RARE DISEASE
Spinocerebellar ataxia type 3
Spinocerebellar ataxia type 3
Spinocerebellar ataxia type 3
Synonyms: Azorean disease of the nervous system, MJD, Machado disease, Machado-Joseph disease, Nigro-spino-dentatal degeneration with nuclear ophthalmoplegia, SCA3
Synonyms: Azorean disease of the nervous system, MJD, Machado disease, Machado-Joseph disease, Nigro-spino-dentatal degeneration with nuclear ophthalmoplegia, SCA3
Synonyms: Azorean disease of the nervous system, MJD, Machado disease, Machado-Joseph disease, Nigro-spino-dentatal degeneration with nuclear ophthalmoplegia, SCA3
Drug discovery
1
drug
With orphan designation
Overview
Spinocerebellar Ataxia Type 3 (SCA3/MJD) is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion in the ATXN3 gene, producing toxic polyglutamine aggregates. It manifests with progressive cerebellar ataxia, dysarthria, pyramidal signs, oculomotor abnormalities, and peripheral neuropathy. Non-motor features include sleep disorders (REM sleep behavior disorder), neuropathic pain, and psychiatric comorbidities. Symptom onset typically occurs in adulthood (2nd–5th decade), with progressive disability leading to wheelchair dependence within 10–20 years. Anticipation correlates with longer CAG repeats [1][6][16].
Therapies
Symptomatic management: Pharmacotherapy for spasticity (baclofen), Parkinsonism (levodopa), and neuropathic pain (antidepressants) [6][8]
Rehabilitative support: Physical/occupational therapy to maintain mobility; speech therapy for dysphagia/dysarthria [18][20]
Experimental approaches: Antisense oligonucleotides, CRISPR-based gene silencing, and HDAC inhibitors in clinical trials [3][13][16]
Categories: rare genetic diseases, rare neurological diseases
Research Papers
689 drug discovery papers about Spinocerebellar ataxia type 3, with 6 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
689 drug discovery papers about Spinocerebellar ataxia type 3, with 6 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
gene therapies
2026-05-12 | Quantitative Ocular Motor / Vestibular Assessment in Patients with Spinocerebellar Ataxia Type 3 (SCA3, Machado Joseph Disease) - Systematic Review of the Literature.
Spinocerebellar ataxia type 3 (SCA3 or Machado-Joseph disease) is the second most common autosomal-dominant hereditary ataxia and often presents with ocular motor and vestibular impairment. The value of ocular motor testing for early disease detection, monitoring disease progression and as a potential treatment biomarker has been acknowledged in several studies. This systematic review aims to summarise the current evidence supporting quantitative eye movement testing in SCA3. Studies reporting on quantitative ocular motor and/or vestibular measurements in SCA3 were searched for in MEDLINE and Embase. Thirty studies reporting on 432 SCA3 patients (including 64 pre-symptomatic carriers) were included. Information on various ocular motor parameters were extracted and correlations with other parameters (including clinical scales, imaging, and genetic testing) were assessed. Ocular motor abnormalities observed comprised (horizontal) pursuit eye-movement (PEM) gain reduction (14/19 patients), saccadic intrusions (principally square-wave jerks (SWJ, 29/45)), gaze-evoked nystagmus (GEN, 65/82), and rebound nystagmus (8/10). Additionally, saccades to target displayed increased latency (13/29), reduced peak velocity (16/49) and dysmetria (33/49). Vestibular deficits measured included vestibulo-ocular reflex (VOR) gain-reductions during quantitative head-impulse testing (qHIT, 117/133) and abnormal responses during caloric irrigation (7/9), impaired visually-enhanced VOR-responses (5/6), and impaired cervical (19/66) and ocular (10/14) vestibular-evoked myogenic-potential testing. In summary, impaired VOR-gains (qHIT), GEN, horizontal PEM-gain decreases, dysmetric saccades, and SWJ were most frequently reported and therefore seem most suitable as potential disease markers. The quantitative ocular motor/vestibular assessment may facilitate early diagnosis, distinction of disease stages and also potentially allow monitoring of disease progression and treatment response.
2026-05-11 | A Severity-Agnostic Atrophy Pattern in Spinocerebellar Ataxia Type 3: Volumetrics from ENIGMA-Ataxia.
Spinocerebellar ataxia type 3 (SCA3) is a rare, inherited neurodegenerative disease characterized by progressive loss of motor coordination. We undertook a multisite magnetic resonance imaging study to profile the spatial spread of atrophy across the brain, determine whether atrophy preferentially maps onto specific functional networks, and investigate the relationship between cerebellar and cerebral atrophy. Whole-brain grey and white matter (GM and WM) voxel-based morphometry was performed on 408 individuals with SCA3 (82 pre-ataxic) and 293 controls. The SCA3 cohort was stratified by ataxia severity to study progression. Cerebellar GM atrophy was mapped onto a task-based functional atlas. Cerebrocerebellar volumetric covariance was assessed to determine whether cerebral and cerebellar atrophy were coupled. The atrophy pattern is spatially consistent but progressive in magnitude across the disease course. The greatest atrophy (Cohen's d > 1.5) occurred in the pons, cerebellar WM, and cerebellar peduncles; correlations with ataxia severity and duration were also strongest (-0.4 > r > -0.65) in those regions. Cerebellar GM atrophy was greatest (d ≅ 0.7) in functional regions associated with motor planning/execution, attention, and emotional processing. Sparse cerebral cortical atrophy appears only in the most severe disease subgroup, while striatal atrophy begins in the earliest stages but does not worsen with increasing clinical severity. Reduced cerebrocerebellar volumetric covariance is observed in SCA3 participants versus controls. Cerebellar and brainstem atrophy underlies greater ataxia severity in SCA3, but the spatial pattern of structural changes remains relatively consistent across the course of the disease. Cerebellar GM atrophy is spatially non-uniform, and occurs maximally in regions consistent with the motor and cognitive clinical presentation of SCA3. Cerebellar atrophy is not mirrored by corresponding cerebral structural changes. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
2026-03-15 | Extracellular vesicles-mediated delivery of SpCas9 RNPs for therapeutic gene editing in Spinocerebellar Ataxia Type 3.
Spinocerebellar Ataxia Type 3 (SCA3) is a neurodegenerative dominantly-inherited disorder caused by an overexpansion of a CAG tract within the ATXN3 gene, conferring toxic properties to the ataxin-3 protein. Genome editing with CRISPR-Cas9 enzymes is a promising strategy to inactivate mutant ATXN3 alleles, however, in vivo delivery remains challenging. Extracellular vesicles (EVs) are promising delivery vehicles for Cas9 and single guide RNA (sgRNA) ribonucleoproteins that minimize genomic exposure to highly active endonucleases. In this study, we designed SpCas9 with a palmitoylation motif that enables SpCas9 and sgRNA enrichment into EVs. Introduction of a photocleavable linker - PhoCl - allowed the photo-inducible release of SpCas9 from the palmitoylation motif in EVs, increasing target engagement to ATXN3 in vitro. EVs loaded with SpCas9 ribonucleoproteins resulted in ATXN3 knockout in SCA3 patient-derived iPSCs and two SCA3 animal models. These findings highlight an innovative route for transient delivery of gene editing tools. This approach provides a promising therapeutic platform for the treatment of genetic diseases, including SCA3.
2026-02-20 | TCF4 intronic CAG repeat length modulates the effect of ATXN3 on age at onset in spinocerebellar ataxia type 3.
Spinocerebellar ataxia type 3 (SCA3) is caused by ATXN3 CAG expansions, yet repeat length explains only 50-70% of age at onset (AO) variability, suggesting the influence of additional genetic modifiers. We investigated whether transcription factor 4 (TCF4), harboring an intronic CAG repeat and highly expressed in SCA3-vulnerable regions, modifies AO. To explore the modifying effect of TCF4 intronic CAG repeats on SCA3 AO and investigate the underlying molecular mechanisms. We conducted a cross-sectional study of 1,439 genetically confirmed Chinese SCA3 individuals (1,212 symptomatic, 227 asymptomatic). TCF4 CAG repeats were categorized as Short (7-13), Medium (14-39), and Long (≥40). Statistical frameworks included hierarchical regression, survival analyses, and extensive sensitivity testing. Functional validation was performed in HEK293T cells stably expressing normal (20Q) or pathogenic (84Q) ataxin-3, transfected with CDS-only or intron-retaining TCF4 constructs harboring 11, 24, or 100 intronic CTG repeats. TCF4 showed no direct effect on AO but significantly modulated the ATXN3-AO relationship. Regression analyses revealed length-dependent amplification of the ATXN3 effect across TCF4 groups (-2.04 to -3.18 years/repeat). Modification was most pronounced in early-onset patients (AO ≤ 25; Δadjusted R2 = 0.048, p < 0.001). Survival analyses and extensive sensitivity tests consistently confirmed these findings. Mechanistically, TCF4 and ataxin-3 exhibited direct physical interaction. Notably, we identified a bidirectional pathogenic synergy: expanded ataxin-3 synergistically exacerbated TCF4 CTG length-dependent splicing defects, protein reduction, and RNA foci formation, while TCF4 expansion reciprocally promoted mutant ataxin-3 aggregation. TCF4 intronic CAG repeat length-dependently modifies SCA3 age at onset through bidirectional molecular synergy with expanded ataxin-3. These findings reveal a novel intronic genetic modifier and establish the pathogenic interaction between non-coding and coding repeat expansion loci as a disease-modifying mechanism in repeat expansion disorders.
2026-02-08 | Cognitive impairment in SCA3: A multi-center cohort study with demographic, imaging, and biomarker correlates.
Cognitive deficits are common in spinocerebellar ataxia type 3 (SCA3), but their neurobiological correlates remain largely unknown. To investigate cognitive performance in a large international cohort of SCA3 mutation carriers covering the entire disease course and to explore associations with posterior cerebellar volumes, basal ganglia and thalamus volumes, and plasma neurofilament light chain (NfL) concentration. The Montreal Cognitive Assessment (MoCA) was used to evaluate cognitive impairment in this prospective, observational cohort study involving 13 ataxia referral centers. Standardized motor assessments, brain MR imaging, and peripheral blood biosampling were also performed. MoCA data were collected from 61 pre-ataxic SCA3 mutation carriers, 231 ataxic SCA3 patients, and 111 healthy controls. After adjustments for educational level and age, there were significant differences in MoCA total score, as well as visuospatial/executive, attention, language, and abstraction subscores, between healthy controls and ataxic, but not pre-ataxic individuals. MoCA scores declined with ataxia severity, especially in patients with a lower educational level. Patients with a MoCA score < 26 had lower pallidal volumes and higher plasma NfL concentrations than those with a score ≥ 26. However, only the interaction term between ataxia severity and educational level was independently associated with cognitive performance in multivariable regression analyses containing demographic, clinical, volumetric, and biochemical parameters. Cognitive deficits in SCA3 generally appear after clinical ataxia onset and progress in parallel with ataxia severity, especially in patients with a lower cognitive reserve. Other measured biochemical and imaging parameters did not have a significant additional contribution.
proteins
2026-05-26 | Polyglutamine-Expanded Ataxin-3 Accelerates CFTR Degradation Through K63-Linked Ubiquitination to Exacerbate Microglial Inflammation.
