving Landscape of Stem Cell Therapies for Huntington's Disease.
Huntington's disease (HD) is a fatal, inherited neurodegenerative disorder marked by the progressive and selective loss of spiny projection neurons (SPNs), resulting in a characteristic triad of motor, cognitive, and psychiatric symptoms. Despite ongoing research, no disease-modifying treatments are available, and existing therapies are limited to symptomatic relief. Stem cell-based approaches represent a promising avenue to restore striatal circuitry by replacing lost neurons and/or delivering trophic support to preserve the remaining neural tissue.In this review, we present a critical analysis of past and current clinical trials exploring cell-based therapies for HD. Early studies using human fetal tissue were hindered by sample heterogeneity and inconsistent outcomes, ultimately limiting their clinical applicability. More recent trials have shifted focus toward mesenchymal stem cells (MSCs), which are valued for their neuroprotective secretome but are not suitable for neuronal replacement. To address these limitations, human pluripotent stem cells (hPSCs) have emerged as a renewable and scalable source for the development of advanced therapy medicinal products (ATMPs). In vitro differentiation protocols mimic key developmental signaling pathways to generate striatal-like neural progenitor cells (NPCs). We review the cellular composition of these hPSC-derived ATMPs and summarize findings from preclinical transplantation studies, including data on graft survival, neuronal maturation, synaptic integration, and functional recovery. In addition, we discuss other emerging strategies such as direct neuronal reprogramming. Finally, we examine the major challenges that remain-such as ensuring graft safety, consistency, and regulatory compliance-and highlight the importance of international collaboration to overcome these barriers and accelerate clinical translation.
proteins
2026-07-07 | CDKN1A protects medium spiny neurons from Huntington's disease pathology.
Huntington's disease (HD) arises from abnormal expansion of CAG trinucleotide repeats within the HTT gene, leading to mutant huntingtin (mHTT) aggregation, progressive loss of striatal medium spiny neurons (MSNs), and progressive neurodegeneration. While the genetic cause is established, the mechanisms that confer selective MSN vulnerability, particularly those linked to aging, remain unclear. We employed a combination of miR-9/9*-124-driven reprogramming and MSN-specific transcription factors to generate patient-derived MSNs from fibroblasts of symptomatic HD patients (HD-MSNs), pre-symptomatic mutation carriers (pre-HD-MSNs), and healthy controls, preserving donor age signatures. Multi-omics analysis integrating RNA-seq and ATAC-seq revealed reduced CDKN1A expression and promoter accessibility in HD-MSNs compared with pre-HD-MSNs. Overexpression of CDKN1A in HD-MSNs alleviated HD pathologies, including DNA double-strand breaks, oxidative DNA damage, and mHTT aggregates, while improving neuronal survival and autophagy-associated activity. Conversely, knockdown of CDKN1A in pre-HD-MSNs elicited opposite effects, revealing a CDKN1A-dependent survival mechanism in HD. Together, these findings suggest that reduced CDKN1A expression may contribute to HD-associated MSN vulnerability and is associated with altered DNA damage responses and autophagy-related processes in HD-MSNs. Our study identifies CDKN1A as a potential modulator of neuronal resilience in HD.
2026-06-27 | Mutant huntingtin in the extracellular matrix: A new perspective on Huntington's disease pathology.
Huntington's disease (HD) is a monogenic neurodegenerative disorder characterized by extensive brain pathology. While its underlying cause has been attributed to intracellular mutant huntingtin (mHTT), growing evidence reveals that mHTT is also present, and biologically active, outside cells. Detected in cerebrospinal fluid, plasma, and brain tissue, extracellular mHTT can induce toxicity and spread between cells. This commentary explores a challenging, yet the largely overlooked possibility that the extracellular matrix (ECM) - a dynamic and highly structured network surrounding neurons and glia - may shape how mHTT aggregates form, accumulate and propagate in the brain. Drawing on parallels with other proteinopathies, we examine how ECM components could create a microenvironment that favors mHTT accumulation and pathogenicity. While direct evidence remains limited, we argue that the ECM may play a more active role in HD than previously recognized. This perspective invites a rethinking of HD pathology and may help guide the development of therapies that extend beyond targeting intracellular mHTT.
2026-05-29 | SQSTM1/p62 UFMylation Enhances Autophagic Clearance of Pathogenic Mutant Huntingtin.
