RARE DISEASE
Spinocerebellar ataxia type 7
Spinocerebellar ataxia type 7
Spinocerebellar ataxia type 7
Synonyms: Ataxia with pigmentary retinopathy, Cerebellar syndrome-pigmentary maculopathy syndrome, SCA7
Synonyms: Ataxia with pigmentary retinopathy, Cerebellar syndrome-pigmentary maculopathy syndrome, SCA7
Synonyms: Ataxia with pigmentary retinopathy, Cerebellar syndrome-pigmentary maculopathy syndrome, SCA7
Drug discovery
1
drug
With orphan designation
Overview
Spinocerebellar ataxia type 7 (SCA7) is a rare autosomal dominant neurodegenerative disorder caused by CAG trinucleotide repeat expansions in the ATXN7 gene. It manifests with progressive cerebellar ataxia, dysarthria, dysphagia, and cone-rod retinal dystrophy leading to vision loss [1][6][15]. Onset ranges from infancy to late adulthood, with earlier presentations linked to larger repeat expansions and accelerated disease progression [6][9][15]. Neurodegeneration primarily affects the cerebellum, brainstem, and retina [3][13].
Population
Global prevalence <1/100,000, accounting for 2-4% of SCAs (up to 7% in some Asian populations) [15][16].
Founder effects increase prevalence in Veracruz, Mexico (~1/125), Scandinavia, and South Africa [6][11][16].
Anticipation occurs in parent-child transmission, particularly with paternal inheritance [2][11].
Burden
Progressive motor disability leads to wheelchair dependence within 10-15 years of symptom onset [5][11].
Early-onset cases (<20 years) show rapid progression (blindness within 5 years) and reduced life expectancy [6][11].
High caregiver burden due to combined visual/physical disability and psychiatric comorbidities (psychosis, cognitive decline) [6][15][19].
Therapies
Supportive care: Physical/occupational therapy, assistive devices, and retinal degeneration management [5][15].
Experimental approaches: Gene-silencing strategies (ASOs, RNAi) targeting mutant ATXN7 mRNA in preclinical models [8][17].
Emerging therapies: Interferon-beta reduced mutant ataxin-7 aggregates and improved motor function in murine models [3][13].
Categories: rare genetic diseases, rare neurological diseases, rare ophthalmic disorders
Research Papers
309 drug discovery papers about Spinocerebellar ataxia type 7, with 4 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
309 drug discovery papers about Spinocerebellar ataxia type 7, with 4 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-10 | Immune Activation and Glial Dysfunction in Spinocerebellar Ataxias: From Cerebellar Landscape to Disease-Driven Mechanisms and Immunomodulation.
Spinocerebellar ataxias (SCAs) comprise a clinically and genetically heterogeneous group of autosomal dominant neurodegenerative disorders. Despite the recognized role of specialized cerebellar glia in cerebellar development and dysfunction, immune activation and non-immune glial responses remain understudied in SCAs. This narrative review compiles evidence from cellular, animal, and human models on the cerebellar immune landscape and the specific pathways that drive homeostatic failure and neuroinflammatory cascades across SCA subtypes. Microgliosis emerges consistently-and often early- as a generalized feature across the SCA spectrum, preceding neurodegeneration in several subtypes. Concurrently, reactive astrogliosis extends broadly, reflecting widespread macroglial surveillance and metabolic stress regulation throughout histologically preserved gray matter, with specialized homeostatic failure of Bergmann glia in SCA1, SCA2, and SCA7. Peripheral inflammation, manifests as early as the prodromal stage and correlates with the cognitive-affective deficits in SCA2 and associates with the mutation size in SCA3, positioning it as integral to pathogenesis rather than epiphenomenal. Diverse, partially shared signaling pathways converge on multi-lineage glial breakdown and reciprocal neuroimmune crosstalk. These mechanisms involve NF-κB (SCA1,3,17), cGAS-STING (SCA2), TLR/MyD88 (SCA6), and JNK/c-Jun (SCA1,2,7). This review establishes abnormal reciprocal immune/non-immune glia crosstalk as a core pathogenic principle across SCAs, revealing novel therapeutic opportunities. In fact, targeting convergent signaling nodes such as NF-κB, or JNK pathways, holds disease-modifying potential across multiple subtypes. Future research should prioritize standardized comparative studies, longitudinal analyses linking both inflammation and non-immune glial pathology to clinical progression, and clinical trials evaluating targeted immunomodulatory and glial homeostatic-supportive agents.
2026-05-28 | Aromatic-Turmerone Analogs Activate Chaperone-Mediated Autophagy and Ameliorate Dendritic Shrinkage in Purkinje Cell Models of Spinocerebellar Ataxia.
We recently demonstrated that aromatic (ar)-turmerone analogs ((E)-5-methyl-1-(p-tolyl)hexa-1,4-dien-3-one [A2] and (E)-1-(4-methoxyphenyl)-5-methylhexa-1,4-dien-3-one [A4]) activate chaperone-mediated autophagy (CMA), a pathway in the autophagy-lysosome protein degradation system, in SH-SY5Y cells. Our previous studies revealed that the impairment of CMA and microautophagy (mA), another autophagy-related pathway, and dendritic shrinkage were observed in primary cultured Purkinje cells (PCs) expressing causal proteins of spinocerebellar ataxia (SCA), an autosomal dominant neurodegenerative disease. In the present study, we first investigated the effects of A2 and A4 on lysosomal protein degradation and dendritic morphology in cerebellar primary cultured PCs. Both compounds enhanced dendritic development and activated CMA in cultured PCs. These effects were significantly suppressed by the inhibitors of nuclear factor erythroid 2-related factor 2 and p38. We next examined the effects of A2 and A4 on PCs expressing several types of SCA-causing proteins (SCA model PCs). Both chemicals ameliorated the dendritic shrinkage and restored the decreased CMA/mA activity in several SCA model PCs. These findings suggest that the ar-turmerone analogs A2 and A4 improve the in vitro phenotype of SCA model PCs through CMA activation, highlighting the therapeutic potential of these analogs for various types of SCAs.
2026-02-22 | Long-term efficacy and disease-specific responsiveness to protirelin in patients with spinocerebellar degeneration: A retrospective study.
The thyrotropin-releasing hormone (TRH) analog protirelin has short-term benefits for cerebellar ataxia (CA), but its long-term efficacy and the subtype-specific responsiveness of spinocerebellar degeneration (SCD) patients remain unclear. We retrospectively reviewed the records of 92 SCD patients (273 courses) treated with protirelin between July 2011 and October 2025, including patients with idiopathic CA (IDCA), multiple system atrophy with predominant CA (MSA-C) or parkinsonism (MSA-P), and genetic subtypes including spinocerebellar ataxia (SCA) type 6, SCA31 and dentatorubral-pallidoluysian atrophy (DRPLA). Responders were defined as showing ≥1-point improvement on the Scale for the Assessment and Rating of Ataxia (SARA). Protirelin was effective in 64.1% of subjects, with significant improvement overall (p < 0.001) and significant SARA gains in MSA-C (p = 0.047), IDCA (p = 0.02), and SCA31 (p = 0.01). Change in SARA score (ΔSARA) correlated negatively with age and positively with total protirelin dose in IDCA, and negatively with age and disease duration and positively with baseline SARA score in SCA31. Several IDCA and DRPLA patients maintained clinical benefit for more than 10 years. All MSA-P discontinued protirelin within 2 years and all MSA-C within 5 years; some SCA6, and SCA31 patients continued for ≥5 years. Adverse effects were infrequent (2/92, 2.2%). Protirelin is efficacious in SCD patients and well-tolerated, particularly in slow-progressing phenotypes (IDCA and SCA31); its benefit in rapidly progressing ataxias (MSA-C) may be confined to early disease stages. Prospective studies with standardized dosing and long-term follow-up are warranted to establish evidence-based protocols for TRH-related therapy for CA.
2026-01-14 | Cardiorenal and hepatic dysfunctions underlie metabolic alterations in the spinocerebellar ataxia type 7 mice
Abstract Spinocerebellar ataxia type 7 (SCA7) is a polyglutamine expansion disorder characterized by progressive cerebellar and retinal degeneration leading to ataxia and blindness. While mutant ATXN7 is ubiquitously expressed, most studies have focused on neurological symptoms, and peripheral contributions to pathology remain poorly understood. Here, we investigated systemic abnormalities in SCA7 140Q/5Q knock-in mice, a model of early-onset disease. Using longitudinal metabolic profiling, ultrasound imaging, and histopathology, we identified early and progressive dysfunction of the kidney, liver, and heart. Renal impairment was marked by uremia, polyuria with abnormal calcium and glucose excretion, tubular epithelial cell loss, and podocyte dedifferentiation, including the reappearance of primary cilia and pedicel effacement. Hepatic alterations included dysregulated lipid metabolism, elevated bilirubin, and reduced iron levels, contributing to anemia. Cardiac dysfunction manifested as reduced stroke volume as early as 11 weeks, suggesting a cardiorenal syndrome. Together, these organ-specific changes resulted in systemic metabolic disturbances such as dyslipidemia, iron deficiency anemia, thrombocytosis, and chronic inflammation, detectable before the onset of motor incoordination. Our findings demonstrate that peripheral organ dysfunction is an early and integral feature of SCA7 pathogenesis, with renal and cardiac impairments emerging prior to neurological decline. These results highlight the value of systemic biomarkers for disease monitoring and suggest that targeting peripheral pathology may provide therapeutic benefit. More broadly, they underscore the need to view SCA7 not solely as a neurodegenerative disorder but as a multi-organ disease.
2025-12-24 | Valosin-Containing Protein as a therapeutic target in CAG repeat-driven Spinocerebellar ataxias: Integrative transcriptomic and computational insights.