The deubiquitinase Ataxin-3 causes spinocerebellar ataxia type 3 (SCA3) upon polyglutamine (polyQ) expansion. While expressed in the nervous system, the function of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel therein remains unclear, as does its potential regulation by Ataxin-3. This study reveals that Ataxin-3 interacts with and promotes CFTR degradation in human microglia by its K63-linked polyubiquitination, thereby shortening CFTR's half-life. Paradoxically, K63-linked polyubiquitin chains also promote the degradation of Ataxin-3 itself, suggesting a complex feedback mechanism. The pathogenic Ataxin-3Q80 mutant exerts a stronger effect than the wild-type protein. Consequently, this Ataxin-3-CFTR axis drives microglial polarization toward a pro-inflammatory phenotype and amplifies neuroinflammation. We thus identify a novel "Ataxin-3-K63 ubiquitin chain-CFTR" pathway that controls microglial activation, offering new mechanistic insight and therapeutic targets for SCA3. Abbreviations: MJDM: achado-Joseph disease; SCA3: spinocerebellar ataxia type 3; PolyQ: polyglutamine; CNS: central nervous system; CFTR: cystic fibrosis transmembrane conductance regulator; CF: cystic fibrosis; UIMs: ubiquitin-interacting motifs; MEM: Minimum Essential Medium; FBS: fetal bovine serum; P/S: penicillin/streptomycin; siRNA: small interfering RNA; BSA: bovine serum albumin; Co-IP: Co-immunoprecipitation; LPS: lipopolysaccharide; WT-CFTR: wild-type CFTR; CHX: Cycloheximide; 3-MA: 3-Methyladenine; IF: Immunofluorescence; IB: immunoblot; Ub: ubiquitin.
2026-03-13 | Revisited case for intranasal neuropeptide Y based therapeutics: From preclinical to clinical.
Compelling evidence from a variety of approaches attributes manifold benefits to NPY in the brain. NPY can reduce stress, depressive symptoms, pain, neuroinflammation, seizures, and is implicated in attenuating alcohol use disorder and neurodegenerative diseases, such as Alzheimer's, Machado-Joseph and Huntington Disease. NPY enhances immune regulation, neuro-proliferation, memory and cognition. However, its therapeutic potential has not yet been realized. Intranasal nose to brain (N2B) delivery is a non-invasive approach that can provide high bioavailability with limited side effects. Here we discuss therapeutic opportunities and challenges of N2B administration of NPY and related agonists. Preclinical N2B administration of NPY, either alone or with other compounds, to experimental animals has been very successful. For example, a single NPY intranasal infusion to male rats was able to prevent, as well as reverse, many behavioral impairments triggered by Single Prolonged Stress model for PTSD. Females were found to require higher doses of NPY, or pretreatment with a DPPIV inhibitor, to provide resilience. In humans, limited studies found that intranasal administration of NPY in saline was well tolerated and showed promise for PTSD or depression at highest dose administered. However, saline should be avoided in favor of water for aqueous delivery, and each sex should be analyzed separately. Overall, these findings call for further work to enhance N2B delivery of NPY or selective agonists to human brain to harness NPY's exciting therapeutic potential.
2026-03-12 | Retrotransposition Events Shape the Evolution of the Ataxin-3 Gene Family in Primates.
Evolutionary studies of disease-associated genes provide crucial insights into pathological mechanisms and potential therapeutic targets. Polyglutamine spinocerebellar ataxias (SCAs) are human neurodegenerative diseases caused by toxic expanded CAG repeats. Studies on SCA1 have shown that a paralog of the causing-gene can partially rescue protein function and alleviate the neuropathology. The most common SCA, Machado-Joseph disease (MJD/SCA3), caused by mutated ataxin-3 gene (ATXN3), has no treatment currently available. Its paralog ataxin-3 like (ATXN3L) remains largely unexplored. Here, we identify three new retrotransposition events of ATXN3: ATXN3L0 in Euarchontoglires, ATXN3L2 in Simiformes, and ATXN3L3 in Cercopithecidae, in addition to ATXN3L (herein called ATXN3L1) originated in Haplorrhini. ATXN3 and ATXN3L1 are both under purifying selection throughout primate evolution, maintaining about 70% of amino acid identity. Also, the high conservation of ATXN3L1 Josephin domain hints at functional redundancy with the parental disease-associated ATXN3. ATXN3L2 presents a remarkable nucleotide similarity to ATXN3 (79%) in an interrupted reading frame, which may produce a regulatory RNA. Conversely, ATXN3L0 is likely a non-functional retrocopy and ATXN3L3 is absent in humans with no relevance for the disease. The comparison of (CAG)n interruption patterns of the different paralogs in several primates elucidates the process leading to the currently observed pure long tracts in human ATXN3, responsible for disease when expanded. This study intends to pioneer the identification of new paralogs of SCA-associated genes and the use of phylogenetic analyses to explore their potential role for targeted therapies.
2026-02-17 | Single-Cell RNA Sequencing Reveals Impaired CHIP-Mediated Heat Stress Response in SCA3 Pathogenesis.
Nine distinct polyglutamine (PolyQ) diseases are caused by CAG repeat expansions in the coding regions of their respective causative genes, among which spinocerebellar ataxia type 3 (SCA3), driven by CAG repeat expansion in the ATXN3 gene, is one of the most common subtypes. SCA3 is characterized by the aggregation of mutant Ataxin-3 (containing an expanded polyglutamine tract, encoded by ATXN3) into neuronal intranuclear inclusions, leading to progressive neurodegeneration. Despite extensive research, the precise molecular mechanisms underlying mutant Ataxin-3-induced neurotoxicity remain elusive, and there is still a lack of effective therapeutic strategies for SCA3. To address these gaps, the present study aimed to elucidate the key pathophysiological cascades driving SCA3 progression and identify potential therapeutic targets by investigating cellular and molecular alterations in SCA3 models. Our results showed that SCA3 cells exhibited significantly reduced viability and increased thermolability. In SCA3 transgenic mice, a large portion of the C terminus of Hsc70-interacting protein (CHIP) was sequestered within neuronal intranuclear inclusions, resulting in a progressive, age-dependent decline in soluble CHIP level. Single-Cell RNA Sequencing (ScRNA-seq) analysis of the cerebellum from these mice revealed dysregulated cellular stress response in SCA3. Native gel electrophoresis revealed that the level of trimerized HSF1 in SCA3 cells was significantly lower than that in wild-type cells, indicating that stress intolerance may be involved in the pathogenesis of SCA3. This further validated and specified results of ScRNA-Seq. Importantly, overexpression of CHIP partially restored HSF1 function, rescued DNAJB1 (homolog of HSP40) and the defective heat stress response, and ameliorated multiple disease-related phenotypes in SCA3 models. This further reveals that the reduction in functional CHIP caused by Ataxin3 mutation may represent an upstream event responsible for stress intolerance in SCA3. Collectively, our findings demonstrate that depletion of soluble CHIP promotes SCA3 progression by disrupting the CHIP-HSF1/DNAJB1 axis. This work not only clarifies a critical pathogenic mechanism of SCA3 but also underscores the therapeutic potential of modulating CHIP activity as a novel intervention strategy for SCA3. These results provide a clearer contextual framework for understanding SCA3 pathogenesis and lay a foundation for the development of targeted therapies.
2025-09-09 | Bioinformatics Analysis of Ataxin-3’s Transcriptional Regulation in Nervous System Inflammation, Metabolism, and Angiogenesis
Utilizing principles of bioinformatics, this study endeavors to elucidate the role of Ataxin-3 in gene expression regulation and propose novel research avenues to unravel the pathophysiological mechanisms of Spinocerebellar Ataxia Type 3 (SCA3), attributed to the functional impairment and deficiency of Ataxin-3. This study accessed the Gene Expression Omnibus (GEO) database to obtain microarray data (GSE117028) from both normal and <i>Atxn3</i> knockout Mouse embryonic fibroblasts (MEFs), aiming to identify differentially expressed genes (DEGs). Tissue expression specificity was analyzed using the BioGPS database. The DAVID 2021 analysis platform is utilized for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. A protein-protein interaction (PPI) network for DEGs was constructed with the STRING database, and PPI data visualization was achieved through the Cytoscape software, with the hub-DEGs identified using the CytoHubba plugin. Enrichment analysis of key differentially expressed proteins and transcriptional regulatory network construction were performed using DAVID 2021 and Cistrome DB databases. Our analysis identified 164 DEGs, which showed pronounced expression specificity in the nervous and immune systems. GO analysis indicated that these DEGs are extensively involved in processes such as multicellular organism development, cell adhesion, and angiogenesis. KEGG analysis highlighted the involvement of DEGs in metabolic processes, immune pathways mediated by cytokines and chemokines, and the IL-17 signaling pathway. PPI network analysis identified six hub proteins: Cxcl1, Cxcl5, Saa3, Eng, Thy1, and Lpl, playing significant roles in the immune-inflammatory pathway. Additionally, transcription factors (TFs) CEBPB, STAT5A, NR3C1, SPI1, and EP300 were found to exert regulatory functions within these pathways. The impairment of Ataxin-3's regulatory function across various signaling pathways is hypothesized to contribute to the pathogenesis of SCA3. These findings suggest that restoring Ataxin-3 function could represent a potential therapeutic strategy for SCA3.
oligonucleotides
2026-08-19 | STM-SCA3-Paper_RNAseq_analysis: RNA-seq analysis code for "Single-nucleotide polymorphism-directed design of allele-specific antisense oligonucleotides for spinocerebellar ataxia type 3"
R code for the RNA-seq analyses underlying the figure 6 of Helm et al., 2026. Starting from gene-level count matrices, the script runs differential expression analysis with DESeq2 and produces the published panels, covering the transcriptomic effects of antisense oligonucleotide (ASO) treatment in SCA3 models and the comparison of differentially expressed genes against in silico predicted off-targets. Input paths, sample-naming conventions and significance thresholds are set in a settings block at the top of each script.
2026-08-01 | Establishing Sensory Neurons as Therapeutic Targets in Peripheral Neuropathy Driven by Polyglutamine Expanded Murine ATXN3.
Repeat expansion mutations underlie diverse neurogenetic disorders, many involving the peripheral nervous system. Despite peripheral neuropathy being the most common neurological disorder worldwide, its contribution to repeat expansion diseases remains poorly defined, and robust preclinical models are limited. We established a translational framework to study peripheral neuropathy in spinocerebellar ataxia type 3 (SCA3), a fatal multisystem disorder caused by a pathogenic CAG expansion in ATXN3. SCA3 Knock-In Atxn3Q300/Q6 (KI) and Atxn3-/- Knock-Out (KO) mice underwent sensorimotor nerve conduction and behavioral testing. Peripheral tissues were evaluated for SCA3-related pathology, and transcriptional changes in KI dorsal root ganglia (DRG) were assessed by bulk RNA sequencing. To test therapeutic relevance, we generated a conditional "OFF" SCA3 knock-in (cKI) mouse and crossed it with Avil-Cre to selectively silence mutant ATXN3 in sensory neurons. Peripheral phenotyping was repeated in Avil-Cre; cKI mice. KI mice developed progressive sensorimotor deficits, peripheral histopathology, and RNA splicing dysregulation that parallel clinical features of SCA3. In contrast, KO mice showed normal peripheral nerve function, implicating toxic gain-of-function from mutant ATXN3 as the causative driver. Sensory neuron-specific silencing of mutant ATXN3 significantly ameliorated peripheral nerve abnormalities and DRG splicing dysregulation. These findings define a pathogenic role for repeat expansion-driven peripheral nerve degeneration in SCA3, identify sensory neurons as key therapeutic targets, and provide a preclinical platform for developing peripheral interventions in SCA3 and related repeat expansion disorders. ANN NEUROL 2026.