Ubiquitin-fold modifier 1 (UFM1) covalently modifies protein substrates (UFMylation) and alters their biological functions. Genetic screening disclosed that enzymes in the UFMylation system play critical roles in regulating autophagy. However, it is still elusive which protein is UFMylated and how this modification modulates autophagy. Here, our quantitative proteomics and biochemical experiments identify SQSTM1/p62 as a UFMylation substrate and discover its two major UFMylation sites, K420 and K435. Mutating them to Arg (p622KR) completely abolishes the effect of p62 on autophagic activity. Fusion of UFM1ΔC4 to p622KR (p622KR-UFM1ΔC4) restores the p62-mediated pathogenic autophagic degradation in primary cortical neurons and Huntington's disease mouse striatum. Mechanistically, p62 UFMylation enhances its interaction with LC3, augments autophagic flux, and eliminates pathogenic mutant huntingtin. Collectively, this work discovers a new post-translational modification, UFMylation, on p62 and establishes this modification as a key regulator of autophagy that promotes the clearance of mutant huntingtin, offering a potential target for therapeutic intervention.
2026-04-08 | Distinct autophagy impairment mechanisms of huntingtin aggregates with different polyQ lengths.
Huntington's disease (HD) is characterized by the aggregation of mutant huntingtin (mHTT) containing elongated polyglutamine (polyQ) tracts. mHTT aggregates that fail to be cleared by autophagy cause neurotoxicity. While the polyQ length in patients with HD ranges from 40 to over 90 repeats, how these varying polyQ lengths affect autophagy impairment remains unclear. Using polyQ aggregation sensors based on bimolecular fluorescence complementation (BiFC), we uncovered distinct autophagy impairment mechanisms: PolyQ103 aggregates evade recognition by autophagy receptor SQSTM1/p62, whereas polyQ43 condensates are recognized by SQSTM1/p62, but their bulky association prevents complete autophagosome formation. Interestingly, overexpression of optineurin (Optn), another autophagy receptor, preferentially binds to polyQ103 aggregates but not polyQ43 condensates, improving cell survival. K63-ubiquitination on polyQ103 aggregates serves as a critical determinant for Optn recruitment via its UBAN domain. These findings reveal polyQ length-dependent pathological mechanisms underlying autophagy impairment of mHTT aggregates, suggesting potential therapeutic strategies for patients with longer polyQ sequences.
2026-04-03 | Modest rescue of RBFOX1 splicing function attenuates Huntington's disease features.
BACKGROUND: RNA mis-splicing underlies a growing number of neurological disorders and, consequently, splicing correction therapies have been developed for some monogenic forms, like spinal muscular atrophy or neuronal ceroid lipofuscinosis. In Huntington’s disease (HD), alternative splicing alteration emerged as a molecular mechanism in view of individually reported mis-splicing events in neurodegeneration-linked genes such as HTT itself, MAPT and TAF1. Later, more systematic genome-wide RNA-seq analyses of HD brains revealed mis-splicing signatures involving additional neurodegeneration-linked genes. Individual correction of each of the potentially pathogenic mis-spliced genes would be unapproachable. However, the identification of upstream pivotal splicing factors altered in HD may be useful to design pleiotropic therapeutic strategies. We previously performed motif-enrichment analyses of the sequences flanking exons that are mis-spliced in HD and identified RBFOX splicing factors as underlying candidates. METHODS: We performed RT-PCR and Western blot analyses of RBFOX in post-mortem brain samples from HD patients and mice. We generated transgenic mouse lines overexpressing RBFOX1 in forebrain neurons and performed RNA-seq to analyze its impact on HD-associated mis-splicing. In addition, we combined HD mice with RBFOX1-overexpressing mice to verify correction of Rbfox1 levels and mis-splicing of RBFOX target genes, and performed histopathological and motor behavioral analyses. RESULTS: We observed that decreased expression of Rbfox1 in striatum of HD mice at early stages of disease progression correlates with a reduction of Rbfox1 immunostaining particularly in the nucleus. This prompted us to generate transgenic mouse lines overexpressing the nuclear isoform of RBFOX1. The overexpression of RBFOX1 in this new transgenic mouse line induced widespread alternative splicing changes that significantly overlapped with genes mis-spliced in brains of both HD patients and mouse models. We found that moderate neuronal RBFOX1 overexpression in HD mice results in correction of several HD-associated mis-splicing events and in attenuation of neurodegeneration and motor symptoms. CONCLUSIONS: These results demonstrate that the observed decrease of RBFOX1 levels in brains of HD patients and mice contributes to HD pathogenesis and suggest therapeutic potential of RBFOX-increasing strategies for HD.
oligonucleotides
2026-08-12 | Blocking somatic repeat expansion and lowering huntingtin by RNAi synergize to attenuate Huntington's disease pathogenesis in mice.