Spinocerebellar ataxias (SCAs) are progressive neurodegenerative disorders caused by abnormal CAG repeat expansions in genes such as ATXN1, ATXN2, and ATXN3, with no effective therapeutic options currently available. To identify key molecular drivers of disease pathology, transcriptomic datasets GSE75249 and GSE151276 were analyzed. Differentially expressed genes were determined, and overlapping upregulated genes from both datasets were extracted for downstream analysis. Functional enrichment revealed significant biological processes and pathways related to protein homeostasis, cellular stress response, and neurodegeneration. Protein-protein interaction networks were constructed to investigate gene connectivity, and hub gene analysis identified Valosin-Containing Protein (VCP) as the top-ranked common hub gene. Importantly, VCP expression was experimentally validated in plasma samples from SCA1, SCA2, and SCA3 patients using ELISA, confirming its dysregulation and central role in SCA pathogenesis. To explore therapeutic potential, pharmacophore-based virtual screening of natural compounds was conducted, followed by molecular docking to evaluate interactions with VCP. Among the shortlisted candidates, sesamolin demonstrated the strongest binding affinity and favorable pharmacological properties. A 250 ns molecular dynamics simulation further confirmed the stability of the VCP-sesamolin complex, revealing sustained interactions, reduced fluctuations, and conformational stabilization of VCP. Collectively, this integrative approach combining transcriptomic profiling, enrichment analysis, hub gene identification, experimental validation, and structure-based drug discovery highlights VCP as a crucial regulator in CAG repeat-associated SCAs and proposes sesamolin as a promising neuroprotective lead compound for further preclinical development.
gene therapies
2026-09-09 | MicroRNAs in polyglutamine diseases: Mechanistic insights, circulating biomarkers, and emerging microRNA-based therapeutic strategies.
MicroRNAs (miRNAs) have emerged as critical regulators in the pathogenesis of polyglutamine (PolyQ) diseases-a group of fatal neurodegenerative disorders caused by CAG repeat expansions, such as Huntington's disease, spinocerebellar ataxias, dentatorubral-pallidoluysian atrophy, and spinal and bulbar muscular atrophy. This review synthesizes recent advances in miRNA dysregulation across all nine PolyQ diseases, focusing on studies published since 2019. We examine how specific miRNAs modulate core pathogenic cascades-including mutant protein aggregation, transcriptional dysregulation, mitochondrial dysfunction, and apoptosis-and then link these molecular events to disease-relevant motor, cognitive, and psychiatric phenotypes. The review highlights therapeutic progress, including the preclinical efficacy of adeno-associated virus (AAV)-delivered artificial miRNAs and emerging exosome-based platforms that target mutant transcripts such as HTT, ATXN1, ATXN3, and ATXN7. AAV5-miHTT has advanced to a first-in-human trial for Huntington's disease (NCT04120493)-a key milestone in clinical translation. Circulating miRNAs in plasma and cerebrospinal fluid show diagnostic potential as minimally invasive, stage-specific biomarkers, but challenges persist in normalization, cross-biofluid concordance, and clinical validation. Despite substantial progress, translational barriers remain-including off-target effects, delivery optimization, immunogenicity, and patient heterogeneity. Overcoming these barriers will require integrative approaches that combine single-cell transcriptomics, engineered delivery systems, machine learning, and longitudinally phenotyped clinical cohorts. This review integrates mechanistic insights, biomarker discovery, and therapeutic development to move miRNA-based strategies toward disease-modifying interventions for PolyQ disorders.
2026-04-30 | Management of spinocerebellar ataxia.
Spinocerebellar ataxias (SCAs) are a group of neurodegenerative diseases characterized by progressive cerebellar dysfunction, which leads to impaired coordination, dysarthria, oculomotor disorders, and subsequently to a marked reduction in quality of life and high disability. In addition to the main motor symptoms, patients often suffer from cerebellar cognitive-affective syndrome, depression, and sleep disturbances. Despite advances in understanding the molecular and genetic underpinnings of SCAs, there are currently no disease-modifying therapies approved by the FDA (U.S. Food and Drug Administration) or EMA (European Medicines Agency), and management remains largely symptomatic, focusing on improving quality of life and functional independence. Recent systematic reviews and clinical guidelines emphasize a combination of pharmacological, non-pharmacological, and novel gene and cell therapies that are currently under investigation, with varying levels of evidence for their efficacy. The transition to precision medicine and early intervention at the pre-ataxic stage are essential for effectively combating neurodegeneration. This review summarizes the latest data on the treatment of SCA, including existing and new treatments, their effectiveness, limitations, and future prospects.
2026-04-24 | Developmental roots of cerebellar degeneration in spinocerebellar ataxia.
Late-onset neurodegenerative diseases have long been conceptualized as disorders arising from cumulative cellular stress and age-related decline, with pathology emerging at the time of symptom onset. However, emerging evidence challenges this view, suggesting that developmental perturbations may establish early vulnerabilities that predispose specific neuronal populations to degeneration later in life. In the cerebellum, mutations causing spinocerebellar ataxias (SCAs) such as SCA1 and SCA6 affect genes involved in normal circuit formation, resulting in subtle early abnormalities in Purkinje cell activity and connectivity. These alterations seem to be initially buffered by compensatory mechanisms, and the eventual breakdown of homeostatic resilience during midlife may thus be the trigger for disease onset and progression. This developmental perspective reframes late-onset neurodegeneration as a lifelong process shaped by the interplay between early developmental wiring, adaptive compensation, and age-dependent vulnerability. Understanding these early developmental alterations provides critical insight into disease mechanisms and opens new avenues for pre-symptomatic intervention and prevention.
2025-11-22 | Development of a Gene Therapy with Lentiviral Vectors for Spinocerebellar Ataxias.
Among viral vectors, lentiviral vectors allow an efficient delivery of nucleic acid to the target cells due to its ability of gene integration into host genome and broad tropism. In this sense, this tool demonstrated to be very promising in genetic disorders, such as polyglutamine spinocerebellar ataxias. Therefore, we describe a protocol that explains in detail the production, purification, and injection of lentiviral vectors in a spinocerebellar ataxia mouse model.
2025-10-07 | Challenges in Polyglutamine Diseases: From Dysfunctional Neuronal Circuitries to Neuron-Specific CAG Repeat Instability
Several genetic diseases affecting the human nervous system are incurable and insufficiently understood. Among them, nine rare diseases form the polyglutamine (polyQ) family: Huntington’s disease (HD), spinocerebellar ataxia types 1, 2, 3, 6, 7, and 17, dentatorubral pallidoluysian atrophy, and spinal and bulbar muscular atrophy. In most patients, these diseases progress over decades to cause severe movement incoordination and neurodegeneration. Although their inherited genes with tandem-repeat elongations and the encoded polyQ-containing proteins have been extensively studied, the neuronal-type-specific pathologies and their long pre-symptomatic latency await further investigations. However, recent advances in detecting the single-nucleus transcriptome, alongside the length of tandem repeats in HD post-mortem brains, have enabled the identification of very high CAG repeat sizes that trigger transcriptional dysregulation and cell death in specific projection neurons. One challenge is to better understand the complexity of movement coordination circuits, including the basal ganglia and cerebellum neurons, which are most vulnerable to the high CAG expansion in each disease. Another challenge is to detect dynamic changes in CAG repeat length and their effects in vulnerable neurons at single-cell resolution. This will offer a platform for identifying pathological events in vulnerable long projection neurons and developing targeted therapies for all tandem-repeat expansions affecting the CNS projection neurons.
proteins
2026-02-19 | The Hsp40 cochaperone DNAJC7 regulates polyglutamine aggregation and exhibits context-dependent effects on polyglycine aggregation.
Protein-encoding nucleotide repeat expansion diseases, including polyglutamine (polyQ) and polyglycine (polyG) diseases, are characterized by the accumulation of aggregation-prone proteins. In the polyQ diseases, including Huntington's disease and several spinocerebellar ataxias, substantial prior evidence supports a pathogenic role for mutant polyQ-expanded protein misfolding and aggregation, with molecular chaperones showing promise in suppressing disease phenotypes in cellular and animal models. The goal of this study is to establish a scalable cell-based model to systematically evaluate genetic modifiers of protein aggregation in both polyQ and polyG diseases. We developed FRET-based reporter systems that model polyQ and polyG aggregation in human cells and used them to perform high-throughput CRISPR interference screens targeting all known molecular chaperones. In the polyQ model, the screen identified multiple Hsp70 chaperones and Hsp40 cochaperones previously implicated in polyQ aggregation and additionally revealed the Hsp40 cochaperone DNAJC7 as a potent and previously unrecognized suppressor of polyQ aggregation. In contrast, in a FRET-based polyG aggregation model of neuronal intranuclear inclusion disease, CRISPR interference screening showed minimal overlap of chaperone modifiers of the polyQ screen. Direct knockdown of DNAJC7 also did not affect polyG aggregation, yet overexpressed DNAJC7 colocalized with both polyQ and polyG aggregates in cells and reduced their aggregation. In addition to establishing new inducible, scalable cellular models for polyQ and polyG aggregation, this work expands the role of DNAJC7 in regulating the folding of disease-associated proteins.
2024-12-27 | Genetic modeling of degenerative diseases and mechanisms of neuronal regeneration in the zebrafish cerebellum.