2026-06-08 | Engineered Exosomes Deliver miR-370 Inhibitor to Regulate DNAJB1 and Synergize With miR-25 in Improving SCA3 Mice Behavior and Neuropathology.
Spinocerebellar ataxia type 3 (SCA3), the most common inherited ataxia, lacks effective therapies. Current microRNA (miRNA) approaches directly targeting ataxin-3 (ATXN3) mRNA risk reducing essential wild-type ATXN3, a key regulator of proteostasis and various signaling pathways. Consequently, developing neuron-targeted, noninvasive miRNA delivery strategies that employ alternative mechanisms is critical for SCA3. In this study, we engineered rabies virus glycoprotein (RVG)-modified exosomes to deliver miR-370 inhibitors to the brains of SCA3 mice, thereby upregulating the molecular chaperone DnaJ homolog subfamily B member 1 (DNAJB1) to promote clearance of mutant ATXN3. Systemic administration of RVG-exosomes carrying miR-370 inhibitors led to increased DNAJB1 expression, reduced mutant ATXN3 aggregation, improved neuronal survival, and restored motor coordination in SCA3 mice. Furthermore, combining miR-370 inhibitors with miR-25-a miRNA that directly targets ATXN3 mRNA-synergistically enhanced the reduction of pathogenic ATXN3 and provided greater neuroprotection compared to either therapy alone. These findings support the use of RVG-exosome-mediated miR-370 inhibition as a noninvasive strategy to improve proteostasis in SCA3 and demonstrate its potential in combination with ATXN3 mRNA-targeting miRNAs, offering a promising therapeutic paradigm for SCA3 and similar neurodegenerative disorders.
2026-01-19 | An acyclic nucleic acid-modified siRNA targeting CAG expansions for polyglutamine disease treatment.
Polyglutamine (polyQ) diseases are inherited neurological disorders caused by an expansion of the cytosine-adenine-guanine (CAG) repeat in the causative genes. These include Huntington's disease, spinal and bulbar muscular atrophy (SBMA), and spinocerebellar ataxias (SCAs). Clinical trials have been conducted using nucleic acid therapeutics to silence the causative gene for these diseases, but none have been approved for use. Furthermore, while oligonucleotides targeting the CAG repeats are an attractive therapeutic option, concomitant silencing of the wild-type allele with normal CAG repeats can result in neuronal dysfunction. In this study, we developed an acyclic serinol nucleic acid (SNA)-modified small interfering RNA (siRNA) targeting CAG repeats. We also evaluated the safety and efficacy of the siRNA in different mouse models of polyQ diseases. Intracerebroventricularly administered siRNA was widely distributed throughout the central nervous system, where it selectively silenced the alleles encoding polyQ proteins without affecting their wild-type counterparts. Consequently, the intranuclear aggregation of polyQ proteins was reduced in mouse models of SBMA and SCA type 3. The siRNA attenuated neuromuscular degeneration and improved the lifespan and motor function of the SBMA mice. These findings suggest that SNA-modified siRNAs targeting CAG repeats represent a promising approach for treating polyQ diseases.
2025-10-13 | Extracellular vesicles-associated AAVs for the treatment of Machado-Joseph disease.
Machado-Joseph disease (MJD) is the most common dominant autosomal inherited ataxia worldwide, caused by the overrepetition of the trinucleotide CAG in the ATXN3 gene. This leads to the accumulation of mutant ataxin-3 protein and neurodegeneration. Currently, treatment remains symptomatic, although gene therapy has emerged as a promising approach. However, efficient and minimally invasive gene delivery to the brain remains a challenge. Extracellular vesicle-associated adeno-associated virus (EV-AAV) vectors are a novel delivery system, combining the ability of AAV vectors to deliver genes with the capacity of extracellular vesicles to bypass the immune system and cross the blood-brain barrier (BBB). Previous studies, however, have only combined AAV serotypes known to efficiently cross the BBB with EVs as a non-invasive delivery system to the brain. Thus, the ability of EV-AAVs to cross the BBB remained inconclusive. In this study, we evaluated whether AAV1/2 serotype, combined with rabies virus glycoprotein (RVg)-coated EVs, could effectively target the brain. Two isolation methods, differential ultracentrifugation and size-exclusion chromatography (SEC) were compared, with SEC yielding higher EV recovery. Moreover, RVg-EV-AAV1/2 successfully crossed the BBB and transduced mouse brains, leading to motor and neuropathologic improvements in an MJD mouse model. This study demonstrates that RVg-EV-AAVs are promising non-invasive delivery systems for MJD gene therapy.
small molecules
2026-09-18 | Metabolic Reconfiguration and Serum Neurofilament Light Chain Dynamics in an N-of-1 Proof-of-Concept Study of Spinocerebellar Ataxia Type 3
Objective. In a proof-of-concept N-of-1 study, to assess whether a closed-loop metabolic intervention can modify the redox-metabolic state and serum NfL trajectory in genetically confirmed spinocerebellar ataxia type 3 (SCA3). Methods. A prospective, patient-scientist N-of-1 study over 14 months, in which biomarker feedback governed titration of a four-component metabolic intervention targeting glutathione disulfide recycling. Serum NfL was measured monthly in a single analytical batch. Intracellular reactive oxygen species (ROS) were profiled by flow cytometry, and oxidative damage by 8-hydroxy-2'-deoxyguanosine (8-OHdG) and malondialdehyde (MDA). Symptomatic medication was withdrawn completely, and tandem gait was recorded at each visit. Results. The bimodal ROS distribution resolved into a single narrow peak and did not revert under a subsequent niacin challenge. 8-OHdG fell by 67% (2.94 to 0.98 ng/mL) and MDA from 12.7 to 1.9–3.6 μmol/L. Serum NfL declined by 13.6 pg/mL, from a transient peak of 37.34 to 23.74 pg/mL, below the initial baseline but within the 95% prediction interval of the pre-transition series. The redox change preceded the oxidative-damage change. After complete withdrawal of baclofen and taltirelin, redox indices and functional status remained stable. No serious adverse event occurred. Interpretation. Coordinated changes in redox indices, oxidative-damage markers and serum NfL occurred while the genetic lesion remained constant. The partial ordering is consistent with, but does not establish, a cascade from metabolic reconfiguration through reduced oxidative injury to altered neuroaxonal dynamics. This N-of-1 proof-of-concept cannot exclude fluctuation, regression to the mean, or non-specific effects of a multi-component intervention; reproducibility remains untested.
2026-09-18 | PolyQ-expanded ataxin-3 is associated with mitochondrial alterations in Machado-Joseph disease.
Spinocerebellar ataxia type 3, also known as Machado-Joseph disease (MJD), is a fatal neurodegenerative disease caused by an expanded CAG repeat in ataxin-3 (ATXN3). Here, we investigated mitochondrial alterations across complementary MJD models, including transgenic zebrafish, CMVMJD135 mice and primary neuronal cultures. Proteomic profiling of brain lysates from male and female wild-type and CMVMJD135 mice identified mitochondrial alterations and altered oxidative phosphorylation-associated protein abundance as major shared features in both male and female MJD mice. Primary neuron cultures derived from CMVMJD135 mice were examined, validating the proteomic findings and revealing alterations in mitochondrial morphology. We further examined a transgenic zebrafish model of MJD that expresses EGFP-fused human ataxin-3 containing 84 glutamines in neurons (driven by the pan-neuronal elavl3/HuC promoter). The MJD zebrafish model also exhibited altered levels of mitochondrial electron transport chain complex proteins and enhanced sensitivity to rotenone. Notably, complex II-associated alterations featured across most assays, supporting complex II-linked dysregulation as a convergent, potentially targetable component of MJD. These phenotypes provide a robust platform for evaluating potential mitochondrial-targeted therapies and support growing evidence that disrupted mitochondrial homeostasis contributes to MJD pathogenesis.
2026-09-15 | Efficacy and Safety of DL-3-n-Butylphthalide in Spinocerebellar Ataxia Type 3.
Preclinical studies have suggested that DL-3-n-butylphthalide (NBP) may exhibit neuroprotective effects in neurodegenerative diseases; however, no human trial has evaluated NBP in spinocerebellar ataxia type 3 (SCA3). The aim of the study was to evaluate the efficacy and safety of oral NBP in patients with SCA3 over 12 months. Patients were randomly assigned (1:1) to oral NBP (200 mg thrice daily) or placebo for 12 months. The primary outcomes were 12-month changes in the Scale for Assessment and Rating of Ataxia (SARA) and Spinocerebellar Ataxia Functional Index (SCAFI). Safety outcomes included adverse events (AEs) and serious adverse events (SAEs). The modified intention-to-treat (mITT) population included 116 patients (NBP, n = 56; placebo, n = 60). The primary endpoints, change in SARA and SCAFI, were significantly different between NBP and placebo groups (SARA, estimated marginal mean difference: -0.86, 95% confidence interval [CI]: -1.56 to -0.16, P = 0.02; SCAFI, estimated marginal mean difference: 0.16, 95% CI: 0.01-0.31, P = 0.03) in mITT population using a mixed-effect model, with improved clinical outcome in the NBP group. Overall, AE rates were not significantly different between groups (13 AEs [23.2%] in NBP vs. 9 AEs [15%] in placebo, P = 0.26), although drug-related AEs were numerically more frequent with NBP (12 [21.4%] vs. 6 [10.0%], P = 0.09); no SAE occurred in either group. Oral administration of NBP was safe and generally well tolerated. Significant differences in clinical outcomes were observed in the treatment group compared to the placebo. NBP administration showed preliminary evidence of clinical benefit in SCA3. © 2026 International Parkinson and Movement Disorder Society.