Huntington's disease (HD) is a progressive neurodegenerative disorder with no approved therapies. Despite multiple clinical trials, huntingtin (HTT)-lowering strategies have yet to show meaningful clinical benefit. Both somatic expansion and toxic HTT species are key molecular drivers of HD, yet therapeutic strategies targeting these pathways have never been directly compared or evaluated in combination. Using therapeutic divalent siRNAs, we assessed the long-term impact of silencing MutS homolog 3 (MSH3), a critical regulator of somatic expansion, HTT, or both in Q111 HD mice (>110 CAGs), which develop robust expansion, mutant HTT inclusions, and transcriptional dysregulation by 12 months. Long-term MSH3 silencing blocked somatic expansion, reduced inclusions, and normalized gene expression. HTT silencing alone had a limited effect, whereas combined MSH3/HTT targeting synergistically eliminated inclusions and restored transcriptomic profiles. Parallel treatment in wild-type mice showed no toxicity, supporting the safety of long-term intervention. These findings position somatic expansion as a promising therapeutic target and demonstrate the potential of RNAi-based cosilencing of MSH3 and HTT as a disease-modifying strategy for HD.
2026-06-27 | Anle138b ameliorates pathological phenotypes in mouse and cellular models of Huntington's disease.
Huntington's disease (HD) is a hereditary movement disorder caused by a CAG repeat expansion in the huntingtin gene. HD is characterized by deposition of mutant huntingtin (mHTT) aggregates, and by severe neurodegeneration of the basal ganglia and neocortex. No cure is currently available, and new treatment options are urgently needed. Here, we show that the oligomer modifying molecule anle138b (INN: emrusolmin) improves multiple disease phenotypes in cell culture and in two mouse models of HD. Application of anle138b reduced mHTT aggregate formation and ameliorated neurotoxicity in primary neurons. Oral administration of anle138b delayed deposition of mHTT inclusions, reduced brain atrophy, mitigated neuroinflammation and transcriptional alterations, improved motor function and extended life span in HD mice. Downregulation of striatal markers and synapse loss in striatal spiny projection neurons were also partially rescued. No adverse effects of anle138b were observed in wildtype animals. Moreover, anle138b markedly decreased mHTT aggregation in human neural precursor cells differentiated from HD patient-derived induced pluripotent stem cells (iPSCs). Altogether these results illustrate the potential of anle138b as a disease-modifying treatment for HD.
2026-06-10 | Which HTT transcript to lower?
Huntington's disease (HD) RNA therapeutics have focused on lowering canonical huntingtin (HTT), yet clinical benefit remains uncertain. Papadopoulou et al. and Bragg et al. suggest that HTT1a-engaging strategies can produce stronger molecular rescue than full-length HTT lowering that spares HTT1a, highlighting transcript-species coverage as a key variable in HTT-lowering pharmacology.
2026-06-06 | Huntington Disease: A Comprehensive Overview of Molecular Genetics, Clinical Pathophysiology, Management and Emerging Therapies
Huntington disease (HD) is a relentlessly progressive, autosomal dominant neurodegenerative disorder caused by an expanded CAG trinucleotide repeat in the HTT gene on chromosome 4p16.3. This mutation translates into an aberrant polyglutamine tract within the huntingtin protein, conferring toxic gain-of-function and dominant-negative loss-of-function effects that preferentially devastate the striatal medium spiny neurons. Clinically, HD manifests in mid-adulthood with a characteristic triad of choreiform motor disturbances, progressive cognitive decline (subcortical dementia), and a spectrum of psychiatric and behavioral abnormalities including apathy, depression, irritability, and psychosis. Juvenile-onset HD (Westphal variant) presents before age 20 with rigidity, bradykinesia, seizures, and rapid cognitive deterioration. Diagnosis rests upon characteristic clinical findings in the context of a positive family history and is confirmed by targeted CAG repeat analysis. While no disease-modifying therapy currently exists, symptomatic management employs VMAT2 inhibitors and antipsychotics for chorea, antidepressants and behavioral interventions for psychiatric symptoms, and comprehensive supportive care including physical, occupational, speech, and nutritional therapy. Disease progression spans 15 to 20 years, with death typically resulting from aspiration pneumonia or suicide. Emerging therapies—including gene silencing (antisense oligonucleotides, RNA interference), cell transplantation, and small molecules targeting excitotoxicity, mitochondrial dysfunction, and protein aggregation—are under active investigation. Optimal patient outcomes require an interprofessional team approach integrating neurology, genetic counseling, nursing, pharmacy, rehabilitation therapies, and social work, with emphasis on early advance care planning and caregiver support.