The cerebellum is a highly conserved brain compartment of vertebrates. Genetic diseases of the human cerebellum often lead to degeneration of the principal neuron, the Purkinje cell, resulting in locomotive deficits and socio-emotional impairments. Due to its relatively simple but highly conserved neuroanatomy and circuitry, these human diseases can be modeled well in vertebrates amenable for genetic manipulation. In the recent years, cerebellar research in zebrafish has contributed to understanding cerebellum development and function, since zebrafish larvae are not only molecularly tractable, but also accessible for high resolution in vivo imaging due to the transparency of the larvae and the ease of access to the zebrafish cerebellar cortex for microscopy approaches. Therefore, zebrafish is increasingly used for genetic modeling of human cerebellar neurodegenerative diseases and in particular of different types of Spinocerebellar Ataxias (SCAs). These models are well suited to address the underlying pathogenic mechanisms by means of in vivo cell biological studies. Furthermore, accompanying circuitry characterizations, physiological studies and behavioral analysis allow for unraveling molecular, structural and functional relationships. Moreover, unlike in mammals, zebrafish possess an astonishing ability to regenerate neuronal populations and their functional circuitry in the central nervous system including the cerebellum. Understanding the cellular and molecular processes of these regenerative processes could well serve to counteract acute and chronic loss of neurons in humans. Based on the high evolutionary conservation of the cerebellum these regeneration studies in zebrafish promise to open therapeutic avenues for counteracting cerebellar neuronal degeneration. The current review aims to provide an overview over currently existing genetic models of human cerebellar neurodegenerative diseases in zebrafish as well as neuroregeneration studies using the zebrafish cerebellum. Due to this solid foundation in cerebellar disease modeling and neuronal regeneration analysis, the zebrafish promises to become a popular model organism for both unraveling pathogenic mechanisms of human cerebellar diseases and providing entry points for therapeutic neuronal regeneration approaches.
2022-08-10 | Rovatirelin ameliorates motor dysfunction in the cytosine arabinoside-induced rat model of spinocerebellar degeneration via acetylcholine and dopamine neurotransmission.
Thyrotropin-releasing hormone (TRH) and the TRH mimetic taltirelin have been used in Japan for the treatment of spinocerebellar degeneration (SCD), a type of progressive ataxia. A TRH mimetic, rovatirelin, ameliorates ataxia symptoms in the rolling mouse Nagoya, a hereditary SCD model. The aim of this study was to verify the effects of oral administration of rovatirelin on a cytosine arabinoside (Ara-C)-induced ataxia rat model, a sporadic SCD model characterized by gait abnormalities and falls because of cerebellar atrophy and investigate the central nervous system mechanism associated with rovatirelin-mediated amelioration of motor dysfunction in these rats. Rovatirelin at ≥3 mg/kg significantly decreased the fall index, which is a primary endpoint of improved motor function calculated by dividing the number of falls by the locomotor activity, in both male and female rats with Ara-C-induced ataxia. Furthermore, rovatirelin caused a significant increase in locomotor activity in a dose-dependent manner. Taltirelin at ≥30 mg/kg ameliorated motor dysfunction in ataxic rats. Moreover, rovatirelin significantly increased acetylcholine (ACh) levels in the medial prefrontal cortex (mPFC) and dopamine (DA) levels in the nucleus accumbens (NAc) at ≥3 mg/kg and significantly increased DA levels in the dorsal striatum at ≥10 mg/kg in normal rats. In conclusion, oral administration of rovatirelin ameliorates motor dysfunction in rats with Ara-C-induced ataxia, owing to its ACh-increasing effects in the mPFC and DA-increasing effects in the dorsal striatum and NAc. Furthermore, the effects of rovatirelin were more potent than those of taltirelin.
2021-11-25 | C-terminus of Hsp70 Interacting Protein (CHIP) and Neurodegeneration: Lessons from the Bench and Bedside.
Neurodegenerative diseases are characterized by the increasing dysfunction and death of neurons, resulting in progressive impairment of a person's mobility and/or cognition. Protein misfolding and aggregation are commonly hypothesized to cause neurotoxicity and, eventually, neuronal degeneration that are associated with these diseases. Emerging experimental evidence, as well as recent findings from human studies, reveal that the C-terminus of Hsp70 Interacting Protein (CHIP), or STIP1 Homology and U-box containing Protein 1 (STUB1), is a quality control protein involved in neurodegeneration. Here, we review evidence that CHIP interacts with and plays a role in regulating proteins implicated in the pathogenesis of Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and polyglutamine diseases, including Huntington's disease and spinocerebellar ataxias. We also review clinical findings identifying mutations in STUB1 as a cause of both autosomal recessive and autosomal dominant forms of cerebellar ataxia. We propose that CHIP modulation may have therapeutic potential for the treatment of multiple neurodegenerative diseases.
2021-05-14 | Differential effects of thyrotropin releasing hormone (TRH) on motor execution and motor adaptation process in patients with spinocerebellar degeneration.
The cerebellum is known to play a crucial role in sensori-motor adaptation, which includes the prism adaptation. TRH has been widely used as a treatment for cerebellar ataxia in Japan, however effects of TRH on cerebellar adaptation process have not been studied. Here, we studied effects of TRH treatment on the prism adaptation task. Eighteen spinocerebellar degeneration (SCD) patients participated in this study. The participants received intravenous injection of 2 mg/day protirelin tartrate once a day for 14 days. In the prism adaptation task, the participants reached to the target on the screen wearing wedge prisms. We compared the Scale for Assessment and Rating of Ataxia (SARA), baseline errors and the aftereffect (AE) of the prism adaptation task between before and after TRH therapy. TRH therapy improved SARA significantly (p = .005). Multiple regression analysis revealed that improvement of SARA score was mainly due to improvement of "Stance" category score. TRH decreased baseline errors of the prism adaptation task (p = .021), while unaffected AEs (p = .252). TRH differentially affected clinical cerebellar ataxia including baseline reaching performance in the prism adaptation task, whereas TRH did not affect the learning process of prism adaptation. Different cerebellar functional aspects may underlie the learning process of sensori-motor adaptation and simple motor execution (clinically evaluated cerebellar ataxia).
oligonucleotides
2026-07-09 | Gene therapy for spinocerebellar ataxias.
Spinocerebellar ataxias (SCAs), rare neurodegenerative disorders characterized by progressive cerebellar degeneration, cause impaired balance and motor dysfunction. Although most cases are inherited, sporadic forms also occur, and effective disease-modifying therapies remain unavailable despite advances in understanding their genetic and molecular mechanisms. This unmet need is particularly significant because many SCAs are monogenic disorders caused by well-characterized mutations, making them promising candidates for gene- and RNA-based therapies. Recent advances in antisense oligonucleotides, RNA interference, vector engineering, and genome editing have increasingly enabled the alignment of therapeutic strategies with specific mutational architectures. Therefore, this review aims to examine how genetic subclassification informs platform selection, summarize recent advances in gene- and RNA-based therapeutics, and outline key translational barriers to clinical implementation in SCAs.
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.
2024-04-15 | AAV-Mediated CAG-Targeting Selectively Reduces Polyglutamine-Expanded Protein and Attenuates Disease Phenotypes in a Spinocerebellar Ataxia Mouse Model
Polyglutamine (polyQ)-encoding CAG repeat expansions represent a common disease-causing mutation responsible for several dominant spinocerebellar ataxias (SCAs). PolyQ-expanded SCA proteins are toxic for cerebellar neurons, with Purkinje cells (PCs) being the most vulnerable. RNA interference (RNAi) reagents targeting transcripts with expanded CAG reduce the level of various mutant SCA proteins in an allele-selective manner in vitro and represent promising universal tools for treating multiple CAG/polyQ SCAs. However, it remains unclear whether the therapeutic targeting of CAG expansion can be achieved in vivo and if it can ameliorate cerebellar functions. Here, using a mouse model of SCA7 expressing a mutant Atxn7 allele with 140 CAGs, we examined the efficacy of short hairpin RNAs (shRNAs) targeting CAG repeats expressed from PHP.eB adeno-associated virus vectors (AAVs), which were introduced into the brain via intravascular injection. We demonstrated that shRNAs carrying various mismatches with the CAG target sequence reduced the level of polyQ-expanded ATXN7 in the cerebellum, albeit with varying degrees of allele selectivity and safety profile. An shRNA named A4 potently reduced the level of polyQ-expanded ATXN7, with no effect on normal ATXN7 levels and no adverse side effects. Furthermore, A4 shRNA treatment improved a range of motor and behavioral parameters 23 weeks after AAV injection and attenuated the disease burden of PCs by preventing the downregulation of several PC-type-specific genes. Our results show the feasibility of the selective targeting of CAG expansion in the cerebellum using a blood–brain barrier-permeable vector to attenuate the disease phenotype in an SCA mouse model. Our study represents a significant advancement in developing CAG-targeting strategies as a potential therapy for SCA7 and possibly other CAG/polyQ SCAs.
2023-11-01 | RNA-sequencing analysis of hereditary ataxia reveals differential transcriptomic signatures across brain regions and disease pathologies
Hereditary ataxias are a heterogeneous group of neurogenetic conditions characterised by incoordination from cerebellar dysfunction. There is currently no treatment, partly due to an incomplete understanding of disease mechanisms. We compared post-mortem paired cerebellar and frontal cortex tissue bulk RNA-sequencing data from 23 ataxia patients and 22 sex-, age-matched controls from two brain banks. Repeat expansion sizes were quantified from DNA (spinocerebellar ataxia (SCA)1, n=3; SCA2, n=3; SCA6, n=3; SCA7, n=2; SCA17, n=1; Friedreich's ataxia, n=4; unknown molecular diagnoses, n=7). We analysed bulk RNA-sequencing data for transcript usage, differential and cell-type-specific expression to transcriptomically profile these diseases. Using this approach, we found: (i) different transcriptional alterations between cerebellar and frontal cortices with unexpected frontal involvement even in 'pure' ataxia syndromes (SCA6); (ii) distinct expression profiles between diseases including molecularly-undiagnosed cases; (iii) downregulation of synaptic and transporter pathways in the ataxia cerebellum and upregulation of immune-associated pathways within the frontal cortex; (iv) neuronal cell-type-specific enrichment in expression including Purkinje cells in downregulated cerebellar genes and upregulation of glial-specific cell types within the frontal cortex of ataxia patients. These findings provide a map of transcriptomic changes in ataxia to further understanding of underlying pathogenesis and have important implications for RNA-targeted therapy development.