2026-09-03 | First-Person Physiology Reveals a Tunable Redox State Transition that Reverses the Neuroaxonal Injury Trajectory in SCA3
Spinocerebellar ataxia type 3 (SCA3) is a fatal monogenic neurodegenerative disease with no disease-modifying therapies. This impasse reflects a paradigm mismatch: static clinical trial designs are poorly suited to dynamic, system-level pathophysiology—a limitation especially consequential during the biomarker stage, when neurofilament light chain (NfL) is already elevated yet MRI volumes remain preserved, beginning on average 21.5 years before clinical onset (Berger et al., 2025). Here, in a first-person N-of-1 investigation, we applied a closed-loop metabolic intervention coupling redox stabilization, mitochondrial flux support, methylation control, and proteostasis clearance to test whether this interception window could be experimentally engaged. By resolving a kinetic bottleneck in glutathione recycling through real-time biomarker-guided titration, we observed a quantifiable transition in intracellular reactive oxygen species from a pathological bimodal to a physiological unimodal distribution. This upstream redox reconfiguration was temporally coupled to reversal of the serum NfL trajectory: following a transient peak at 37.34 pg/mL, NfL declined to 23.74 pg/mL (overall slope −2.27 pg/mL/month, R² = 0.807), falling below the initial baseline despite one intervening measurement that rose. This directional reversal is discordant with the natural-history pattern in 291 SCA3 mutation carriers, in whom NfL "slowly increased and stayed at elevated levels throughout the disease course" (Berger et al., 2025). This trajectory reversal persisted over fourteen months despite withdrawal of all symptomatic medications. These findings support the interpretation that, in this individual, neuroaxonal injury became partially constrained by a modifiable metabolic state despite persistence of the causal mutation—suggesting that clinical phenotype in monogenic neurodegeneration may reflect not genotype alone, but the dynamic resilience of the metabolic system through which it is expressed.
2026-08-10 | Ficd loss rescues motor impairments and reverses oligodendrocyte maturation deficits in a mouse model of spinocerebellar ataxia type 3
Abstract Spinocerebellar ataxia type 3 (SCA3) is an inherited, fatal neurodegenerative disease caused by a pathological CAG repeat expansion in the ATXN3 gene, resulting in the selective degeneration of vulnerable neuronal populations. Recent work has identified impairments in oligodendrocyte maturation as a novel and robust feature of SCA3 pathogenesis. Oligodendrocytes synthesize myelin structural components through the endoplasmic reticulum (ER), rendering this organelle essential for white matter integrity. Despite this, the role of ER function in SCA3 remains unclear. In this study, we show that loss of FICD-mediated AMPylation, a post-translational modification regulating the ER-resident HSP70 chaperone, BiP, rescues motor impairments in a transgenic SCA3 mouse model. Ficd -/- SCA3 mice exhibit significantly reduced levels of nuclear ATXN3 in vulnerable brain regions, while Ficd +/+ littermates show an increased burden of AMPylated BiP in the spinal cord, identifying aberrant AMPylation as a novel contributor of SCA3 pathology. Using unbiased proteomics, we demonstrate that Ficd deletion mitigates the pathological decrease in myelin structural proteins and oligodendrocyte maturation factors, restoring levels of mature, myelinating oligodendrocytes. In parallel, we show that Ficd activates SREBP2-dependent cholesterol biosynthesis to support myelination. Taken as a whole, these findings posit ER homeostasis as a critical driver of oligodendrocyte pathology and identify FICD as a novel target for alleviating non-neuronal toxicity in SCA3.
other
2026-08-20 | Supplemental Material for: First, Allogeneic, Adipose-Derived, Mesenchymal Stem Cell Treatment of a Patient with Spinocerebellar Ataxia Type 3 in the United States: Case Report
Introduction: No disease-modifying therapies are approved to treat spinocerebellar ataxia (SCA), rare neurogenerative diseases that lead to progressive uncoordinated gait and dysphagia. Allogeneic, adipose-derived, mesenchymal stem cells cultured and expanded with a proprietary process (pADMSCs; Stemchymal, Steminent Biotherapeutics, Taipei, Taiwan) have shown promising inhibition of disease progression in placebo-controlled, phase 2 studies in Japan (n=59) and Taiwan (n=56).Case Presentation: Here, the first use of allogeneic, pADMSCs for treating a US patient with SCA3 according to a phase 2, investigational drug application with the US Food and Drug Administration is reported. An Asian woman (age 58 yrs) had SCA 3 symptoms for 10 years, with central vestibular dizziness and double vision that progressed to unstable standing/walking and painful neck/upper back dystonia. Several medications failed for dizziness/disequilibrium/diplopia; onabotulinumtoxinA provided partial upper back/shoulder pain relief. Several other lifestyle, pharmacologic, and physical therapies were not effective. Since May 2018, she had been taking compassionate troriluzole (200 mg/day [stable dose]). Starting in May 2021, she received 3 monthly intravenous infusions of pADMSCs (7 x 107 cells/dose). Her Scale for the Assessment and Rating of Ataxia (SARA) score was moderately high (7.5) at baseline. By the third pADMSC infusion, it dropped to 3.5, was 4.5 at 3 months after the last infusion, remained at 4.5 until ~12 months after the last infusion, and began to rise again after 1 yr from the final infusion. Her central vestibular dizziness and neck dystonia did not improve during treatment. pADMSC post-infusion side effects included hot flushes, low fever, and mild queasiness; increased tightness and pressure in the neck and upper back; retro-orbital headache; and mildly elevated pulse and blood pressure. All resolved by the day following infusion.Conclusion: This United States, phase 2, expanded-access, single-patient case study of pADMSCs in a woman with SCA taking troriluzole suggests that these allogeneic pADMSCs may be the first use of cell therapy to potentially inhibit SCA3 disease progression.
2026-07-02 | Adipose-Derived Mesenchymal Stem Cells Improve Motor Function and Reduce Neuroinflammation and Mutant Ataxin-3 Protein Levels in SCA3 Mice.
The CAG expansion in the ataxin-3 (ATXN3) protein is the underlying cause of Spinocerebellar Ataxia Type 3 (SCA3), a polyglutamine disease. The aggregation of mutant ATXN3 protein is hypothesized to contribute to neuronal dysfunction, neurodegeneration, or neuroinflammation. Mesenchymal stem cells have pleiotropic therapeutic properties, and adipose-derived mesenchymal stem cells (ADMSC) have been shown to be safe and well-tolerated in SCA3 patients. In this study, we evaluated the therapeutic effects of ADMSC in SCA3 mice. In a mouse model of SCA3, the Purkinje-cell-specific L7 promoter drives the expression of a truncated form of human ataxin-3 with 69 glutamine repeats. SCA3 mice exhibited cerebellar Purkinje cell degeneration, reduced myelination, and increased gliosis; pathological features also observed in SCA3 patients. SCA3 mice received repeated intravenous administrations of ADMSC, and efficacy was assessed by rotarod performance, molecular and pathological changes, and serum neurofilament light chain (NfL) levels. ADMSC-treated SCA3 mice showed significant improvements in rotarod performance, a reduction in accumulated toxic mutant ATXN3-69Q protein in Purkinje cells, decreased demyelination, and alleviation of neuroinflammatory and systemic inflammatory responses during disease progression. Furthermore, NfL levels, a potential biomarker for SCA3 disease progression, were inversely correlated with the rotarod performance. Based on these findings, we conclude that ADMSC enhance motor function in SCA3 mice by reducing neuroinflammation, demyelination and aggregated mutant ataxin-3 protein levels in Purkinje cells. ADMSC have the potential to serve as a disease-modifying therapy for SCA3 patients.
2026-02-03 | Mesenchymal Stromal Cell Therapeutic Potential to Restore Neurovascular Integrity in Machado-Joseph Disease
Abstract Background Machado-Joseph disease (MJD), or Spinocerebellar Ataxia type 3 (SCA3), is a neurodegenerative disorder caused by an expansion of the CAG repeat in the MJD1/ATXN3 gene, which encodes for a polyglutamine-expansion in Ataxin-3. Similar to what occurs in other neurodegenerative disorders, the cerebrovascular system, particularly the blood-brain barrier (BBB), is impaired in MJD. BBB is an important cellular barrier that controls homeostasis of the central nervous system, and its disruption compromises neuronal function. To date, there is no disease-modifying therapy for MJD. Our group previously demonstrated that MSC administration can ameliorate the phenotype of MJD transgenic mice. However, the effect of MSC on the neurovascular unit and BBB integrity remains unexplored in the context of MJD. In the present work, we aimed to evaluate the therapeutic potential of MSC in mitigating vascular abnormalities and BBB disruption in MJD. Methods Eight-month-old MJD transgenic mice were treated with two consecutive bone marrow-MSC intravenous injections (1 week apart). Behavioral tests to assess motor coordination were conducted before and after treatment. Vascular structure, function, and BBB disruption were evaluated by immunohistochemistry and western blot. Results MSC administration partially restored vascular impairment in MJD transgenic mice. Treated mice exhibited improved gait and motor performance footprint and beam walking tests) and concurrently attenuated vascular dysfunction. Specifically, MSC-treated mice exhibited a decrease in collagen IV surface area and stabilized cerebellar blood supply. Additionally, MSC treatment diminished BBB permeability to the Evans blue (EB) dye in MJD mice and restored the levels of important adherent and tight junction-associated proteins in the cellular membrane, including vascular endothelial cadherin (VE-cadherin), claudin-5, and occludin, in a sex-specific manner. Conclusions our results highlight significant cerebrovascular dysregulations in MJD, which are sex-dependent and progress with the disease stage. Moreover, our findings suggest that MSC administration partially reverted vascular impairments, providing valuable insights into the mechanisms underlying the therapeutic potential of MSC in MJD. Graphical Abstract MSC treatment partially reverts neurovascular dysregulation in MJD. MJD mice exhibit increased vessel coverage, increased BBB permeability, and altered TJ and AJ expression and subcellular localization. MSC administration modulates vessel coverage, reduces BBB leakage, and partially normalizes TJ/AJ subcellular localization. List of abbreviations: AJ – Adherent junction; BBB – Blood-Brain barrier; MJD- Machado-Joseph disease; MSC – mesenchymal stromal cell; TJ – thigh junction. Created with BioRender.com
2024-02-28 | Effectiveness of High-Frequency Repetitive Transcranial Magnetic Stimulation in Patients With Spinocerebellar Ataxia Type 3.
To investigate the effectiveness of high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) on improvement of clinical symptoms in patients with spinocerebellar ataxia type 3 (SCA3). Sixteen SCA3 participants diagnosed by genetic testing were enrolled in this sham-controlled and double-blind trial. They received either a 2-week 10-Hz rTMS intervention or sham stimulation targeting the vermis and cerebellum. The Scale for Assessment and Rating of Ataxia and the International Cooperative Ataxia Rating Scale were completed at baseline and poststimulation. Compared with baseline, the HF-rTMS group demonstrated a significant improvement in the total Scale for Assessment and Rating of Ataxia ( P < 0.0001) and the International Cooperative Ataxia Rating Scale scores ( P = 0.002). After 2-week treatment, the real group exhibited decreasing pattern in 3 subgroups, especially for limb kinetic function ( P < 0.0001). Short-term HF-rTMS treatment is a potentially promising and feasible tool for rehabilitation in patients with SCA3. Studies with long-term follow-up need to be carried out in the future and further need to assess gait, limb kinetic function, speech and oculomotor disorders.
2024-02-14 | Graft-derived neurons and bystander effects are maintained for six months after human iPSC-derived NESC transplantation in mice's cerebella.