2026-03-18 | Lowering the HTT1a transcript as an effective therapy for Huntington's disease in a knockin mouse model.
Lowering huntingtin (HTT) transcript levels has been a major focus of therapeutic development for Huntington's disease (HD), but which transcript should be lowered? HD is caused by a CAG repeat expansion in exon 1 of the HTT gene, and the rate of somatic expansion of this CAG repeat throughout life drives the age of onset and rate of disease progression. As the CAG repeat expands, the extent to which the HTT mRNA is alternatively processed to generate the HTT1a transcript and highly aggregation-prone and pathogenic HTT1a protein increases. Several HTT-lowering modalities have entered clinical trials that target either both HTT and HTT1a together or full-length HTT alone. We have developed siRNAs that target the Htt1a mouse transcript (634/486) and used these, together with a potent Htt-targeting siRNA (10150), to compare the efficacy of lowering either full-length Htt or Htt1a. zQ175 and wild-type mice were treated with 10150 or 634/486 alongside control groups at 2 months of age and euthanized at 6 months, at 2 months and again at 6 months and euthanized at 10 months, or at 6 months and euthanized at 10 months. The siRNA potency and durability were most effective in the hippocampus. Although both strategies showed benefits, despite the greater potency of 10150, targeting Htt1a was more effective at delaying HTT aggregation and transcriptional dysregulation than targeting full-length Htt. These data support HTT-lowering strategies that are designed to target the HTT1a transcript, either alone or together with lowering full-length HTT.
other
2026-07-24 | IL17A disrupts autophagy-lysosomal function and lysosome reformation through the GSK3B-TFE3 signaling pathway in Huntington disease.
Huntington disease (HD) is a progressive neurodegenerative disease caused by an expanded CAG repeat in the HTT (huntingtin) gene, leading to the accumulation of mutant HTT (mHTT). IL17A (interleukin 17A), a proinflammatory cytokine primarily secreted by Th17 and γδ T cells, has been implicated in immune-mediated neurodegeneration. However, the role of IL17A in the pathogenesis of HD remains poorly understood. Here, we identify IL17A as a critical pathogenic factor in HD that promotes neuroinflammation, mHTT aggregation, and autophagy-lysosomal dysfunction. IL17A disrupts autophagic flux by downregulating CTSB and CTSD, inducing SQSTM1/p62 and MAP1LC3B-II/LC3-II accumulation, and impairing lysosomal reformation. Mechanistically, IL17A suppresses lysosomal biogenesis by inhibiting the nuclear translocation of TFE3. This regulation occurs via a novel GSK3B/GSK-3β-TFE3 signaling pathway. Therapeutic neutralization of IL17A with a monoclonal antibody (IL17A mAb) ameliorates disease phenotypes in R6/2 HD mice, improving motor performance, extending survival, and reducing gliosis. IL17A mAb also attenuates mHTT aggregation and enhances neuroprotective signaling, as evidenced by increased expression of DLG4/PSD-95, phosphorylated CREB1, and BDNF. Moreover, IL17A mAb restores autophagy-lysosomal function by facilitating the clearance of protein aggregates and upregulating lysosomal enzymes and biogenesis markers, including CTSB, CTSD, PIP5K1A, and LAMP2. These findings establish IL17A as a key modulator of HD pathophysiology and highlight IL17A inhibition as a promising therapeutic strategy for targeting autophagy-lysosomal dysfunction in HD.
2026-07-13 | CRISPR-Cas9-based therapies for Huntington's disease and Friedreich's ataxia: mechanisms, advances, and future perspectives.
Huntington's disease (HD) and Friedreich's ataxia (FRDA) are progressive inherited neurodegenerative disorders caused by trinucleotide repeat expansions but characterized by distinct pathogenic mechanisms. HD arises from a coding-region CAG expansion in the HTT gene that produces toxic gain-of-function effects of mutant huntingtin (mHTT), whereas FRDA results primarily from intronic GAA repeat expansion in FXN, leading to epigenetic repression and frataxin deficiency. The emergence of CRISPR-based genome engineering has created new opportunities to address these diseases at their genetic origin. This review examines current CRISPR therapeutic strategies for HD and FRDA, including allele-specific editing, transcriptional suppression, repeat excision, epigenetic reactivation, and emerging precision editing approaches such as base editing and prime editing. We compare the molecular rationale, preclinical outcomes, and translational limitations associated with each approach while highlighting how disease architecture influences therapeutic design. Although preclinical studies demonstrate promising restoration of cellular phenotypes and functional improvement, significant barriers remain. Efficient delivery to the central nervous system and cardiac tissue, control of editing duration, immune responses, off-target activity, and emerging concerns regarding on-target genomic instability continue to limit clinical translation. Recent advances in delivery engineering, non-viral systems, and programmable editing platforms suggest that future therapeutic success will depend on integrating disease-specific biology with increasingly precise and controllable genome engineering technologies. Ethical and regulatory concerns remain substantial, particularly regarding informed consent in the context of cognitive decline and the irreversibility of genomic modification.