2023-09-30 | Widespread alternative splicing dysregulation occurs presymptomatically in CAG expansion spinocerebellar ataxias
Abstract The spinocerebellar ataxias (SCAs) are a group of dominantly inherited neurodegenerative diseases, several of which are caused by CAG expansion mutations (SCAs 1, 2, 3, 6, 7 and 12) and more broadly belong to the large family of over 40 microsatellite expansion diseases. While dysregulation of alternative splicing is a well defined driver of disease pathogenesis across several microsatellite diseases, the contribution of alternative splicing in CAG expansion SCAs is poorly understood. Furthermore, despite extensive studies on differential gene expression, there remains a gap in our understanding of presymptomatic transcriptomic drivers of disease. We sought to address these knowledge gaps through a comprehensive study of 29 publicly available RNA-sequencing datasets. We identified that dysregulation of alternative splicing is widespread across CAG expansion mouse models of SCAs 1, 3 and 7. These changes were detected presymptomatically, persisted throughout disease progression, were repeat length-dependent, and were present in brain regions implicated in SCA pathogenesis including the cerebellum, pons and medulla. Across disease progression, changes in alternative splicing occurred in genes that function in pathways and processes known to be impaired in SCAs, such as ion channels, synaptic signalling, transcriptional regulation and the cytoskeleton. We validated several key alternative splicing events with known functional consequences, including Trpc3 exon 9 and Kcnma1 exon 23b, in the Atxn1154Q/2Q mouse model. Finally, we demonstrated that alternative splicing dysregulation is responsive to therapeutic intervention in CAG expansion SCAs with Atxn1 targeting antisense oligonucleotide rescuing key splicing events. Taken together, these data demonstrate that widespread presymptomatic dysregulation of alternative splicing in CAG expansion SCAs may contribute to disease onset, early neuronal dysfunction and may represent novel biomarkers across this devastating group of neurodegenerative disorders.
other
2026-07-11 | Safety and preliminary efficacy of autologous bone marrow-derived mesenchymal stem cell transplantation in hereditary cerebellar ataxia: phase I/IIa clinical trial.
Hereditary cerebellar ataxias (HCA) encompass a spectrum of pathological conditions affecting the cerebellum. Currently, there is growing interest in the potential role of mesenchymal stem cells (MSCs) as an investigational therapeutic approach for this condition. Hence, the objective of this single-center, open-label, phase I/IIa clinical trial was to assess the safety and exploratory clinical and biomarker changes following a single intrathecal injection of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) in HCA. Ten confirmed patients with HCA entered the study and underwent a single dose of (1 × 106 cells/kg BW) intrathecal transplantation of BM-MSCs at passage 3. During the follow-up, patients were evaluated four times (one month before the intervention (-1), months 1, 3, and 6). Assessments included safety evaluation, Scale for the Assessment and Rating of Ataxia (SARA), GAD 65-antibody, and specific cytokines in the patient's serum and cerebrospinal fluid (CSF) samples. No severe adverse effects were observed following the cell transplantation procedure. A decreasing trend in SARA score was observed, with a statistically significant difference at month 6 compared with baseline. Except for one patient, GAD-65 antibody levels remained within the normal range in all patients. In one patient with markedly elevated baseline GAD-65 titers, serum and CSF GAD-65 levels decreased from 814 IU/mL and 781 IU/mL, respectively, to values within the normal range after 3 months. Significant changes were observed in selected inflammatory biomarkers, including decreased serum IL-6 at month 3, decreased CSF TNF-alpha at months 1 and 3, and increased serum IL-10 during follow-up. CSF IL-6 did not show a significant decrease. The findings support the short-term safety and tolerability of a single intrathecal dose of autologous BM-MSCs in this small HCA cohort. The study provides preliminary signals of possible clinical and biomarker changes; however, efficacy cannot be established due to the uncontrolled design, small sample size, disease heterogeneity, and short follow-up. Larger randomized controlled trials are required to validate these exploratory findings. This clinical trial was registered with the Iranian Registry of Clinical Trials (ID: IRCT20160809029275N3).
2026-04-13 | Cell-Based Therapies for Spinocerebellar Degenerations: A Systematic Review of Human Clinical Evidence.
Spinocerebellar degenerations (SCDs) are progressive hereditary and selected sporadic cerebellar neurodegenerative disorders with limited disease-modifying options. Cell-based therapies particularly, mesenchymal stromal/stem cells (MSCs), neural stem/progenitor cells, olfactory ensheathing cells (OECs), cord blood mononuclear cells (CBMCs), and hematopoietic stem cell transplantation (HSCT) are biologically plausible candidates, but their clinical efficacy and safety remain uncertain. We searched MEDLINE/PubMed, Embase, Scopus, Web of Science, and Cochrane Library from inception to 10 October 2025 (no language restrictions). The OSF-registered protocol prespecified eligibility, outcomes, and design-specific risk-of-bias (RoB) tools, with harmonized overall RoB judgments. We included human interventional or observational reports of cell-based or cell-derived products in hereditary ataxias and selected cerebellar-predominant degenerative syndromes within the OPCA/MSA-C spectrum, and extracted clinical efficacy, safety, and follow-up. Of 603 records screened, 17 reports met the protocol-defined inclusion criteria (15 full texts; 2 abstracts; 2006–2025). Most were small, uncontrolled case series, predominantly from China. Cell types: MSCs (9/17), HSCT in ataxia-telangiectasia (3/17), OECs (3/17), and others (neural stem cells [NSCs], CBMCs; 2/17). Routes were intrathecal and/or intravenous for MSC/CBMC; OEC/NSC were intracerebral/intraspinal; HSCT was delivered intravenously. Primary follow-up was typically 1–6 months. Safety was generally acceptable for MSC/CBMC/OEC with no treatment-related deaths and mostly transient post-procedural symptoms; HSCT exhibited regimen-related toxicities consistent with conditioning intensity. Efficacy signals were modest and often transient: short-term International Cooperative Ataxia Rating Scale (ICARS) improvements were reported across multiple series. Cell-based therapies for SCDs show biological plausibility and generally reassuring short-term safety, but current human evidence, dominated by uncontrolled, high-bias studies does not establish efficacy or durability. Priority should shift to rigorously controlled trials, standardized good manufacturing practice (GMP)-characterized products, blinded centralized ratings, careful control of co-interventions, and objective biomarkers.
2025-09-27 | Roots of Progress: Uncovering Cerebellar Ataxias Using iPSC Models.
The inaccessibility of human cerebellar tissue and the complexity of its development have historically hindered the study of cerebellar ataxias, a genetically diverse group of neurodegenerative disorders. Induced pluripotent stem cell (iPSC) technology offers a powerful solution, enabling the generation of patient-specific cerebellar models that retain individual genetic backgrounds. This review examines recent progress in iPSC-derived cerebellar models and their application in relation to major hereditary ataxias, including Friedreich's ataxia, ataxia-telangiectasia, and spinocerebellar ataxias (SCAs). These models have provided valuable insights into disease mechanisms and supported the development of therapeutic strategies, such as gene therapy and high-throughput drug screening. However, challenges remain, particularly in achieving the full maturation of cerebellar cell types and incorporating microglial interactions. Moreover, emerging evidence suggests that neurodevelopmental alterations may act as early contributors to degeneration. Despite the current limitations, the advancement of patient-derived iPSC cerebellar models holds great promise for uncovering novel disease pathways and for driving precision medicine approaches in cerebellar ataxia research.
2025-06-01 | Accurate Quantification of Mutant and Wild-Type polyQ Proteins Using Simple Western Capillary Immunoassays.
Polyglutamine (polyQ) diseases are monogenic fatal neurodegenerative disorders caused by a CAG repeat expansion that is translated into a toxic polyQ tract. There are nine polyQ diseases: Huntington's disease (HD), spinocerebellar ataxias 1, 2, 3, 6, 7 and 17 (SCA1, 2, 3, 6, 7, 17), dentatorubral-pallidoluysian atrophy (DRPLA) and spinal and bulbar muscular atrophy (SBMA). Although no disease-modifying therapies are available, lowering levels of the causative mutant polyQ protein is a promising potential treatment. Preclinically, the efficacy of polyQ protein-lowering compounds is often assessed using time-consuming Western blots (WB), which can produce variable results. Therefore, to improve throughput and accuracy of polyQ protein level quantification, Simple Western (SW) capillary immunoassays were developed. A panel of antibodies was screened for reactivity to the polyQ proteins on SW. The most promising antibodies were selected for further assay development. This resulted in optimised SW immunoassays for huntingtin (HTT), ataxin 1, 2 and 3 (ATXN1, 2, 3), atrophin 1 (ATN1) and androgen receptor (AR). Additionally, size-separation of the wild-type and polyQ-expanded mutant protein isoforms on SW was shown for ATXN1, ATXN3 and ATN1, allowing for their separate quantification. To facilitate size-separation of the larger HTT protein (≥ 348 kDa), a novel caspase 3-based assay was developed to generate N-terminal wild-type and mutant HTT fragments that could be separately quantified on SW in contrast to full-length HTT. In conclusion, SW capillary immunoassays were developed for polyQ proteins to improve preclinical research and aid the development of polyQ-lowering therapies for polyQ diseases.