Machado-Joseph disease (MJD) is a neurodegenerative disorder characterized by widespread neuronal death affecting the cerebellum. Cell therapy can trigger neuronal replacement and neuroprotection through bystander effects providing a therapeutic option for neurodegenerative diseases. Here, human control (CNT) and MJD iPSC-derived neuroepithelial stem cells (NESC) were established and tested for their therapeutic potential. Cells' neuroectodermal phenotype was demonstrated. Brain organoids obtained from the Control NESC showed higher mRNA levels of genes related to stem cells' bystander effects, such as BDNF, NEUROD1, and NOTCH1, as compared with organoids produced from MJD NESC, suggesting that Control NESC have a higher therapeutic potential. Graft-derived glia and neurons, such as cells positive for markers of cerebellar neurons, were detected six months after NESC transplantation in mice cerebella. The graft-derived neurons established excitatory and inhibitory synapses in the host cerebella, although CNT neurons exhibited higher excitatory synapse numbers compared with MJD neurons. Cell grafts, mainly CNT NESC, sustained the bystander effects through modulation of inflammatory interleukins (IL1B and IL10), neurotrophic factors (NGF), and neurogenesis-related proteins (Msi1 and NeuroD1), for six months in the mice cerebella. Altogether this study demonstrates the long-lasting therapeutic potential of human iPSC-derived NESC in the cerebellum.
gene therapies
2026-05-12 | Quantitative Ocular Motor / Vestibular Assessment in Patients with Spinocerebellar Ataxia Type 3 (SCA3, Machado Joseph Disease) - Systematic Review of the Literature.
Spinocerebellar ataxia type 3 (SCA3 or Machado-Joseph disease) is the second most common autosomal-dominant hereditary ataxia and often presents with ocular motor and vestibular impairment. The value of ocular motor testing for early disease detection, monitoring disease progression and as a potential treatment biomarker has been acknowledged in several studies. This systematic review aims to summarise the current evidence supporting quantitative eye movement testing in SCA3. Studies reporting on quantitative ocular motor and/or vestibular measurements in SCA3 were searched for in MEDLINE and Embase. Thirty studies reporting on 432 SCA3 patients (including 64 pre-symptomatic carriers) were included. Information on various ocular motor parameters were extracted and correlations with other parameters (including clinical scales, imaging, and genetic testing) were assessed. Ocular motor abnormalities observed comprised (horizontal) pursuit eye-movement (PEM) gain reduction (14/19 patients), saccadic intrusions (principally square-wave jerks (SWJ, 29/45)), gaze-evoked nystagmus (GEN, 65/82), and rebound nystagmus (8/10). Additionally, saccades to target displayed increased latency (13/29), reduced peak velocity (16/49) and dysmetria (33/49). Vestibular deficits measured included vestibulo-ocular reflex (VOR) gain-reductions during quantitative head-impulse testing (qHIT, 117/133) and abnormal responses during caloric irrigation (7/9), impaired visually-enhanced VOR-responses (5/6), and impaired cervical (19/66) and ocular (10/14) vestibular-evoked myogenic-potential testing. In summary, impaired VOR-gains (qHIT), GEN, horizontal PEM-gain decreases, dysmetric saccades, and SWJ were most frequently reported and therefore seem most suitable as potential disease markers. The quantitative ocular motor/vestibular assessment may facilitate early diagnosis, distinction of disease stages and also potentially allow monitoring of disease progression and treatment response.
2026-05-11 | A Severity-Agnostic Atrophy Pattern in Spinocerebellar Ataxia Type 3: Volumetrics from ENIGMA-Ataxia.
Spinocerebellar ataxia type 3 (SCA3) is a rare, inherited neurodegenerative disease characterized by progressive loss of motor coordination. We undertook a multisite magnetic resonance imaging study to profile the spatial spread of atrophy across the brain, determine whether atrophy preferentially maps onto specific functional networks, and investigate the relationship between cerebellar and cerebral atrophy. Whole-brain grey and white matter (GM and WM) voxel-based morphometry was performed on 408 individuals with SCA3 (82 pre-ataxic) and 293 controls. The SCA3 cohort was stratified by ataxia severity to study progression. Cerebellar GM atrophy was mapped onto a task-based functional atlas. Cerebrocerebellar volumetric covariance was assessed to determine whether cerebral and cerebellar atrophy were coupled. The atrophy pattern is spatially consistent but progressive in magnitude across the disease course. The greatest atrophy (Cohen's d > 1.5) occurred in the pons, cerebellar WM, and cerebellar peduncles; correlations with ataxia severity and duration were also strongest (-0.4 > r > -0.65) in those regions. Cerebellar GM atrophy was greatest (d ≅ 0.7) in functional regions associated with motor planning/execution, attention, and emotional processing. Sparse cerebral cortical atrophy appears only in the most severe disease subgroup, while striatal atrophy begins in the earliest stages but does not worsen with increasing clinical severity. Reduced cerebrocerebellar volumetric covariance is observed in SCA3 participants versus controls. Cerebellar and brainstem atrophy underlies greater ataxia severity in SCA3, but the spatial pattern of structural changes remains relatively consistent across the course of the disease. Cerebellar GM atrophy is spatially non-uniform, and occurs maximally in regions consistent with the motor and cognitive clinical presentation of SCA3. Cerebellar atrophy is not mirrored by corresponding cerebral structural changes. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
2026-03-15 | Extracellular vesicles-mediated delivery of SpCas9 RNPs for therapeutic gene editing in Spinocerebellar Ataxia Type 3.
Spinocerebellar Ataxia Type 3 (SCA3) is a neurodegenerative dominantly-inherited disorder caused by an overexpansion of a CAG tract within the ATXN3 gene, conferring toxic properties to the ataxin-3 protein. Genome editing with CRISPR-Cas9 enzymes is a promising strategy to inactivate mutant ATXN3 alleles, however, in vivo delivery remains challenging. Extracellular vesicles (EVs) are promising delivery vehicles for Cas9 and single guide RNA (sgRNA) ribonucleoproteins that minimize genomic exposure to highly active endonucleases. In this study, we designed SpCas9 with a palmitoylation motif that enables SpCas9 and sgRNA enrichment into EVs. Introduction of a photocleavable linker - PhoCl - allowed the photo-inducible release of SpCas9 from the palmitoylation motif in EVs, increasing target engagement to ATXN3 in vitro. EVs loaded with SpCas9 ribonucleoproteins resulted in ATXN3 knockout in SCA3 patient-derived iPSCs and two SCA3 animal models. These findings highlight an innovative route for transient delivery of gene editing tools. This approach provides a promising therapeutic platform for the treatment of genetic diseases, including SCA3.
2026-02-20 | TCF4 intronic CAG repeat length modulates the effect of ATXN3 on age at onset in spinocerebellar ataxia type 3.
Spinocerebellar ataxia type 3 (SCA3) is caused by ATXN3 CAG expansions, yet repeat length explains only 50-70% of age at onset (AO) variability, suggesting the influence of additional genetic modifiers. We investigated whether transcription factor 4 (TCF4), harboring an intronic CAG repeat and highly expressed in SCA3-vulnerable regions, modifies AO. To explore the modifying effect of TCF4 intronic CAG repeats on SCA3 AO and investigate the underlying molecular mechanisms. We conducted a cross-sectional study of 1,439 genetically confirmed Chinese SCA3 individuals (1,212 symptomatic, 227 asymptomatic). TCF4 CAG repeats were categorized as Short (7-13), Medium (14-39), and Long (≥40). Statistical frameworks included hierarchical regression, survival analyses, and extensive sensitivity testing. Functional validation was performed in HEK293T cells stably expressing normal (20Q) or pathogenic (84Q) ataxin-3, transfected with CDS-only or intron-retaining TCF4 constructs harboring 11, 24, or 100 intronic CTG repeats. TCF4 showed no direct effect on AO but significantly modulated the ATXN3-AO relationship. Regression analyses revealed length-dependent amplification of the ATXN3 effect across TCF4 groups (-2.04 to -3.18 years/repeat). Modification was most pronounced in early-onset patients (AO ≤ 25; Δadjusted R2 = 0.048, p < 0.001). Survival analyses and extensive sensitivity tests consistently confirmed these findings. Mechanistically, TCF4 and ataxin-3 exhibited direct physical interaction. Notably, we identified a bidirectional pathogenic synergy: expanded ataxin-3 synergistically exacerbated TCF4 CTG length-dependent splicing defects, protein reduction, and RNA foci formation, while TCF4 expansion reciprocally promoted mutant ataxin-3 aggregation. TCF4 intronic CAG repeat length-dependently modifies SCA3 age at onset through bidirectional molecular synergy with expanded ataxin-3. These findings reveal a novel intronic genetic modifier and establish the pathogenic interaction between non-coding and coding repeat expansion loci as a disease-modifying mechanism in repeat expansion disorders.
2026-02-08 | Cognitive impairment in SCA3: A multi-center cohort study with demographic, imaging, and biomarker correlates.
Cognitive deficits are common in spinocerebellar ataxia type 3 (SCA3), but their neurobiological correlates remain largely unknown. To investigate cognitive performance in a large international cohort of SCA3 mutation carriers covering the entire disease course and to explore associations with posterior cerebellar volumes, basal ganglia and thalamus volumes, and plasma neurofilament light chain (NfL) concentration. The Montreal Cognitive Assessment (MoCA) was used to evaluate cognitive impairment in this prospective, observational cohort study involving 13 ataxia referral centers. Standardized motor assessments, brain MR imaging, and peripheral blood biosampling were also performed. MoCA data were collected from 61 pre-ataxic SCA3 mutation carriers, 231 ataxic SCA3 patients, and 111 healthy controls. After adjustments for educational level and age, there were significant differences in MoCA total score, as well as visuospatial/executive, attention, language, and abstraction subscores, between healthy controls and ataxic, but not pre-ataxic individuals. MoCA scores declined with ataxia severity, especially in patients with a lower educational level. Patients with a MoCA score < 26 had lower pallidal volumes and higher plasma NfL concentrations than those with a score ≥ 26. However, only the interaction term between ataxia severity and educational level was independently associated with cognitive performance in multivariable regression analyses containing demographic, clinical, volumetric, and biochemical parameters. Cognitive deficits in SCA3 generally appear after clinical ataxia onset and progress in parallel with ataxia severity, especially in patients with a lower cognitive reserve. Other measured biochemical and imaging parameters did not have a significant additional contribution.
proteins
2026-05-26 | Polyglutamine-Expanded Ataxin-3 Accelerates CFTR Degradation Through K63-Linked Ubiquitination to Exacerbate Microglial Inflammation.
The deubiquitinase Ataxin-3 causes spinocerebellar ataxia type 3 (SCA3) upon polyglutamine (polyQ) expansion. While expressed in the nervous system, the function of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel therein remains unclear, as does its potential regulation by Ataxin-3. This study reveals that Ataxin-3 interacts with and promotes CFTR degradation in human microglia by its K63-linked polyubiquitination, thereby shortening CFTR's half-life. Paradoxically, K63-linked polyubiquitin chains also promote the degradation of Ataxin-3 itself, suggesting a complex feedback mechanism. The pathogenic Ataxin-3Q80 mutant exerts a stronger effect than the wild-type protein. Consequently, this Ataxin-3-CFTR axis drives microglial polarization toward a pro-inflammatory phenotype and amplifies neuroinflammation. We thus identify a novel "Ataxin-3-K63 ubiquitin chain-CFTR" pathway that controls microglial activation, offering new mechanistic insight and therapeutic targets for SCA3. Abbreviations: MJDM: achado-Joseph disease; SCA3: spinocerebellar ataxia type 3; PolyQ: polyglutamine; CNS: central nervous system; CFTR: cystic fibrosis transmembrane conductance regulator; CF: cystic fibrosis; UIMs: ubiquitin-interacting motifs; MEM: Minimum Essential Medium; FBS: fetal bovine serum; P/S: penicillin/streptomycin; siRNA: small interfering RNA; BSA: bovine serum albumin; Co-IP: Co-immunoprecipitation; LPS: lipopolysaccharide; WT-CFTR: wild-type CFTR; CHX: Cycloheximide; 3-MA: 3-Methyladenine; IF: Immunofluorescence; IB: immunoblot; Ub: ubiquitin.