2026-06-26 | Childhood to Adult Neurodevelopment in Gene-Expanded Huntington's Disease (ChANGE-HD): A prospective longitudinal neurodevelopmental study of Huntington's disease.
Although adult Huntington's disease (HD) studies have significantly advanced our understanding of the course of degeneration, they may underrepresent critical neurodevelopmental aspects of the disease. Significant gaps remain in understanding how mutant huntingtin affects early neurodevelopment, its long-term impact, as well as potential implications for treatment outcomes. The Childhood to Adult Neurodevelopment in Gene-Expanded Huntington's Disease (ChANGE-HD; NCT01951588) study aims to evaluate brain structure and function in premanifest, at-risk children and young adults, and explore HD's developmental origins. Here, we introduce the ChANGE-HD study, which will investigate and integrate the neurodevelopmental and neurodegenerative aspects of HD. The ChANGE-HD study is a prospective, seven-year multi-site observational study with an accelerated longitudinal design, where participants are not bound to a fixed schedule across multiple visits. Four hundred and fifty participants aged 6-30 years who are at risk for HD will be recruited and asked to return for multiple visits (if possible). At each visit, cognitive, motor, behavioral, blood/saliva, and MRI data are collected. Alongside ChANGE-HD, we are also recruiting individuals for the juvenile-onset HD (JOHD) study to investigate the neuropathology of this rarer form of HD. ChANGE-HD represents the first prospective multi-site study to systematically document brain structure and function during the premanifest phase of HD in children and young adults. Data collection is ongoing with first results anticipated in 2026-2027. The ChANGE-HD approach is likely to provide novel physiological insights and guide the development of therapeutic strategies tailored to both the developmental and degenerative phases of the disease.
2026-06-11 | Recognizing repeat expansion disorders in clinical practice.
Repeat expansion disorders are caused by unstable DNA sequences that exceed pathogenic thresholds, disrupting normal gene function. These conditions often affect the nervous system, but may involve multiple organs, with presentations ranging from subtle cognitive or motor changes to overt neuromuscular or neurodevelopmental syndromes. Early symptoms can mimic common conditions, making clinical suspicion, family history, and awareness of intergenerational patterns essential. Molecular features, including repeat size, sequence, location and stability, determine disease severity and variability. Nurse practitioners are well positioned to recognize early signs, make early referrals to genetics, and support families with education, anticipatory guidance, and coordination of follow-up care. Case examples include Huntington disease, fragile X syndrome, and myotonic dystrophy and illustrate clinical heterogeneity, premutation effects, and genetic anticipation. Early recognition and referral remain crucial, particularly as emerging gene-targeted therapies may offer potential disease-modifying options.
2026-06-03 | Friend or foe? Glial-vascular interactions in health and neurodegenerative disease.
Dysfunction of glial and vascular cells is increasingly recognized as a central feature of neurodegenerative diseases. Growing evidence points to disruptions in glial-vascular interactions, which are critical for maintaining the functions of the neurogliovascular unit throughout the lifespan, as key contributors to disease initiation and progression. However, the mechanisms governing this complex intercellular crosstalk and its potential role in disease pathogenesis remain incompletely understood. In this review, we summarize the current understanding of glial-vascular communication across health and disease, with a particular focus on Alzheimer disease, stroke, cerebral small vessel disease, Parkinson disease, Huntington disease, and multiple sclerosis. We highlight emerging cellular and molecular interactions of interest, outline major gaps in our understanding, and discuss innovative tools, including transcriptomics, which are reshaping the study of neurogliovascular dynamics. A central unresolved question is whether glial and/or vascular dysfunction represents the primary initiating event across neurodegenerative diseases, or whether these processes emerge in parallel through shared upstream drivers. Unraveling these interactions may ultimately reveal novel therapeutic opportunities for a broad range of neurodegenerative conditions. SIGNIFICANCE STATEMENT: Neurogliovascular unit interactions are fundamental to brain homeostasis, yet the molecular basis of this crosstalk and its disruption in neurodegeneration remains poorly understood. This review provides the first comprehensive synthesis of molecular mechanisms governing the Neurogliovascular unit interface across physiological and pathological conditions, integrating evidence from related disorders. By consolidating key signaling pathways, disease-associated alterations, and emerging experimental approaches, this review offers a unifying framework to guide biomarker development and therapeutic targeting.