2025-01-03 | Transcriptomic analysis of repeat expansion-ataxias uncovers distinct non-neuronal cell type-specific signatures of disease across the human brain
Abstract Hereditary ataxias are a heterogeneous group of neurogenetic conditions characterised by the clinical syndrome of progressive loss of coordination from neurodegeneration of the cerebellum. A commonality across the most prevalent ataxias is the underlying disease mechanism secondary to expansions of short tandem DNA repeats. There is currently an incomplete understanding of the pathogenic mechanisms of these repeat expansion disorders, a core feature of which revolves around RNA-dysregulation. In this study, we used both bulk and single nuclear RNA-sequencing to study post-mortem brain tissue of human donors with a range of repeat-expansion ataxias to reveal further mechanistic insights. We compared post-mortem paired cerebellar and frontal cortex tissue bulk RNA-sequencing data from 23 ataxia patients and 22 sex-, age-matched controls from two brain banks (spinocerebellar ataxia (SCA)1, SCA2, SCA6, SCA7, SCA17, Friedreich’s ataxia (FRDA), and 7 cases with unknown molecular diagnoses). We analysed bulk RNA-sequencing data for transcript usage, differential and cell-type-specific expression to transcriptomically profile these diseases. We also generated single nuclear RNA-sequencing data of the cerebellum from donors with SCA1, SCA2, SCA6 and FRDA to decipher changes in cell type proportions in the disease state. Using this approach, we found that: (i) despite the commonalities in the genetics of ataxia, there were components of their transcriptional signatures which were distinct; (ii) there were extensive transcriptional changes evident not only in the cerebellum but also the frontal cortex in ataxia cases; (iii) activation of immune and inflammatory pathways, as well as involvement of non-neuronal cell types was a feature of all ataxias to a lesser or greater extent. This study provides a novel resource to understand the mechanisms of disease in ataxia. Furthermore, taken together, these results highlight immune pathways and the role of non-neuronal cell types as early and potentially important therapeutic targets. These findings provide a map of transcriptomic changes in ataxia to further understanding of the underlying pathogenesis.
small molecules
2026-07-10 | Immune Activation and Glial Dysfunction in Spinocerebellar Ataxias: From Cerebellar Landscape to Disease-Driven Mechanisms and Immunomodulation.
Spinocerebellar ataxias (SCAs) comprise a clinically and genetically heterogeneous group of autosomal dominant neurodegenerative disorders. Despite the recognized role of specialized cerebellar glia in cerebellar development and dysfunction, immune activation and non-immune glial responses remain understudied in SCAs. This narrative review compiles evidence from cellular, animal, and human models on the cerebellar immune landscape and the specific pathways that drive homeostatic failure and neuroinflammatory cascades across SCA subtypes. Microgliosis emerges consistently-and often early- as a generalized feature across the SCA spectrum, preceding neurodegeneration in several subtypes. Concurrently, reactive astrogliosis extends broadly, reflecting widespread macroglial surveillance and metabolic stress regulation throughout histologically preserved gray matter, with specialized homeostatic failure of Bergmann glia in SCA1, SCA2, and SCA7. Peripheral inflammation, manifests as early as the prodromal stage and correlates with the cognitive-affective deficits in SCA2 and associates with the mutation size in SCA3, positioning it as integral to pathogenesis rather than epiphenomenal. Diverse, partially shared signaling pathways converge on multi-lineage glial breakdown and reciprocal neuroimmune crosstalk. These mechanisms involve NF-κB (SCA1,3,17), cGAS-STING (SCA2), TLR/MyD88 (SCA6), and JNK/c-Jun (SCA1,2,7). This review establishes abnormal reciprocal immune/non-immune glia crosstalk as a core pathogenic principle across SCAs, revealing novel therapeutic opportunities. In fact, targeting convergent signaling nodes such as NF-κB, or JNK pathways, holds disease-modifying potential across multiple subtypes. Future research should prioritize standardized comparative studies, longitudinal analyses linking both inflammation and non-immune glial pathology to clinical progression, and clinical trials evaluating targeted immunomodulatory and glial homeostatic-supportive agents.
2026-05-28 | Aromatic-Turmerone Analogs Activate Chaperone-Mediated Autophagy and Ameliorate Dendritic Shrinkage in Purkinje Cell Models of Spinocerebellar Ataxia.
We recently demonstrated that aromatic (ar)-turmerone analogs ((E)-5-methyl-1-(p-tolyl)hexa-1,4-dien-3-one [A2] and (E)-1-(4-methoxyphenyl)-5-methylhexa-1,4-dien-3-one [A4]) activate chaperone-mediated autophagy (CMA), a pathway in the autophagy-lysosome protein degradation system, in SH-SY5Y cells. Our previous studies revealed that the impairment of CMA and microautophagy (mA), another autophagy-related pathway, and dendritic shrinkage were observed in primary cultured Purkinje cells (PCs) expressing causal proteins of spinocerebellar ataxia (SCA), an autosomal dominant neurodegenerative disease. In the present study, we first investigated the effects of A2 and A4 on lysosomal protein degradation and dendritic morphology in cerebellar primary cultured PCs. Both compounds enhanced dendritic development and activated CMA in cultured PCs. These effects were significantly suppressed by the inhibitors of nuclear factor erythroid 2-related factor 2 and p38. We next examined the effects of A2 and A4 on PCs expressing several types of SCA-causing proteins (SCA model PCs). Both chemicals ameliorated the dendritic shrinkage and restored the decreased CMA/mA activity in several SCA model PCs. These findings suggest that the ar-turmerone analogs A2 and A4 improve the in vitro phenotype of SCA model PCs through CMA activation, highlighting the therapeutic potential of these analogs for various types of SCAs.
2026-02-22 | Long-term efficacy and disease-specific responsiveness to protirelin in patients with spinocerebellar degeneration: A retrospective study.
The thyrotropin-releasing hormone (TRH) analog protirelin has short-term benefits for cerebellar ataxia (CA), but its long-term efficacy and the subtype-specific responsiveness of spinocerebellar degeneration (SCD) patients remain unclear. We retrospectively reviewed the records of 92 SCD patients (273 courses) treated with protirelin between July 2011 and October 2025, including patients with idiopathic CA (IDCA), multiple system atrophy with predominant CA (MSA-C) or parkinsonism (MSA-P), and genetic subtypes including spinocerebellar ataxia (SCA) type 6, SCA31 and dentatorubral-pallidoluysian atrophy (DRPLA). Responders were defined as showing ≥1-point improvement on the Scale for the Assessment and Rating of Ataxia (SARA). Protirelin was effective in 64.1% of subjects, with significant improvement overall (p < 0.001) and significant SARA gains in MSA-C (p = 0.047), IDCA (p = 0.02), and SCA31 (p = 0.01). Change in SARA score (ΔSARA) correlated negatively with age and positively with total protirelin dose in IDCA, and negatively with age and disease duration and positively with baseline SARA score in SCA31. Several IDCA and DRPLA patients maintained clinical benefit for more than 10 years. All MSA-P discontinued protirelin within 2 years and all MSA-C within 5 years; some SCA6, and SCA31 patients continued for ≥5 years. Adverse effects were infrequent (2/92, 2.2%). Protirelin is efficacious in SCD patients and well-tolerated, particularly in slow-progressing phenotypes (IDCA and SCA31); its benefit in rapidly progressing ataxias (MSA-C) may be confined to early disease stages. Prospective studies with standardized dosing and long-term follow-up are warranted to establish evidence-based protocols for TRH-related therapy for CA.
2026-01-14 | Cardiorenal and hepatic dysfunctions underlie metabolic alterations in the spinocerebellar ataxia type 7 mice
Abstract Spinocerebellar ataxia type 7 (SCA7) is a polyglutamine expansion disorder characterized by progressive cerebellar and retinal degeneration leading to ataxia and blindness. While mutant ATXN7 is ubiquitously expressed, most studies have focused on neurological symptoms, and peripheral contributions to pathology remain poorly understood. Here, we investigated systemic abnormalities in SCA7 140Q/5Q knock-in mice, a model of early-onset disease. Using longitudinal metabolic profiling, ultrasound imaging, and histopathology, we identified early and progressive dysfunction of the kidney, liver, and heart. Renal impairment was marked by uremia, polyuria with abnormal calcium and glucose excretion, tubular epithelial cell loss, and podocyte dedifferentiation, including the reappearance of primary cilia and pedicel effacement. Hepatic alterations included dysregulated lipid metabolism, elevated bilirubin, and reduced iron levels, contributing to anemia. Cardiac dysfunction manifested as reduced stroke volume as early as 11 weeks, suggesting a cardiorenal syndrome. Together, these organ-specific changes resulted in systemic metabolic disturbances such as dyslipidemia, iron deficiency anemia, thrombocytosis, and chronic inflammation, detectable before the onset of motor incoordination. Our findings demonstrate that peripheral organ dysfunction is an early and integral feature of SCA7 pathogenesis, with renal and cardiac impairments emerging prior to neurological decline. These results highlight the value of systemic biomarkers for disease monitoring and suggest that targeting peripheral pathology may provide therapeutic benefit. More broadly, they underscore the need to view SCA7 not solely as a neurodegenerative disorder but as a multi-organ disease.
2025-12-24 | Valosin-Containing Protein as a therapeutic target in CAG repeat-driven Spinocerebellar ataxias: Integrative transcriptomic and computational insights.
Spinocerebellar ataxias (SCAs) are progressive neurodegenerative disorders caused by abnormal CAG repeat expansions in genes such as ATXN1, ATXN2, and ATXN3, with no effective therapeutic options currently available. To identify key molecular drivers of disease pathology, transcriptomic datasets GSE75249 and GSE151276 were analyzed. Differentially expressed genes were determined, and overlapping upregulated genes from both datasets were extracted for downstream analysis. Functional enrichment revealed significant biological processes and pathways related to protein homeostasis, cellular stress response, and neurodegeneration. Protein-protein interaction networks were constructed to investigate gene connectivity, and hub gene analysis identified Valosin-Containing Protein (VCP) as the top-ranked common hub gene. Importantly, VCP expression was experimentally validated in plasma samples from SCA1, SCA2, and SCA3 patients using ELISA, confirming its dysregulation and central role in SCA pathogenesis. To explore therapeutic potential, pharmacophore-based virtual screening of natural compounds was conducted, followed by molecular docking to evaluate interactions with VCP. Among the shortlisted candidates, sesamolin demonstrated the strongest binding affinity and favorable pharmacological properties. A 250 ns molecular dynamics simulation further confirmed the stability of the VCP-sesamolin complex, revealing sustained interactions, reduced fluctuations, and conformational stabilization of VCP. Collectively, this integrative approach combining transcriptomic profiling, enrichment analysis, hub gene identification, experimental validation, and structure-based drug discovery highlights VCP as a crucial regulator in CAG repeat-associated SCAs and proposes sesamolin as a promising neuroprotective lead compound for further preclinical development.
gene therapies
2026-09-09 | MicroRNAs in polyglutamine diseases: Mechanistic insights, circulating biomarkers, and emerging microRNA-based therapeutic strategies.