2026-03-13 | Revisited case for intranasal neuropeptide Y based therapeutics: From preclinical to clinical.
Compelling evidence from a variety of approaches attributes manifold benefits to NPY in the brain. NPY can reduce stress, depressive symptoms, pain, neuroinflammation, seizures, and is implicated in attenuating alcohol use disorder and neurodegenerative diseases, such as Alzheimer's, Machado-Joseph and Huntington Disease. NPY enhances immune regulation, neuro-proliferation, memory and cognition. However, its therapeutic potential has not yet been realized. Intranasal nose to brain (N2B) delivery is a non-invasive approach that can provide high bioavailability with limited side effects. Here we discuss therapeutic opportunities and challenges of N2B administration of NPY and related agonists. Preclinical N2B administration of NPY, either alone or with other compounds, to experimental animals has been very successful. For example, a single NPY intranasal infusion to male rats was able to prevent, as well as reverse, many behavioral impairments triggered by Single Prolonged Stress model for PTSD. Females were found to require higher doses of NPY, or pretreatment with a DPPIV inhibitor, to provide resilience. In humans, limited studies found that intranasal administration of NPY in saline was well tolerated and showed promise for PTSD or depression at highest dose administered. However, saline should be avoided in favor of water for aqueous delivery, and each sex should be analyzed separately. Overall, these findings call for further work to enhance N2B delivery of NPY or selective agonists to human brain to harness NPY's exciting therapeutic potential.
2026-03-12 | Retrotransposition Events Shape the Evolution of the Ataxin-3 Gene Family in Primates.
Evolutionary studies of disease-associated genes provide crucial insights into pathological mechanisms and potential therapeutic targets. Polyglutamine spinocerebellar ataxias (SCAs) are human neurodegenerative diseases caused by toxic expanded CAG repeats. Studies on SCA1 have shown that a paralog of the causing-gene can partially rescue protein function and alleviate the neuropathology. The most common SCA, Machado-Joseph disease (MJD/SCA3), caused by mutated ataxin-3 gene (ATXN3), has no treatment currently available. Its paralog ataxin-3 like (ATXN3L) remains largely unexplored. Here, we identify three new retrotransposition events of ATXN3: ATXN3L0 in Euarchontoglires, ATXN3L2 in Simiformes, and ATXN3L3 in Cercopithecidae, in addition to ATXN3L (herein called ATXN3L1) originated in Haplorrhini. ATXN3 and ATXN3L1 are both under purifying selection throughout primate evolution, maintaining about 70% of amino acid identity. Also, the high conservation of ATXN3L1 Josephin domain hints at functional redundancy with the parental disease-associated ATXN3. ATXN3L2 presents a remarkable nucleotide similarity to ATXN3 (79%) in an interrupted reading frame, which may produce a regulatory RNA. Conversely, ATXN3L0 is likely a non-functional retrocopy and ATXN3L3 is absent in humans with no relevance for the disease. The comparison of (CAG)n interruption patterns of the different paralogs in several primates elucidates the process leading to the currently observed pure long tracts in human ATXN3, responsible for disease when expanded. This study intends to pioneer the identification of new paralogs of SCA-associated genes and the use of phylogenetic analyses to explore their potential role for targeted therapies.
2026-02-17 | Single-Cell RNA Sequencing Reveals Impaired CHIP-Mediated Heat Stress Response in SCA3 Pathogenesis.
Nine distinct polyglutamine (PolyQ) diseases are caused by CAG repeat expansions in the coding regions of their respective causative genes, among which spinocerebellar ataxia type 3 (SCA3), driven by CAG repeat expansion in the ATXN3 gene, is one of the most common subtypes. SCA3 is characterized by the aggregation of mutant Ataxin-3 (containing an expanded polyglutamine tract, encoded by ATXN3) into neuronal intranuclear inclusions, leading to progressive neurodegeneration. Despite extensive research, the precise molecular mechanisms underlying mutant Ataxin-3-induced neurotoxicity remain elusive, and there is still a lack of effective therapeutic strategies for SCA3. To address these gaps, the present study aimed to elucidate the key pathophysiological cascades driving SCA3 progression and identify potential therapeutic targets by investigating cellular and molecular alterations in SCA3 models. Our results showed that SCA3 cells exhibited significantly reduced viability and increased thermolability. In SCA3 transgenic mice, a large portion of the C terminus of Hsc70-interacting protein (CHIP) was sequestered within neuronal intranuclear inclusions, resulting in a progressive, age-dependent decline in soluble CHIP level. Single-Cell RNA Sequencing (ScRNA-seq) analysis of the cerebellum from these mice revealed dysregulated cellular stress response in SCA3. Native gel electrophoresis revealed that the level of trimerized HSF1 in SCA3 cells was significantly lower than that in wild-type cells, indicating that stress intolerance may be involved in the pathogenesis of SCA3. This further validated and specified results of ScRNA-Seq. Importantly, overexpression of CHIP partially restored HSF1 function, rescued DNAJB1 (homolog of HSP40) and the defective heat stress response, and ameliorated multiple disease-related phenotypes in SCA3 models. This further reveals that the reduction in functional CHIP caused by Ataxin3 mutation may represent an upstream event responsible for stress intolerance in SCA3. Collectively, our findings demonstrate that depletion of soluble CHIP promotes SCA3 progression by disrupting the CHIP-HSF1/DNAJB1 axis. This work not only clarifies a critical pathogenic mechanism of SCA3 but also underscores the therapeutic potential of modulating CHIP activity as a novel intervention strategy for SCA3. These results provide a clearer contextual framework for understanding SCA3 pathogenesis and lay a foundation for the development of targeted therapies.
2025-09-09 | Bioinformatics Analysis of Ataxin-3’s Transcriptional Regulation in Nervous System Inflammation, Metabolism, and Angiogenesis
Utilizing principles of bioinformatics, this study endeavors to elucidate the role of Ataxin-3 in gene expression regulation and propose novel research avenues to unravel the pathophysiological mechanisms of Spinocerebellar Ataxia Type 3 (SCA3), attributed to the functional impairment and deficiency of Ataxin-3. This study accessed the Gene Expression Omnibus (GEO) database to obtain microarray data (GSE117028) from both normal and <i>Atxn3</i> knockout Mouse embryonic fibroblasts (MEFs), aiming to identify differentially expressed genes (DEGs). Tissue expression specificity was analyzed using the BioGPS database. The DAVID 2021 analysis platform is utilized for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. A protein-protein interaction (PPI) network for DEGs was constructed with the STRING database, and PPI data visualization was achieved through the Cytoscape software, with the hub-DEGs identified using the CytoHubba plugin. Enrichment analysis of key differentially expressed proteins and transcriptional regulatory network construction were performed using DAVID 2021 and Cistrome DB databases. Our analysis identified 164 DEGs, which showed pronounced expression specificity in the nervous and immune systems. GO analysis indicated that these DEGs are extensively involved in processes such as multicellular organism development, cell adhesion, and angiogenesis. KEGG analysis highlighted the involvement of DEGs in metabolic processes, immune pathways mediated by cytokines and chemokines, and the IL-17 signaling pathway. PPI network analysis identified six hub proteins: Cxcl1, Cxcl5, Saa3, Eng, Thy1, and Lpl, playing significant roles in the immune-inflammatory pathway. Additionally, transcription factors (TFs) CEBPB, STAT5A, NR3C1, SPI1, and EP300 were found to exert regulatory functions within these pathways. The impairment of Ataxin-3's regulatory function across various signaling pathways is hypothesized to contribute to the pathogenesis of SCA3. These findings suggest that restoring Ataxin-3 function could represent a potential therapeutic strategy for SCA3.
oligonucleotides
2026-08-19 | STM-SCA3-Paper_RNAseq_analysis: RNA-seq analysis code for "Single-nucleotide polymorphism-directed design of allele-specific antisense oligonucleotides for spinocerebellar ataxia type 3"
R code for the RNA-seq analyses underlying the figure 6 of Helm et al., 2026. Starting from gene-level count matrices, the script runs differential expression analysis with DESeq2 and produces the published panels, covering the transcriptomic effects of antisense oligonucleotide (ASO) treatment in SCA3 models and the comparison of differentially expressed genes against in silico predicted off-targets. Input paths, sample-naming conventions and significance thresholds are set in a settings block at the top of each script.
2026-08-01 | Establishing Sensory Neurons as Therapeutic Targets in Peripheral Neuropathy Driven by Polyglutamine Expanded Murine ATXN3.
Repeat expansion mutations underlie diverse neurogenetic disorders, many involving the peripheral nervous system. Despite peripheral neuropathy being the most common neurological disorder worldwide, its contribution to repeat expansion diseases remains poorly defined, and robust preclinical models are limited. We established a translational framework to study peripheral neuropathy in spinocerebellar ataxia type 3 (SCA3), a fatal multisystem disorder caused by a pathogenic CAG expansion in ATXN3. SCA3 Knock-In Atxn3Q300/Q6 (KI) and Atxn3-/- Knock-Out (KO) mice underwent sensorimotor nerve conduction and behavioral testing. Peripheral tissues were evaluated for SCA3-related pathology, and transcriptional changes in KI dorsal root ganglia (DRG) were assessed by bulk RNA sequencing. To test therapeutic relevance, we generated a conditional "OFF" SCA3 knock-in (cKI) mouse and crossed it with Avil-Cre to selectively silence mutant ATXN3 in sensory neurons. Peripheral phenotyping was repeated in Avil-Cre; cKI mice. KI mice developed progressive sensorimotor deficits, peripheral histopathology, and RNA splicing dysregulation that parallel clinical features of SCA3. In contrast, KO mice showed normal peripheral nerve function, implicating toxic gain-of-function from mutant ATXN3 as the causative driver. Sensory neuron-specific silencing of mutant ATXN3 significantly ameliorated peripheral nerve abnormalities and DRG splicing dysregulation. These findings define a pathogenic role for repeat expansion-driven peripheral nerve degeneration in SCA3, identify sensory neurons as key therapeutic targets, and provide a preclinical platform for developing peripheral interventions in SCA3 and related repeat expansion disorders. ANN NEUROL 2026.
2026-06-08 | Engineered Exosomes Deliver miR-370 Inhibitor to Regulate DNAJB1 and Synergize With miR-25 in Improving SCA3 Mice Behavior and Neuropathology.