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Drug Discovery Landscape
78 orphan drug designations for Huntington disease, including 3 approved therapies.
78 orphan drug designations for Huntington disease, including 3 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
21-amino acid peptide targeting expanded CAG repeat RNA | peptides | FDA | 2026-08-03 | — | Rare Power Limited |
sulphamic acid, 6,7,8,9,10,11-hexahydro-6-oxobenzo[b]cyclohepta[d]pyran-3-yl ester | small molecules | FDA | 2026-03-16 | — | Olavide Neuron STX S.L. |
a small molecule agonist of TrkB receptor | small molecules | FDA | 2026-03-12 | — | Shaanxi Micot Technology Co., Ltd. |
tiapride | small molecules | FDA | 2025-10-22 | — | ArKri Therapeutics |
Bevantolol hydrochloride | small molecules | EMA | 2025-10-22 | — | Som Innovation Biotech S.A. |
monosialotetrahexosylganglioside sodium salt of porcine brain origin (pGM1) | other | FDA | 2025-10-16 | — | Zulia Biotech Inc. |
Votoplam | small molecules | EMA | 2024-12-13 | — | Novartis Europharm Limited |
2'-O-(2-methoxyethyl) and 2¿-O-methyl modified antisense oligonucleotide targeted to mutant huntingtin RNA | oligonucleotides | FDA | 2024-11-07 | — | Wave Life Sciences USA, Inc. |
votoplam | small molecules | FDA | 2024-10-25 | — | Novartis Pharmaceuticals Corporation |
(3beta,24S)-25,25,25-trifluoro-3-methyl-26,27-dinorergost-5-ene-3,24-diol | small molecules | FDA | 2023-10-16 | — | Sage Therapeutics |
Virus-like particle containing Cas9/gRNA ribonucleoprotein targeting the human HTT gene | gene therapies | FDA | 2023-10-05 | — | Shanghai BDgene Co., Ltd. |
Virus-like particle containing Cas9/gRNA ribonucleoprotein targeting the human HTT gene | gene editing enzymes | EMA | 2023-08-16 | — | Laura Nae |
A plasmid encoding a rabies virus glycoprotein tag & lysosome-associated membrane glycoprotein 2 fusion protein gene and a mutant huntingtin small interfering RNA | combination | FDA | 2023-04-10 | — | ExoRNA Bioscience Nanjing Co. Ltd. |
Dalzanemdor | small molecules | EMA | 2023-02-15 | — | Raremoon Consulting Esp S.L. |
valbenazine [Ingrezza] | small molecules | FDA | 2022-05-10 | 2023-08-18 | Neurocrine Biosciences Inc. |
synthetic 23 amino acid peptide AASSGVSTPGSAGHDIITEQPRS derived from the Huntingtin protein | peptides | FDA | 2021-11-04 | — | centre national de la recherche scientifique |
humanized recombinant immunoglobulin G (IgG) 4 monoclonal antibody against C1q | antibodies | FDA | 2021-10-25 | — | Annexon, Inc. |
an antisense oligonucleotide that has been developed to target expanded CAG repeats in messenger ribonucleic acid (mRNA) | oligonucleotides | FDA | 2021-07-27 | — | Vico Therapeutics B.V. |
Bevantolol Hydrochloride (HCl) | small molecules | FDA | 2021-06-24 | — | SOM Innovation Biotech S.A. |
Branaplam | small molecules | FDA | 2020-10-19 | — | Novartis Pharmaceuticals Corporation |
fasudil HCL | small molecules | FDA | 2020-08-25 | — | Woolsey Pharmaceuticals, Inc. |
Umbilical Cord Mesenchymal Stem Cells | cell therapies | FDA | 2020-01-28 | — | Acen Regenerative Medicine Sci-Tech Co., Ltd. |
2-(3,7-dimethyl-octa-2, 6-dienyl)-6-ethylamino-3-hydroxy-5-pentyl-[1,4]benzoquinone | small molecules | EMA | 2020-01-09 | — | Emerald Health Pharmaceuticals España, S.L. |
vasopressin 1a receptor antagonist | small molecules | FDA | 2019-10-30 | — | Azevan Pharmaceuticals, Inc. |