MicroRNAs (miRNAs) have emerged as critical regulators in the pathogenesis of polyglutamine (PolyQ) diseases-a group of fatal neurodegenerative disorders caused by CAG repeat expansions, such as Huntington's disease, spinocerebellar ataxias, dentatorubral-pallidoluysian atrophy, and spinal and bulbar muscular atrophy. This review synthesizes recent advances in miRNA dysregulation across all nine PolyQ diseases, focusing on studies published since 2019. We examine how specific miRNAs modulate core pathogenic cascades-including mutant protein aggregation, transcriptional dysregulation, mitochondrial dysfunction, and apoptosis-and then link these molecular events to disease-relevant motor, cognitive, and psychiatric phenotypes. The review highlights therapeutic progress, including the preclinical efficacy of adeno-associated virus (AAV)-delivered artificial miRNAs and emerging exosome-based platforms that target mutant transcripts such as HTT, ATXN1, ATXN3, and ATXN7. AAV5-miHTT has advanced to a first-in-human trial for Huntington's disease (NCT04120493)-a key milestone in clinical translation. Circulating miRNAs in plasma and cerebrospinal fluid show diagnostic potential as minimally invasive, stage-specific biomarkers, but challenges persist in normalization, cross-biofluid concordance, and clinical validation. Despite substantial progress, translational barriers remain-including off-target effects, delivery optimization, immunogenicity, and patient heterogeneity. Overcoming these barriers will require integrative approaches that combine single-cell transcriptomics, engineered delivery systems, machine learning, and longitudinally phenotyped clinical cohorts. This review integrates mechanistic insights, biomarker discovery, and therapeutic development to move miRNA-based strategies toward disease-modifying interventions for PolyQ disorders.
2026-04-30 | Management of spinocerebellar ataxia.
Spinocerebellar ataxias (SCAs) are a group of neurodegenerative diseases characterized by progressive cerebellar dysfunction, which leads to impaired coordination, dysarthria, oculomotor disorders, and subsequently to a marked reduction in quality of life and high disability. In addition to the main motor symptoms, patients often suffer from cerebellar cognitive-affective syndrome, depression, and sleep disturbances. Despite advances in understanding the molecular and genetic underpinnings of SCAs, there are currently no disease-modifying therapies approved by the FDA (U.S. Food and Drug Administration) or EMA (European Medicines Agency), and management remains largely symptomatic, focusing on improving quality of life and functional independence. Recent systematic reviews and clinical guidelines emphasize a combination of pharmacological, non-pharmacological, and novel gene and cell therapies that are currently under investigation, with varying levels of evidence for their efficacy. The transition to precision medicine and early intervention at the pre-ataxic stage are essential for effectively combating neurodegeneration. This review summarizes the latest data on the treatment of SCA, including existing and new treatments, their effectiveness, limitations, and future prospects.
2026-04-24 | Developmental roots of cerebellar degeneration in spinocerebellar ataxia.
Late-onset neurodegenerative diseases have long been conceptualized as disorders arising from cumulative cellular stress and age-related decline, with pathology emerging at the time of symptom onset. However, emerging evidence challenges this view, suggesting that developmental perturbations may establish early vulnerabilities that predispose specific neuronal populations to degeneration later in life. In the cerebellum, mutations causing spinocerebellar ataxias (SCAs) such as SCA1 and SCA6 affect genes involved in normal circuit formation, resulting in subtle early abnormalities in Purkinje cell activity and connectivity. These alterations seem to be initially buffered by compensatory mechanisms, and the eventual breakdown of homeostatic resilience during midlife may thus be the trigger for disease onset and progression. This developmental perspective reframes late-onset neurodegeneration as a lifelong process shaped by the interplay between early developmental wiring, adaptive compensation, and age-dependent vulnerability. Understanding these early developmental alterations provides critical insight into disease mechanisms and opens new avenues for pre-symptomatic intervention and prevention.
2025-11-22 | Development of a Gene Therapy with Lentiviral Vectors for Spinocerebellar Ataxias.
Among viral vectors, lentiviral vectors allow an efficient delivery of nucleic acid to the target cells due to its ability of gene integration into host genome and broad tropism. In this sense, this tool demonstrated to be very promising in genetic disorders, such as polyglutamine spinocerebellar ataxias. Therefore, we describe a protocol that explains in detail the production, purification, and injection of lentiviral vectors in a spinocerebellar ataxia mouse model.
2025-10-07 | Challenges in Polyglutamine Diseases: From Dysfunctional Neuronal Circuitries to Neuron-Specific CAG Repeat Instability
Several genetic diseases affecting the human nervous system are incurable and insufficiently understood. Among them, nine rare diseases form the polyglutamine (polyQ) family: Huntington’s disease (HD), spinocerebellar ataxia types 1, 2, 3, 6, 7, and 17, dentatorubral pallidoluysian atrophy, and spinal and bulbar muscular atrophy. In most patients, these diseases progress over decades to cause severe movement incoordination and neurodegeneration. Although their inherited genes with tandem-repeat elongations and the encoded polyQ-containing proteins have been extensively studied, the neuronal-type-specific pathologies and their long pre-symptomatic latency await further investigations. However, recent advances in detecting the single-nucleus transcriptome, alongside the length of tandem repeats in HD post-mortem brains, have enabled the identification of very high CAG repeat sizes that trigger transcriptional dysregulation and cell death in specific projection neurons. One challenge is to better understand the complexity of movement coordination circuits, including the basal ganglia and cerebellum neurons, which are most vulnerable to the high CAG expansion in each disease. Another challenge is to detect dynamic changes in CAG repeat length and their effects in vulnerable neurons at single-cell resolution. This will offer a platform for identifying pathological events in vulnerable long projection neurons and developing targeted therapies for all tandem-repeat expansions affecting the CNS projection neurons.
proteins
2026-02-19 | The Hsp40 cochaperone DNAJC7 regulates polyglutamine aggregation and exhibits context-dependent effects on polyglycine aggregation.
Protein-encoding nucleotide repeat expansion diseases, including polyglutamine (polyQ) and polyglycine (polyG) diseases, are characterized by the accumulation of aggregation-prone proteins. In the polyQ diseases, including Huntington's disease and several spinocerebellar ataxias, substantial prior evidence supports a pathogenic role for mutant polyQ-expanded protein misfolding and aggregation, with molecular chaperones showing promise in suppressing disease phenotypes in cellular and animal models. The goal of this study is to establish a scalable cell-based model to systematically evaluate genetic modifiers of protein aggregation in both polyQ and polyG diseases. We developed FRET-based reporter systems that model polyQ and polyG aggregation in human cells and used them to perform high-throughput CRISPR interference screens targeting all known molecular chaperones. In the polyQ model, the screen identified multiple Hsp70 chaperones and Hsp40 cochaperones previously implicated in polyQ aggregation and additionally revealed the Hsp40 cochaperone DNAJC7 as a potent and previously unrecognized suppressor of polyQ aggregation. In contrast, in a FRET-based polyG aggregation model of neuronal intranuclear inclusion disease, CRISPR interference screening showed minimal overlap of chaperone modifiers of the polyQ screen. Direct knockdown of DNAJC7 also did not affect polyG aggregation, yet overexpressed DNAJC7 colocalized with both polyQ and polyG aggregates in cells and reduced their aggregation. In addition to establishing new inducible, scalable cellular models for polyQ and polyG aggregation, this work expands the role of DNAJC7 in regulating the folding of disease-associated proteins.
2024-12-27 | Genetic modeling of degenerative diseases and mechanisms of neuronal regeneration in the zebrafish cerebellum.
The cerebellum is a highly conserved brain compartment of vertebrates. Genetic diseases of the human cerebellum often lead to degeneration of the principal neuron, the Purkinje cell, resulting in locomotive deficits and socio-emotional impairments. Due to its relatively simple but highly conserved neuroanatomy and circuitry, these human diseases can be modeled well in vertebrates amenable for genetic manipulation. In the recent years, cerebellar research in zebrafish has contributed to understanding cerebellum development and function, since zebrafish larvae are not only molecularly tractable, but also accessible for high resolution in vivo imaging due to the transparency of the larvae and the ease of access to the zebrafish cerebellar cortex for microscopy approaches. Therefore, zebrafish is increasingly used for genetic modeling of human cerebellar neurodegenerative diseases and in particular of different types of Spinocerebellar Ataxias (SCAs). These models are well suited to address the underlying pathogenic mechanisms by means of in vivo cell biological studies. Furthermore, accompanying circuitry characterizations, physiological studies and behavioral analysis allow for unraveling molecular, structural and functional relationships. Moreover, unlike in mammals, zebrafish possess an astonishing ability to regenerate neuronal populations and their functional circuitry in the central nervous system including the cerebellum. Understanding the cellular and molecular processes of these regenerative processes could well serve to counteract acute and chronic loss of neurons in humans. Based on the high evolutionary conservation of the cerebellum these regeneration studies in zebrafish promise to open therapeutic avenues for counteracting cerebellar neuronal degeneration. The current review aims to provide an overview over currently existing genetic models of human cerebellar neurodegenerative diseases in zebrafish as well as neuroregeneration studies using the zebrafish cerebellum. Due to this solid foundation in cerebellar disease modeling and neuronal regeneration analysis, the zebrafish promises to become a popular model organism for both unraveling pathogenic mechanisms of human cerebellar diseases and providing entry points for therapeutic neuronal regeneration approaches.
2022-08-10 | Rovatirelin ameliorates motor dysfunction in the cytosine arabinoside-induced rat model of spinocerebellar degeneration via acetylcholine and dopamine neurotransmission.
