Autosomal dominant cerebellar ataxia: Research & Drug Discovery Data

Drug discovery

drugs

With orphan designations

Overview

Autosomal dominant cerebellar ataxia (ADCA) encompasses genetically heterogeneous neurodegenerative disorders characterized by progressive cerebellar dysfunction (gait ataxia, dysarthria, oculomotor deficits) and variable extracerebellar features. Classified into ADCA types I-IV, it includes spinocerebellar ataxias (SCAs) with subtypes involving retinal degeneration, brainstem involvement, or pure cerebellar pathology. Neurodegeneration stems primarily from polyglutamine expansions, RNA toxicity, or channelopathies, leading to multisystem neuronal loss [1][2][4][5].

Population

Global prevalence ~1/37,000, with SCA3 (ADCA type I) most common. Founder effects influence regional prevalence (e.g., SCA36 in Asia) [2][7][12].

Burden

Progressive disability requiring assistive devices within 10-20 years of onset. Reduced lifespan in polyQ subtypes (SCA1/2/3). Cognitive decline, neuropathy, and systemic complications increase care needs, with significant psychosocial/economic impacts [5][12][15].

Therapies

Supportive care (physical/speech therapy), symptomatic agents (riluzole, varenicline), and experimental approaches (antisense oligonucleotides, RNAi, trehalose). Clinical trials target gene silencing and protein aggregation [3][8][13][16].

Categories: rare genetic diseases, rare neurological diseases

Research Papers

287 drug discovery papers related to Autosomal dominant cerebellar ataxia, with 4 first-in-class and 3 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:

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.

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2026-05-25 | Intermittent Theta-Burst Stimulation (iTBS) Improves Motor Coordination and Modulates Neuroinflammation and Autophagy in SCA3/MJD Mice.

Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is an autosomal dominant neurodegenerative disorder characterized by misfolded ataxin-3 aggregation and neuronal intranuclear inclusions. Its primary symptom is progressive ataxia, progressively restricting daily living activities. While repetitive transcranial magnetic stimulation (rTMS) may alleviate symptoms, the effects and mechanisms of specific rTMS paradigms, particularly intermittent and continuous theta burst stimulation (iTBS/cTBS), remain unclear in SCA3. This study therefore aimed to investigate the impacts of iTBS and cTBS on motor coordination, cerebellar neuroinflammation, and autophagy in SCA3 transgenic mice. Thirty 14-week-old SCA3 transgenic mice were randomly divided into sham, cTBS, and iTBS groups. Cerebellar stimulation was delivered at 30% maximum output (600 pulses/session, once daily, 5 days/week for 2 weeks). Motor coordination was assessed via rotarod and CatWalk gait analysis. Pathological changes were evaluated by measuring ataxin-3 protein and ubiquitin-positive inclusions. Cerebellar neuroinflammation was analyzed using Iba-1, CD206, and a cytokine array, while autophagy was assessed via Beclin-1 and LC3B expression. iTBS significantly improved motor coordination in SCA3 mice, reducing rotarod falls (vs. sham P < 0.001, vs. cTBS P < 0.05) and improving gait symmetry (vs. sham P < 0.05) and regularity index (vs. sham P < 0.01, vs. cTBS P < 0.01). It also alleviated cerebellar pathology, lowering ataxin-3 expression (vs. sham P < 0.01, vs. cTBS P < 0.01) and ubiquitin-positive inclusions (vs. sham P < 0.01, vs. cTBS P < 0.05). While both iTBS and cTBS increased Iba-1-positive cells (P < 0.05 and P < 0.05, respectively, vs. sham), only iTBS raised CD206-positive cells (vs. sham P < 0.05) and downregulated pro-inflammatory cytokines. Furthermore, iTBS activated autophagy, enhancing Beclin-1 (vs. sham P < 0.05) and LC3B expression (vs. sham P < 0.0001, vs. cTBS P < 0.001). iTBS improved motor coordination and alleviated core cerebellar pathology in SCA3 mice. This effect may be mediated through the downregulation of cerebellar neuroinflammation and the activation of autophagy. Furthermore, the therapeutic efficacy of iTBS was superior to that of cTBS across multiple dimensions, demonstrating distinct paradigm specificity.