glycerol tribenzoate | small molecules | FDA | 2019-09-10 | — | Forest Hills Partners Hong Kong Limited |
(1E,6E)-1,7-Bis(3,4-dimethoxyphenyl)-4-cyclobutylmethyl-1,6-heptadiene-3,5-dione OR [(1E,4Z,6E)-4-(cyclobutylmethyl)-1,7-bis(3,4-dimethoxyphenyl)-5-hydroxyhepta-1,4,6-trien-3-one] | small molecules | FDA | 2019-05-14 | — | AnnJi Pharmaceutical Co. Ltd. |
ADENO-ASSOCIATED VIRAL VECTOR SEROTYPE RH10 CONTAINING THE HUMAN CHOLESTEROL 24-HYDROXYLASE GENE | gene therapies | EMA | 2019-04-01 | — | AskBio France |
recombinant adeno-associated virus, serotype 1, containing a transgene that encodes a microRNA targeting huntingtin messenger RNA | gene therapies | FDA | 2019-03-15 | — | Voyager Therapeutics |
2,4-dinitrophenol | small molecules | FDA | 2019-02-11 | — | Mitochon Pharmaceuticals, Inc. |
delta-9-tetrahydrocannabinol and cannabidiol | small molecules | FDA | 2019-01-29 | — | MMJ International Holdings |
(+)-alpha-dihydrotetrabenazine | small molecules | FDA | 2018-12-05 | — | Adeptio Pharmaceuticals, Ltd |
recombinant adeno-associated virus vector containing DNA encoding INT41 intrabody | gene therapies | FDA | 2018-11-30 | — | Vybion Inc. |
monosialotetrahexosylganglioside | small molecules | FDA | 2018-08-07 | — | Qilu Pharmaceutical Co., Ltd. |
2-(3,7-Dimethyl-octa-2, 6-dienyl)¿6-ethylamino-3-hydroxy-5-pentyl-[1,4]benzoquinone | small molecules | FDA | 2018-02-01 | — | Emerald Health Pharmaceuticals Inc. |
Adeno-associated viral vector serotype 5 encoding a microRNA targeted to human huntingtin gene | gene therapies | EMA | 2018-01-17 | — | uniQure Biopharma B.V. |
adeno-associated viral vector serotype 5 encoding a microRNA targeted to human huntingtin gene | gene therapies | FDA | 2017-09-27 | — | uniQure Biopharma B.V. |
synthetic stereopure antisense oligonucleotide specific to the mutant huntingtin mRNA transcript at the U variant of single nucleotide polymorphism rs326331 | oligonucleotides | FDA | 2017-09-05 | — | Wave Life Sciences Ltd. |
laquinimod sodium | small molecules | FDA | 2017-01-31 | — | Active Biotech AB |
Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Gly-Gly-Asp-Leu-Leu-Pro-Arg-Gly-Ser | peptides | EMA | 2016-11-18 | — | Granzer Regulatory Consulting & Services GmbH |
humanized IgG4 monoclonal antibody that binds to the SEMA4D antigen | antibodies | FDA | 2016-08-16 | — | Vaccinex, Inc. |
Mardepodect [PF-02545920] | small molecules | EMA | 2016-07-14 | — | Pfizer Limited |
antisense oligonucleotide targeting the U isoform of SNP rs362307 | oligonucleotides | FDA | 2016-06-16 | — | Wave LIfe Sciences |
Tominersen | oligonucleotides | FDA | 2015-12-29 | — | Genentech, Inc. |
5,7-dichloro-2-dimethylaminomethyl-8-hydroxyquinoline | small molecules | EMA | 2015-05-21 | — | [INACTIVE] Veristat Spain S.L. |
AASSGVSTPGSAGHDIITEQPRS | peptides | EMA | 2015-05-21 | — | Centre National de la Recherche Scientifique (CNRS) |
4-[2-(aminomethyl)-1,3-thiazol-4-yl]-2,6-ditert-butylphenol hydrochloride [BN82451B] | small molecules | EMA | 2015-04-24 | — | Ipsen Pharma |
Chimeric 2'-O-(2-methoxyethyl) modified oligonucleotide targeted to huntingtin RNA | oligonucleotides | EMA | 2015-03-19 | — | Roche Registration GmbH |
phenol, 4-[2-(aminomethyl)-4-thiazolyl]-2,6-bis (1,1-dimethyethyl) monohydrochloride | small molecules | FDA | 2015-03-16 | — | Ipsen Biopharmaceuticals, Inc. |
2'-O-methyl phosphorothioate RNA oligonucleotide, 5'-m5CUGm5CUGm5CUGm5CUGm5CUGm5CUGm5CUG-3' | oligonucleotides | EMA | 2015-02-18 | — | Vico Therapeutics B.V. |