Thyrotropin-releasing hormone (TRH) and the TRH mimetic taltirelin have been used in Japan for the treatment of spinocerebellar degeneration (SCD), a type of progressive ataxia. A TRH mimetic, rovatirelin, ameliorates ataxia symptoms in the rolling mouse Nagoya, a hereditary SCD model. The aim of this study was to verify the effects of oral administration of rovatirelin on a cytosine arabinoside (Ara-C)-induced ataxia rat model, a sporadic SCD model characterized by gait abnormalities and falls because of cerebellar atrophy and investigate the central nervous system mechanism associated with rovatirelin-mediated amelioration of motor dysfunction in these rats. Rovatirelin at ≥3 mg/kg significantly decreased the fall index, which is a primary endpoint of improved motor function calculated by dividing the number of falls by the locomotor activity, in both male and female rats with Ara-C-induced ataxia. Furthermore, rovatirelin caused a significant increase in locomotor activity in a dose-dependent manner. Taltirelin at ≥30 mg/kg ameliorated motor dysfunction in ataxic rats. Moreover, rovatirelin significantly increased acetylcholine (ACh) levels in the medial prefrontal cortex (mPFC) and dopamine (DA) levels in the nucleus accumbens (NAc) at ≥3 mg/kg and significantly increased DA levels in the dorsal striatum at ≥10 mg/kg in normal rats. In conclusion, oral administration of rovatirelin ameliorates motor dysfunction in rats with Ara-C-induced ataxia, owing to its ACh-increasing effects in the mPFC and DA-increasing effects in the dorsal striatum and NAc. Furthermore, the effects of rovatirelin were more potent than those of taltirelin.
2021-11-25 | C-terminus of Hsp70 Interacting Protein (CHIP) and Neurodegeneration: Lessons from the Bench and Bedside.
Neurodegenerative diseases are characterized by the increasing dysfunction and death of neurons, resulting in progressive impairment of a person's mobility and/or cognition. Protein misfolding and aggregation are commonly hypothesized to cause neurotoxicity and, eventually, neuronal degeneration that are associated with these diseases. Emerging experimental evidence, as well as recent findings from human studies, reveal that the C-terminus of Hsp70 Interacting Protein (CHIP), or STIP1 Homology and U-box containing Protein 1 (STUB1), is a quality control protein involved in neurodegeneration. Here, we review evidence that CHIP interacts with and plays a role in regulating proteins implicated in the pathogenesis of Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and polyglutamine diseases, including Huntington's disease and spinocerebellar ataxias. We also review clinical findings identifying mutations in STUB1 as a cause of both autosomal recessive and autosomal dominant forms of cerebellar ataxia. We propose that CHIP modulation may have therapeutic potential for the treatment of multiple neurodegenerative diseases.
2021-05-14 | Differential effects of thyrotropin releasing hormone (TRH) on motor execution and motor adaptation process in patients with spinocerebellar degeneration.
The cerebellum is known to play a crucial role in sensori-motor adaptation, which includes the prism adaptation. TRH has been widely used as a treatment for cerebellar ataxia in Japan, however effects of TRH on cerebellar adaptation process have not been studied. Here, we studied effects of TRH treatment on the prism adaptation task. Eighteen spinocerebellar degeneration (SCD) patients participated in this study. The participants received intravenous injection of 2 mg/day protirelin tartrate once a day for 14 days. In the prism adaptation task, the participants reached to the target on the screen wearing wedge prisms. We compared the Scale for Assessment and Rating of Ataxia (SARA), baseline errors and the aftereffect (AE) of the prism adaptation task between before and after TRH therapy. TRH therapy improved SARA significantly (p = .005). Multiple regression analysis revealed that improvement of SARA score was mainly due to improvement of "Stance" category score. TRH decreased baseline errors of the prism adaptation task (p = .021), while unaffected AEs (p = .252). TRH differentially affected clinical cerebellar ataxia including baseline reaching performance in the prism adaptation task, whereas TRH did not affect the learning process of prism adaptation. Different cerebellar functional aspects may underlie the learning process of sensori-motor adaptation and simple motor execution (clinically evaluated cerebellar ataxia).
oligonucleotides
2026-07-09 | Gene therapy for spinocerebellar ataxias.
Spinocerebellar ataxias (SCAs), rare neurodegenerative disorders characterized by progressive cerebellar degeneration, cause impaired balance and motor dysfunction. Although most cases are inherited, sporadic forms also occur, and effective disease-modifying therapies remain unavailable despite advances in understanding their genetic and molecular mechanisms. This unmet need is particularly significant because many SCAs are monogenic disorders caused by well-characterized mutations, making them promising candidates for gene- and RNA-based therapies. Recent advances in antisense oligonucleotides, RNA interference, vector engineering, and genome editing have increasingly enabled the alignment of therapeutic strategies with specific mutational architectures. Therefore, this review aims to examine how genetic subclassification informs platform selection, summarize recent advances in gene- and RNA-based therapeutics, and outline key translational barriers to clinical implementation in SCAs.
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.
2024-04-15 | AAV-Mediated CAG-Targeting Selectively Reduces Polyglutamine-Expanded Protein and Attenuates Disease Phenotypes in a Spinocerebellar Ataxia Mouse Model
Polyglutamine (polyQ)-encoding CAG repeat expansions represent a common disease-causing mutation responsible for several dominant spinocerebellar ataxias (SCAs). PolyQ-expanded SCA proteins are toxic for cerebellar neurons, with Purkinje cells (PCs) being the most vulnerable. RNA interference (RNAi) reagents targeting transcripts with expanded CAG reduce the level of various mutant SCA proteins in an allele-selective manner in vitro and represent promising universal tools for treating multiple CAG/polyQ SCAs. However, it remains unclear whether the therapeutic targeting of CAG expansion can be achieved in vivo and if it can ameliorate cerebellar functions. Here, using a mouse model of SCA7 expressing a mutant Atxn7 allele with 140 CAGs, we examined the efficacy of short hairpin RNAs (shRNAs) targeting CAG repeats expressed from PHP.eB adeno-associated virus vectors (AAVs), which were introduced into the brain via intravascular injection. We demonstrated that shRNAs carrying various mismatches with the CAG target sequence reduced the level of polyQ-expanded ATXN7 in the cerebellum, albeit with varying degrees of allele selectivity and safety profile. An shRNA named A4 potently reduced the level of polyQ-expanded ATXN7, with no effect on normal ATXN7 levels and no adverse side effects. Furthermore, A4 shRNA treatment improved a range of motor and behavioral parameters 23 weeks after AAV injection and attenuated the disease burden of PCs by preventing the downregulation of several PC-type-specific genes. Our results show the feasibility of the selective targeting of CAG expansion in the cerebellum using a blood–brain barrier-permeable vector to attenuate the disease phenotype in an SCA mouse model. Our study represents a significant advancement in developing CAG-targeting strategies as a potential therapy for SCA7 and possibly other CAG/polyQ SCAs.
2023-11-01 | RNA-sequencing analysis of hereditary ataxia reveals differential transcriptomic signatures across brain regions and disease pathologies
Hereditary ataxias are a heterogeneous group of neurogenetic conditions characterised by incoordination from cerebellar dysfunction. There is currently no treatment, partly due to an incomplete understanding of disease mechanisms. We compared post-mortem paired cerebellar and frontal cortex tissue bulk RNA-sequencing data from 23 ataxia patients and 22 sex-, age-matched controls from two brain banks. Repeat expansion sizes were quantified from DNA (spinocerebellar ataxia (SCA)1, n=3; SCA2, n=3; SCA6, n=3; SCA7, n=2; SCA17, n=1; Friedreich's ataxia, n=4; unknown molecular diagnoses, n=7). We analysed bulk RNA-sequencing data for transcript usage, differential and cell-type-specific expression to transcriptomically profile these diseases. Using this approach, we found: (i) different transcriptional alterations between cerebellar and frontal cortices with unexpected frontal involvement even in 'pure' ataxia syndromes (SCA6); (ii) distinct expression profiles between diseases including molecularly-undiagnosed cases; (iii) downregulation of synaptic and transporter pathways in the ataxia cerebellum and upregulation of immune-associated pathways within the frontal cortex; (iv) neuronal cell-type-specific enrichment in expression including Purkinje cells in downregulated cerebellar genes and upregulation of glial-specific cell types within the frontal cortex of ataxia patients. These findings provide a map of transcriptomic changes in ataxia to further understanding of underlying pathogenesis and have important implications for RNA-targeted therapy development.
2023-09-30 | Widespread alternative splicing dysregulation occurs presymptomatically in CAG expansion spinocerebellar ataxias
Abstract The spinocerebellar ataxias (SCAs) are a group of dominantly inherited neurodegenerative diseases, several of which are caused by CAG expansion mutations (SCAs 1, 2, 3, 6, 7 and 12) and more broadly belong to the large family of over 40 microsatellite expansion diseases. While dysregulation of alternative splicing is a well defined driver of disease pathogenesis across several microsatellite diseases, the contribution of alternative splicing in CAG expansion SCAs is poorly understood. Furthermore, despite extensive studies on differential gene expression, there remains a gap in our understanding of presymptomatic transcriptomic drivers of disease. We sought to address these knowledge gaps through a comprehensive study of 29 publicly available RNA-sequencing datasets. We identified that dysregulation of alternative splicing is widespread across CAG expansion mouse models of SCAs 1, 3 and 7. These changes were detected presymptomatically, persisted throughout disease progression, were repeat length-dependent, and were present in brain regions implicated in SCA pathogenesis including the cerebellum, pons and medulla. Across disease progression, changes in alternative splicing occurred in genes that function in pathways and processes known to be impaired in SCAs, such as ion channels, synaptic signalling, transcriptional regulation and the cytoskeleton. We validated several key alternative splicing events with known functional consequences, including Trpc3 exon 9 and Kcnma1 exon 23b, in the Atxn1154Q/2Q mouse model. Finally, we demonstrated that alternative splicing dysregulation is responsive to therapeutic intervention in CAG expansion SCAs with Atxn1 targeting antisense oligonucleotide rescuing key splicing events. Taken together, these data demonstrate that widespread presymptomatic dysregulation of alternative splicing in CAG expansion SCAs may contribute to disease onset, early neuronal dysfunction and may represent novel biomarkers across this devastating group of neurodegenerative disorders.