Spinocerebellar ataxia type 3 (SCA3), the most common inherited ataxia, lacks effective therapies. Current microRNA (miRNA) approaches directly targeting ataxin-3 (ATXN3) mRNA risk reducing essential wild-type ATXN3, a key regulator of proteostasis and various signaling pathways. Consequently, developing neuron-targeted, noninvasive miRNA delivery strategies that employ alternative mechanisms is critical for SCA3. In this study, we engineered rabies virus glycoprotein (RVG)-modified exosomes to deliver miR-370 inhibitors to the brains of SCA3 mice, thereby upregulating the molecular chaperone DnaJ homolog subfamily B member 1 (DNAJB1) to promote clearance of mutant ATXN3. Systemic administration of RVG-exosomes carrying miR-370 inhibitors led to increased DNAJB1 expression, reduced mutant ATXN3 aggregation, improved neuronal survival, and restored motor coordination in SCA3 mice. Furthermore, combining miR-370 inhibitors with miR-25-a miRNA that directly targets ATXN3 mRNA-synergistically enhanced the reduction of pathogenic ATXN3 and provided greater neuroprotection compared to either therapy alone. These findings support the use of RVG-exosome-mediated miR-370 inhibition as a noninvasive strategy to improve proteostasis in SCA3 and demonstrate its potential in combination with ATXN3 mRNA-targeting miRNAs, offering a promising therapeutic paradigm for SCA3 and similar neurodegenerative disorders.
2026-01-19 | An acyclic nucleic acid-modified siRNA targeting CAG expansions for polyglutamine disease treatment.
Polyglutamine (polyQ) diseases are inherited neurological disorders caused by an expansion of the cytosine-adenine-guanine (CAG) repeat in the causative genes. These include Huntington's disease, spinal and bulbar muscular atrophy (SBMA), and spinocerebellar ataxias (SCAs). Clinical trials have been conducted using nucleic acid therapeutics to silence the causative gene for these diseases, but none have been approved for use. Furthermore, while oligonucleotides targeting the CAG repeats are an attractive therapeutic option, concomitant silencing of the wild-type allele with normal CAG repeats can result in neuronal dysfunction. In this study, we developed an acyclic serinol nucleic acid (SNA)-modified small interfering RNA (siRNA) targeting CAG repeats. We also evaluated the safety and efficacy of the siRNA in different mouse models of polyQ diseases. Intracerebroventricularly administered siRNA was widely distributed throughout the central nervous system, where it selectively silenced the alleles encoding polyQ proteins without affecting their wild-type counterparts. Consequently, the intranuclear aggregation of polyQ proteins was reduced in mouse models of SBMA and SCA type 3. The siRNA attenuated neuromuscular degeneration and improved the lifespan and motor function of the SBMA mice. These findings suggest that SNA-modified siRNAs targeting CAG repeats represent a promising approach for treating polyQ diseases.
2025-10-13 | Extracellular vesicles-associated AAVs for the treatment of Machado-Joseph disease.
Machado-Joseph disease (MJD) is the most common dominant autosomal inherited ataxia worldwide, caused by the overrepetition of the trinucleotide CAG in the ATXN3 gene. This leads to the accumulation of mutant ataxin-3 protein and neurodegeneration. Currently, treatment remains symptomatic, although gene therapy has emerged as a promising approach. However, efficient and minimally invasive gene delivery to the brain remains a challenge. Extracellular vesicle-associated adeno-associated virus (EV-AAV) vectors are a novel delivery system, combining the ability of AAV vectors to deliver genes with the capacity of extracellular vesicles to bypass the immune system and cross the blood-brain barrier (BBB). Previous studies, however, have only combined AAV serotypes known to efficiently cross the BBB with EVs as a non-invasive delivery system to the brain. Thus, the ability of EV-AAVs to cross the BBB remained inconclusive. In this study, we evaluated whether AAV1/2 serotype, combined with rabies virus glycoprotein (RVg)-coated EVs, could effectively target the brain. Two isolation methods, differential ultracentrifugation and size-exclusion chromatography (SEC) were compared, with SEC yielding higher EV recovery. Moreover, RVg-EV-AAV1/2 successfully crossed the BBB and transduced mouse brains, leading to motor and neuropathologic improvements in an MJD mouse model. This study demonstrates that RVg-EV-AAVs are promising non-invasive delivery systems for MJD gene therapy.
small molecules
2026-09-18 | Metabolic Reconfiguration and Serum Neurofilament Light Chain Dynamics in an N-of-1 Proof-of-Concept Study of Spinocerebellar Ataxia Type 3
Objective. In a proof-of-concept N-of-1 study, to assess whether a closed-loop metabolic intervention can modify the redox-metabolic state and serum NfL trajectory in genetically confirmed spinocerebellar ataxia type 3 (SCA3). Methods. A prospective, patient-scientist N-of-1 study over 14 months, in which biomarker feedback governed titration of a four-component metabolic intervention targeting glutathione disulfide recycling. Serum NfL was measured monthly in a single analytical batch. Intracellular reactive oxygen species (ROS) were profiled by flow cytometry, and oxidative damage by 8-hydroxy-2'-deoxyguanosine (8-OHdG) and malondialdehyde (MDA). Symptomatic medication was withdrawn completely, and tandem gait was recorded at each visit. Results. The bimodal ROS distribution resolved into a single narrow peak and did not revert under a subsequent niacin challenge. 8-OHdG fell by 67% (2.94 to 0.98 ng/mL) and MDA from 12.7 to 1.9–3.6 μmol/L. Serum NfL declined by 13.6 pg/mL, from a transient peak of 37.34 to 23.74 pg/mL, below the initial baseline but within the 95% prediction interval of the pre-transition series. The redox change preceded the oxidative-damage change. After complete withdrawal of baclofen and taltirelin, redox indices and functional status remained stable. No serious adverse event occurred. Interpretation. Coordinated changes in redox indices, oxidative-damage markers and serum NfL occurred while the genetic lesion remained constant. The partial ordering is consistent with, but does not establish, a cascade from metabolic reconfiguration through reduced oxidative injury to altered neuroaxonal dynamics. This N-of-1 proof-of-concept cannot exclude fluctuation, regression to the mean, or non-specific effects of a multi-component intervention; reproducibility remains untested.
2026-09-18 | PolyQ-expanded ataxin-3 is associated with mitochondrial alterations in Machado-Joseph disease.
Spinocerebellar ataxia type 3, also known as Machado-Joseph disease (MJD), is a fatal neurodegenerative disease caused by an expanded CAG repeat in ataxin-3 (ATXN3). Here, we investigated mitochondrial alterations across complementary MJD models, including transgenic zebrafish, CMVMJD135 mice and primary neuronal cultures. Proteomic profiling of brain lysates from male and female wild-type and CMVMJD135 mice identified mitochondrial alterations and altered oxidative phosphorylation-associated protein abundance as major shared features in both male and female MJD mice. Primary neuron cultures derived from CMVMJD135 mice were examined, validating the proteomic findings and revealing alterations in mitochondrial morphology. We further examined a transgenic zebrafish model of MJD that expresses EGFP-fused human ataxin-3 containing 84 glutamines in neurons (driven by the pan-neuronal elavl3/HuC promoter). The MJD zebrafish model also exhibited altered levels of mitochondrial electron transport chain complex proteins and enhanced sensitivity to rotenone. Notably, complex II-associated alterations featured across most assays, supporting complex II-linked dysregulation as a convergent, potentially targetable component of MJD. These phenotypes provide a robust platform for evaluating potential mitochondrial-targeted therapies and support growing evidence that disrupted mitochondrial homeostasis contributes to MJD pathogenesis.
2026-09-15 | Efficacy and Safety of DL-3-n-Butylphthalide in Spinocerebellar Ataxia Type 3.
Preclinical studies have suggested that DL-3-n-butylphthalide (NBP) may exhibit neuroprotective effects in neurodegenerative diseases; however, no human trial has evaluated NBP in spinocerebellar ataxia type 3 (SCA3). The aim of the study was to evaluate the efficacy and safety of oral NBP in patients with SCA3 over 12 months. Patients were randomly assigned (1:1) to oral NBP (200 mg thrice daily) or placebo for 12 months. The primary outcomes were 12-month changes in the Scale for Assessment and Rating of Ataxia (SARA) and Spinocerebellar Ataxia Functional Index (SCAFI). Safety outcomes included adverse events (AEs) and serious adverse events (SAEs). The modified intention-to-treat (mITT) population included 116 patients (NBP, n = 56; placebo, n = 60). The primary endpoints, change in SARA and SCAFI, were significantly different between NBP and placebo groups (SARA, estimated marginal mean difference: -0.86, 95% confidence interval [CI]: -1.56 to -0.16, P = 0.02; SCAFI, estimated marginal mean difference: 0.16, 95% CI: 0.01-0.31, P = 0.03) in mITT population using a mixed-effect model, with improved clinical outcome in the NBP group. Overall, AE rates were not significantly different between groups (13 AEs [23.2%] in NBP vs. 9 AEs [15%] in placebo, P = 0.26), although drug-related AEs were numerically more frequent with NBP (12 [21.4%] vs. 6 [10.0%], P = 0.09); no SAE occurred in either group. Oral administration of NBP was safe and generally well tolerated. Significant differences in clinical outcomes were observed in the treatment group compared to the placebo. NBP administration showed preliminary evidence of clinical benefit in SCA3. © 2026 International Parkinson and Movement Disorder Society.
2026-09-03 | First-Person Physiology Reveals a Tunable Redox State Transition that Reverses the Neuroaxonal Injury Trajectory in SCA3
Spinocerebellar ataxia type 3 (SCA3) is a fatal monogenic neurodegenerative disease with no disease-modifying therapies. This impasse reflects a paradigm mismatch: static clinical trial designs are poorly suited to dynamic, system-level pathophysiology—a limitation especially consequential during the biomarker stage, when neurofilament light chain (NfL) is already elevated yet MRI volumes remain preserved, beginning on average 21.5 years before clinical onset (Berger et al., 2025). Here, in a first-person N-of-1 investigation, we applied a closed-loop metabolic intervention coupling redox stabilization, mitochondrial flux support, methylation control, and proteostasis clearance to test whether this interception window could be experimentally engaged. By resolving a kinetic bottleneck in glutathione recycling through real-time biomarker-guided titration, we observed a quantifiable transition in intracellular reactive oxygen species from a pathological bimodal to a physiological unimodal distribution. This upstream redox reconfiguration was temporally coupled to reversal of the serum NfL trajectory: following a transient peak at 37.34 pg/mL, NfL declined to 23.74 pg/mL (overall slope −2.27 pg/mL/month, R² = 0.807), falling below the initial baseline despite one intervening measurement that rose. This directional reversal is discordant with the natural-history pattern in 291 SCA3 mutation carriers, in whom NfL "slowly increased and stayed at elevated levels throughout the disease course" (Berger et al., 2025). This trajectory reversal persisted over fourteen months despite withdrawal of all symptomatic medications. These findings support the interpretation that, in this individual, neuroaxonal injury became partially constrained by a modifiable metabolic state despite persistence of the causal mutation—suggesting that clinical phenotype in monogenic neurodegeneration may reflect not genotype alone, but the dynamic resilience of the metabolic system through which it is expressed.