5-bromo-N-(prop-2-yn-1-yl)-2-(1H-1,2,4-triazol-1-yl)pyrimidine-4,6-diamine | small molecules | EMA | 2014-12-16 | — | Palobiofarma S.L. |
d6-tetrabenazine, deutetrabenazine [Austedo] | small molecules | FDA | 2014-11-05 | 2017-04-03 | Teva Branded Pharmaceutical Products R&D, Inc. |
5,7-dichloro-2-dimethylaminomethyl-8-hydroxyquinoline hydrochloride | small molecules | FDA | 2014-09-04 | — | Prana Biotechnology Limited |
Cysteamine bitartrate | small molecules | EMA | 2014-07-29 | — | Chiesi Farmaceutici S.p.A. |
carbenoxolone | small molecules | FDA | 2014-07-02 | — | Oxalys Pharmaceuticals, Inc. |
2-[4-(1-Methyl-4-pyridin-4-yl-lH-pyrazol-3-yl)-phenoxymethyl]-quinoline succinic acid | small molecules | FDA | 2014-06-02 | — | Pfizer Inc. |
small molecule inhibitor of phosphodiesterase 10 | small molecules | FDA | 2013-09-26 | — | Omeros Corporation |
lithium citrate tetrahydrate (in reverse micelle formulation) | small molecules | FDA | 2010-12-13 | — | Medesis Pharma |
Lithium citrate tetrahydrate (in reverse-micelle formulation) | small molecules | EMA | 2010-01-28 | — | Medesis Pharma |
selisistat | small molecules | FDA | 2009-12-07 | — | AOP Orphan Pharmaceuticals AG |
6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide | small molecules | EMA | 2009-10-28 | — | Aop Orphan Pharmaceuticals GmbH |
recombinant adeno-associated virus encoded gene for X-linked mammalian inhibitor of apoptosis protein (XIAP) | gene therapies | FDA | 2009-08-25 | — | Neurologix, Inc. |
dimebon | small molecules | FDA | 2009-05-12 | — | Medivation, Inc. |
Latrepirdine dihydrochloride | small molecules | EMA | 2009-01-20 | — | IDEA Innovative Drug European Associates Limited |
cysteamine | small molecules | FDA | 2008-05-09 | — | Horizon Therapeutics USA, Inc. |
Clotrimazole | small molecules | FDA | 2006-03-13 | — | EnVivo Pharmaceuticals, Inc. |
4-(3-Methanesulfonyl-phenyl)-1-propylpiperidine HCl | small molecules | FDA | 2005-12-12 | — | Prilenia Therapeutics |
Creatine | small molecules | FDA | 2005-10-11 | — | Marathon Pharmaceuticals, LLC |
4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine x HCl | small molecules | EMA | 2005-06-20 | — | Ferrer Internacional S.A. |
ubiquinol | small molecules | FDA | 2004-04-12 | — | Gel-Tec, Division of Tishcon Corp. |
Coenzyme Q10 | small molecules | FDA | 2001-03-05 | — | Integrative Therapeutics, Inc. |
Ethyl Eicosopentaenoate | small molecules | EMA | 2000-12-29 | — | Amarin Neuroscience Limited |
Ethyl eicosapentaenoate | small molecules | FDA | 2000-04-06 | — | Laxdale Ltd. |
Remacemide | small molecules | FDA | 2000-03-06 | — | AstraZeneca LP |
Tiapride | — | FDA | 1998-04-21 | — | Sanofi-Synthelabo, Inc. |
Tetrabenazine [Xenazine] | small molecules | FDA | 1997-12-11 | 2008-08-15 | Prestwick Pharmaceuticals, Inc |
Porcine fetal neural gabaergic cells and/or precursors aseptically prepared for intracerebral implantation for Huntington's disease. | cell therapies | FDA | 1996-12-10 | — | Diacrin/Genzyme LLC |
Porcine fetal neural gabaergic cells and/or precursors aseptically prepared and coated with anti-MHC-1 Ab for intracerebral implantation | cell therapies | FDA | 1996-12-10 | — | Diacrin/Genzyme LLC |
Riluzole | small molecules | FDA | 1996-10-15 | — | Rhone-Poulenc Rorer Pharmaceuticals, Inc. |
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