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2026-07-11 | Safety and preliminary efficacy of autologous bone marrow-derived mesenchymal stem cell transplantation in hereditary cerebellar ataxia: phase I/IIa clinical trial.
Hereditary cerebellar ataxias (HCA) encompass a spectrum of pathological conditions affecting the cerebellum. Currently, there is growing interest in the potential role of mesenchymal stem cells (MSCs) as an investigational therapeutic approach for this condition. Hence, the objective of this single-center, open-label, phase I/IIa clinical trial was to assess the safety and exploratory clinical and biomarker changes following a single intrathecal injection of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) in HCA. Ten confirmed patients with HCA entered the study and underwent a single dose of (1 × 106 cells/kg BW) intrathecal transplantation of BM-MSCs at passage 3. During the follow-up, patients were evaluated four times (one month before the intervention (-1), months 1, 3, and 6). Assessments included safety evaluation, Scale for the Assessment and Rating of Ataxia (SARA), GAD 65-antibody, and specific cytokines in the patient's serum and cerebrospinal fluid (CSF) samples. No severe adverse effects were observed following the cell transplantation procedure. A decreasing trend in SARA score was observed, with a statistically significant difference at month 6 compared with baseline. Except for one patient, GAD-65 antibody levels remained within the normal range in all patients. In one patient with markedly elevated baseline GAD-65 titers, serum and CSF GAD-65 levels decreased from 814 IU/mL and 781 IU/mL, respectively, to values within the normal range after 3 months. Significant changes were observed in selected inflammatory biomarkers, including decreased serum IL-6 at month 3, decreased CSF TNF-alpha at months 1 and 3, and increased serum IL-10 during follow-up. CSF IL-6 did not show a significant decrease. The findings support the short-term safety and tolerability of a single intrathecal dose of autologous BM-MSCs in this small HCA cohort. The study provides preliminary signals of possible clinical and biomarker changes; however, efficacy cannot be established due to the uncontrolled design, small sample size, disease heterogeneity, and short follow-up. Larger randomized controlled trials are required to validate these exploratory findings. This clinical trial was registered with the Iranian Registry of Clinical Trials (ID: IRCT20160809029275N3).
2026-04-13 | Cell-Based Therapies for Spinocerebellar Degenerations: A Systematic Review of Human Clinical Evidence.
Spinocerebellar degenerations (SCDs) are progressive hereditary and selected sporadic cerebellar neurodegenerative disorders with limited disease-modifying options. Cell-based therapies particularly, mesenchymal stromal/stem cells (MSCs), neural stem/progenitor cells, olfactory ensheathing cells (OECs), cord blood mononuclear cells (CBMCs), and hematopoietic stem cell transplantation (HSCT) are biologically plausible candidates, but their clinical efficacy and safety remain uncertain. We searched MEDLINE/PubMed, Embase, Scopus, Web of Science, and Cochrane Library from inception to 10 October 2025 (no language restrictions). The OSF-registered protocol prespecified eligibility, outcomes, and design-specific risk-of-bias (RoB) tools, with harmonized overall RoB judgments. We included human interventional or observational reports of cell-based or cell-derived products in hereditary ataxias and selected cerebellar-predominant degenerative syndromes within the OPCA/MSA-C spectrum, and extracted clinical efficacy, safety, and follow-up. Of 603 records screened, 17 reports met the protocol-defined inclusion criteria (15 full texts; 2 abstracts; 2006–2025). Most were small, uncontrolled case series, predominantly from China. Cell types: MSCs (9/17), HSCT in ataxia-telangiectasia (3/17), OECs (3/17), and others (neural stem cells [NSCs], CBMCs; 2/17). Routes were intrathecal and/or intravenous for MSC/CBMC; OEC/NSC were intracerebral/intraspinal; HSCT was delivered intravenously. Primary follow-up was typically 1–6 months. Safety was generally acceptable for MSC/CBMC/OEC with no treatment-related deaths and mostly transient post-procedural symptoms; HSCT exhibited regimen-related toxicities consistent with conditioning intensity. Efficacy signals were modest and often transient: short-term International Cooperative Ataxia Rating Scale (ICARS) improvements were reported across multiple series. Cell-based therapies for SCDs show biological plausibility and generally reassuring short-term safety, but current human evidence, dominated by uncontrolled, high-bias studies does not establish efficacy or durability. Priority should shift to rigorously controlled trials, standardized good manufacturing practice (GMP)-characterized products, blinded centralized ratings, careful control of co-interventions, and objective biomarkers.
2025-09-27 | Roots of Progress: Uncovering Cerebellar Ataxias Using iPSC Models.
The inaccessibility of human cerebellar tissue and the complexity of its development have historically hindered the study of cerebellar ataxias, a genetically diverse group of neurodegenerative disorders. Induced pluripotent stem cell (iPSC) technology offers a powerful solution, enabling the generation of patient-specific cerebellar models that retain individual genetic backgrounds. This review examines recent progress in iPSC-derived cerebellar models and their application in relation to major hereditary ataxias, including Friedreich's ataxia, ataxia-telangiectasia, and spinocerebellar ataxias (SCAs). These models have provided valuable insights into disease mechanisms and supported the development of therapeutic strategies, such as gene therapy and high-throughput drug screening. However, challenges remain, particularly in achieving the full maturation of cerebellar cell types and incorporating microglial interactions. Moreover, emerging evidence suggests that neurodevelopmental alterations may act as early contributors to degeneration. Despite the current limitations, the advancement of patient-derived iPSC cerebellar models holds great promise for uncovering novel disease pathways and for driving precision medicine approaches in cerebellar ataxia research.
2025-06-01 | Accurate Quantification of Mutant and Wild-Type polyQ Proteins Using Simple Western Capillary Immunoassays.
Polyglutamine (polyQ) diseases are monogenic fatal neurodegenerative disorders caused by a CAG repeat expansion that is translated into a toxic polyQ tract. There are nine polyQ diseases: Huntington's disease (HD), spinocerebellar ataxias 1, 2, 3, 6, 7 and 17 (SCA1, 2, 3, 6, 7, 17), dentatorubral-pallidoluysian atrophy (DRPLA) and spinal and bulbar muscular atrophy (SBMA). Although no disease-modifying therapies are available, lowering levels of the causative mutant polyQ protein is a promising potential treatment. Preclinically, the efficacy of polyQ protein-lowering compounds is often assessed using time-consuming Western blots (WB), which can produce variable results. Therefore, to improve throughput and accuracy of polyQ protein level quantification, Simple Western (SW) capillary immunoassays were developed. A panel of antibodies was screened for reactivity to the polyQ proteins on SW. The most promising antibodies were selected for further assay development. This resulted in optimised SW immunoassays for huntingtin (HTT), ataxin 1, 2 and 3 (ATXN1, 2, 3), atrophin 1 (ATN1) and androgen receptor (AR). Additionally, size-separation of the wild-type and polyQ-expanded mutant protein isoforms on SW was shown for ATXN1, ATXN3 and ATN1, allowing for their separate quantification. To facilitate size-separation of the larger HTT protein (≥ 348 kDa), a novel caspase 3-based assay was developed to generate N-terminal wild-type and mutant HTT fragments that could be separately quantified on SW in contrast to full-length HTT. In conclusion, SW capillary immunoassays were developed for polyQ proteins to improve preclinical research and aid the development of polyQ-lowering therapies for polyQ diseases.
2025-01-03 | Transcriptomic analysis of repeat expansion-ataxias uncovers distinct non-neuronal cell type-specific signatures of disease across the human brain
Abstract Hereditary ataxias are a heterogeneous group of neurogenetic conditions characterised by the clinical syndrome of progressive loss of coordination from neurodegeneration of the cerebellum. A commonality across the most prevalent ataxias is the underlying disease mechanism secondary to expansions of short tandem DNA repeats. There is currently an incomplete understanding of the pathogenic mechanisms of these repeat expansion disorders, a core feature of which revolves around RNA-dysregulation. In this study, we used both bulk and single nuclear RNA-sequencing to study post-mortem brain tissue of human donors with a range of repeat-expansion ataxias to reveal further mechanistic insights. We compared post-mortem paired cerebellar and frontal cortex tissue bulk RNA-sequencing data from 23 ataxia patients and 22 sex-, age-matched controls from two brain banks (spinocerebellar ataxia (SCA)1, SCA2, SCA6, SCA7, SCA17, Friedreich’s ataxia (FRDA), and 7 cases with unknown molecular diagnoses). We analysed bulk RNA-sequencing data for transcript usage, differential and cell-type-specific expression to transcriptomically profile these diseases. We also generated single nuclear RNA-sequencing data of the cerebellum from donors with SCA1, SCA2, SCA6 and FRDA to decipher changes in cell type proportions in the disease state. Using this approach, we found that: (i) despite the commonalities in the genetics of ataxia, there were components of their transcriptional signatures which were distinct; (ii) there were extensive transcriptional changes evident not only in the cerebellum but also the frontal cortex in ataxia cases; (iii) activation of immune and inflammatory pathways, as well as involvement of non-neuronal cell types was a feature of all ataxias to a lesser or greater extent. This study provides a novel resource to understand the mechanisms of disease in ataxia. Furthermore, taken together, these results highlight immune pathways and the role of non-neuronal cell types as early and potentially important therapeutic targets. These findings provide a map of transcriptomic changes in ataxia to further understanding of the underlying pathogenesis.
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Drug Discovery Landscape
1 orphan drug designation for Spinocerebellar ataxia type 7.
1 orphan drug designation for Spinocerebellar ataxia type 7.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
befiradol | small molecules | FDA | — | Neurolixis, Inc. |
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