2026-08-10 | Ficd loss rescues motor impairments and reverses oligodendrocyte maturation deficits in a mouse model of spinocerebellar ataxia type 3
Abstract Spinocerebellar ataxia type 3 (SCA3) is an inherited, fatal neurodegenerative disease caused by a pathological CAG repeat expansion in the ATXN3 gene, resulting in the selective degeneration of vulnerable neuronal populations. Recent work has identified impairments in oligodendrocyte maturation as a novel and robust feature of SCA3 pathogenesis. Oligodendrocytes synthesize myelin structural components through the endoplasmic reticulum (ER), rendering this organelle essential for white matter integrity. Despite this, the role of ER function in SCA3 remains unclear. In this study, we show that loss of FICD-mediated AMPylation, a post-translational modification regulating the ER-resident HSP70 chaperone, BiP, rescues motor impairments in a transgenic SCA3 mouse model. Ficd -/- SCA3 mice exhibit significantly reduced levels of nuclear ATXN3 in vulnerable brain regions, while Ficd +/+ littermates show an increased burden of AMPylated BiP in the spinal cord, identifying aberrant AMPylation as a novel contributor of SCA3 pathology. Using unbiased proteomics, we demonstrate that Ficd deletion mitigates the pathological decrease in myelin structural proteins and oligodendrocyte maturation factors, restoring levels of mature, myelinating oligodendrocytes. In parallel, we show that Ficd activates SREBP2-dependent cholesterol biosynthesis to support myelination. Taken as a whole, these findings posit ER homeostasis as a critical driver of oligodendrocyte pathology and identify FICD as a novel target for alleviating non-neuronal toxicity in SCA3.
other
2026-08-20 | Supplemental Material for: First, Allogeneic, Adipose-Derived, Mesenchymal Stem Cell Treatment of a Patient with Spinocerebellar Ataxia Type 3 in the United States: Case Report
Introduction: No disease-modifying therapies are approved to treat spinocerebellar ataxia (SCA), rare neurogenerative diseases that lead to progressive uncoordinated gait and dysphagia. Allogeneic, adipose-derived, mesenchymal stem cells cultured and expanded with a proprietary process (pADMSCs; Stemchymal, Steminent Biotherapeutics, Taipei, Taiwan) have shown promising inhibition of disease progression in placebo-controlled, phase 2 studies in Japan (n=59) and Taiwan (n=56).Case Presentation: Here, the first use of allogeneic, pADMSCs for treating a US patient with SCA3 according to a phase 2, investigational drug application with the US Food and Drug Administration is reported. An Asian woman (age 58 yrs) had SCA 3 symptoms for 10 years, with central vestibular dizziness and double vision that progressed to unstable standing/walking and painful neck/upper back dystonia. Several medications failed for dizziness/disequilibrium/diplopia; onabotulinumtoxinA provided partial upper back/shoulder pain relief. Several other lifestyle, pharmacologic, and physical therapies were not effective. Since May 2018, she had been taking compassionate troriluzole (200 mg/day [stable dose]). Starting in May 2021, she received 3 monthly intravenous infusions of pADMSCs (7 x 107 cells/dose). Her Scale for the Assessment and Rating of Ataxia (SARA) score was moderately high (7.5) at baseline. By the third pADMSC infusion, it dropped to 3.5, was 4.5 at 3 months after the last infusion, remained at 4.5 until ~12 months after the last infusion, and began to rise again after 1 yr from the final infusion. Her central vestibular dizziness and neck dystonia did not improve during treatment. pADMSC post-infusion side effects included hot flushes, low fever, and mild queasiness; increased tightness and pressure in the neck and upper back; retro-orbital headache; and mildly elevated pulse and blood pressure. All resolved by the day following infusion.Conclusion: This United States, phase 2, expanded-access, single-patient case study of pADMSCs in a woman with SCA taking troriluzole suggests that these allogeneic pADMSCs may be the first use of cell therapy to potentially inhibit SCA3 disease progression.
2026-07-02 | Adipose-Derived Mesenchymal Stem Cells Improve Motor Function and Reduce Neuroinflammation and Mutant Ataxin-3 Protein Levels in SCA3 Mice.
The CAG expansion in the ataxin-3 (ATXN3) protein is the underlying cause of Spinocerebellar Ataxia Type 3 (SCA3), a polyglutamine disease. The aggregation of mutant ATXN3 protein is hypothesized to contribute to neuronal dysfunction, neurodegeneration, or neuroinflammation. Mesenchymal stem cells have pleiotropic therapeutic properties, and adipose-derived mesenchymal stem cells (ADMSC) have been shown to be safe and well-tolerated in SCA3 patients. In this study, we evaluated the therapeutic effects of ADMSC in SCA3 mice. In a mouse model of SCA3, the Purkinje-cell-specific L7 promoter drives the expression of a truncated form of human ataxin-3 with 69 glutamine repeats. SCA3 mice exhibited cerebellar Purkinje cell degeneration, reduced myelination, and increased gliosis; pathological features also observed in SCA3 patients. SCA3 mice received repeated intravenous administrations of ADMSC, and efficacy was assessed by rotarod performance, molecular and pathological changes, and serum neurofilament light chain (NfL) levels. ADMSC-treated SCA3 mice showed significant improvements in rotarod performance, a reduction in accumulated toxic mutant ATXN3-69Q protein in Purkinje cells, decreased demyelination, and alleviation of neuroinflammatory and systemic inflammatory responses during disease progression. Furthermore, NfL levels, a potential biomarker for SCA3 disease progression, were inversely correlated with the rotarod performance. Based on these findings, we conclude that ADMSC enhance motor function in SCA3 mice by reducing neuroinflammation, demyelination and aggregated mutant ataxin-3 protein levels in Purkinje cells. ADMSC have the potential to serve as a disease-modifying therapy for SCA3 patients.
2026-02-03 | Mesenchymal Stromal Cell Therapeutic Potential to Restore Neurovascular Integrity in Machado-Joseph Disease
Abstract Background Machado-Joseph disease (MJD), or Spinocerebellar Ataxia type 3 (SCA3), is a neurodegenerative disorder caused by an expansion of the CAG repeat in the MJD1/ATXN3 gene, which encodes for a polyglutamine-expansion in Ataxin-3. Similar to what occurs in other neurodegenerative disorders, the cerebrovascular system, particularly the blood-brain barrier (BBB), is impaired in MJD. BBB is an important cellular barrier that controls homeostasis of the central nervous system, and its disruption compromises neuronal function. To date, there is no disease-modifying therapy for MJD. Our group previously demonstrated that MSC administration can ameliorate the phenotype of MJD transgenic mice. However, the effect of MSC on the neurovascular unit and BBB integrity remains unexplored in the context of MJD. In the present work, we aimed to evaluate the therapeutic potential of MSC in mitigating vascular abnormalities and BBB disruption in MJD. Methods Eight-month-old MJD transgenic mice were treated with two consecutive bone marrow-MSC intravenous injections (1 week apart). Behavioral tests to assess motor coordination were conducted before and after treatment. Vascular structure, function, and BBB disruption were evaluated by immunohistochemistry and western blot. Results MSC administration partially restored vascular impairment in MJD transgenic mice. Treated mice exhibited improved gait and motor performance footprint and beam walking tests) and concurrently attenuated vascular dysfunction. Specifically, MSC-treated mice exhibited a decrease in collagen IV surface area and stabilized cerebellar blood supply. Additionally, MSC treatment diminished BBB permeability to the Evans blue (EB) dye in MJD mice and restored the levels of important adherent and tight junction-associated proteins in the cellular membrane, including vascular endothelial cadherin (VE-cadherin), claudin-5, and occludin, in a sex-specific manner. Conclusions our results highlight significant cerebrovascular dysregulations in MJD, which are sex-dependent and progress with the disease stage. Moreover, our findings suggest that MSC administration partially reverted vascular impairments, providing valuable insights into the mechanisms underlying the therapeutic potential of MSC in MJD. Graphical Abstract MSC treatment partially reverts neurovascular dysregulation in MJD. MJD mice exhibit increased vessel coverage, increased BBB permeability, and altered TJ and AJ expression and subcellular localization. MSC administration modulates vessel coverage, reduces BBB leakage, and partially normalizes TJ/AJ subcellular localization. List of abbreviations: AJ – Adherent junction; BBB – Blood-Brain barrier; MJD- Machado-Joseph disease; MSC – mesenchymal stromal cell; TJ – thigh junction. Created with BioRender.com
2024-02-28 | Effectiveness of High-Frequency Repetitive Transcranial Magnetic Stimulation in Patients With Spinocerebellar Ataxia Type 3.
To investigate the effectiveness of high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) on improvement of clinical symptoms in patients with spinocerebellar ataxia type 3 (SCA3). Sixteen SCA3 participants diagnosed by genetic testing were enrolled in this sham-controlled and double-blind trial. They received either a 2-week 10-Hz rTMS intervention or sham stimulation targeting the vermis and cerebellum. The Scale for Assessment and Rating of Ataxia and the International Cooperative Ataxia Rating Scale were completed at baseline and poststimulation. Compared with baseline, the HF-rTMS group demonstrated a significant improvement in the total Scale for Assessment and Rating of Ataxia ( P < 0.0001) and the International Cooperative Ataxia Rating Scale scores ( P = 0.002). After 2-week treatment, the real group exhibited decreasing pattern in 3 subgroups, especially for limb kinetic function ( P < 0.0001). Short-term HF-rTMS treatment is a potentially promising and feasible tool for rehabilitation in patients with SCA3. Studies with long-term follow-up need to be carried out in the future and further need to assess gait, limb kinetic function, speech and oculomotor disorders.
2024-02-14 | Graft-derived neurons and bystander effects are maintained for six months after human iPSC-derived NESC transplantation in mice's cerebella.
Machado-Joseph disease (MJD) is a neurodegenerative disorder characterized by widespread neuronal death affecting the cerebellum. Cell therapy can trigger neuronal replacement and neuroprotection through bystander effects providing a therapeutic option for neurodegenerative diseases. Here, human control (CNT) and MJD iPSC-derived neuroepithelial stem cells (NESC) were established and tested for their therapeutic potential. Cells' neuroectodermal phenotype was demonstrated. Brain organoids obtained from the Control NESC showed higher mRNA levels of genes related to stem cells' bystander effects, such as BDNF, NEUROD1, and NOTCH1, as compared with organoids produced from MJD NESC, suggesting that Control NESC have a higher therapeutic potential. Graft-derived glia and neurons, such as cells positive for markers of cerebellar neurons, were detected six months after NESC transplantation in mice cerebella. The graft-derived neurons established excitatory and inhibitory synapses in the host cerebella, although CNT neurons exhibited higher excitatory synapse numbers compared with MJD neurons. Cell grafts, mainly CNT NESC, sustained the bystander effects through modulation of inflammatory interleukins (IL1B and IL10), neurotrophic factors (NGF), and neurogenesis-related proteins (Msi1 and NeuroD1), for six months in the mice cerebella. Altogether this study demonstrates the long-lasting therapeutic potential of human iPSC-derived NESC in the cerebellum.
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Drug Discovery Landscape
1 orphan drug designation for Spinocerebellar ataxia type 3.
1 orphan drug designation for Spinocerebellar ataxia type 3.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
trehalose | small molecules | FDA | Seelos Therapeutics, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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