Open article ↗

2026-05-28 | Aromatic-Turmerone Analogs Activate Chaperone-Mediated Autophagy and Ameliorate Dendritic Shrinkage in Purkinje Cell Models of Spinocerebellar Ataxia.

Open article ↗

2026-05-25 | Intermittent Theta-Burst Stimulation (iTBS) Improves Motor Coordination and Modulates Neuroinflammation and Autophagy in SCA3/MJD Mice.

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Drug Discovery Landscape

16 orphan drug designations for Autosomal dominant cerebellar ataxia.

Drug	Therapy type	Regulator	Orphan designation	Approval	Sponsor
4-aminopyridine (4-AP)	small molecules	FDA	2024-07-26	—	Solaxa, Inc.
Befiradol fumarate	small molecules	EMA	2024-07-25	—	Neurolixis
Rovatirelin	small molecules	EMA	2022-11-10	—	3R Pharma Consulting GmbH
Rovatirelin	small molecules	FDA	2022-08-15	—	BioPharma Global, a division of Pace Life Sciences
Troriluzole hydrochloride	small molecules	EMA	2021-12-10	—	Biohaven Bioscience Ireland Limited
2'-O-methylphosphorothioate RNAoligonucleotide, 5'- m5CUGm5CUGm5CUGm5CUGm5CUGm5CUGm5CUG-3'"	oligonucleotides	FDA	2021-06-22	—	Vico Therapeutics B.V.
2'-O-methyl phosphorothioate RNA oligonucleotide, 5'‑m5CUGm5CUGm5CUGm5CUGm5CUGm5CUGm5CUG-3'	oligonucleotides	EMA	2021-02-19	—	Vico Therapeutics B.V.
(1E,6E)-1,7-Bis(3,4-dimethoxyphenyl)-4-cyclobutylmethyl-1,6-heptadiene-3,5-dione and [(1E,4Z,6E)-4-(cyclobutylmethyl)-1,7-bis(3,4-dimethoxyphenyl)-5-hydroxyhepta-1,4,6-trien-3-one]	small molecules	FDA	2019-09-24	—	AnnJi Pharmaceutical Co. Ltd.
N-(4,4-difluorocyclohexyl)-2-(3-methyl-1H-pyrazol-1-yl)-6-morpholinopyrimidin-4-amine	small molecules	FDA	2019-05-22	—	Novartis Pharmaceuticals Corporation
Acetylleucine	small molecules	EMA	2018-08-24	—	IntraBio Ireland Ltd
N-acetyl-DL-leucine	small molecules	FDA	2018-06-06	—	IntraBio Inc.
Trans-resveratrol	small molecules	EMA	2017-01-12	—	Luis Pereira de Almeida
2-amino-N-({methyl-[(6-trifluoromethoxy-benzothiazol-2-ylcarbamoyl)-methyl]-carbamoyl}-methyl)-acetamide monohydrochloride	small molecules	FDA	2016-05-18	—	Biohaven Pharmaceuticals, Inc.
riluzole	small molecules	FDA	2016-02-23	—	Biohaven Pharmaceutical Holding Company, Ltd.
Trehalose	small molecules	EMA	2015-06-19	—	FGK Representative Service GmbH
Ceftriaxone	small molecules	EMA	2015-01-15	—	Ospedale San Raffaele s.r.l.

Autosomal dominant cerebellar ataxia

Autosomal dominant cerebellar ataxia

Autosomal dominant cerebellar ataxia

Overview

Population

Burden

Therapies

Categories: rare genetic diseases, rare neurological diseases

Research Papers

2026-05-28 | Aromatic-Turmerone Analogs Activate Chaperone-Mediated Autophagy and Ameliorate Dendritic Shrinkage in Purkinje Cell Models of Spinocerebellar Ataxia.

2026-05-25 | Intermittent Theta-Burst Stimulation (iTBS) Improves Motor Coordination and Modulates Neuroinflammation and Autophagy in SCA3/MJD Mice.

2026-05-28 | Aromatic-Turmerone Analogs Activate Chaperone-Mediated Autophagy and Ameliorate Dendritic Shrinkage in Purkinje Cell Models of Spinocerebellar Ataxia.

2026-05-25 | Intermittent Theta-Burst Stimulation (iTBS) Improves Motor Coordination and Modulates Neuroinflammation and Autophagy in SCA3/MJD Mice.

Drug Discovery Landscape

Updated: Aug 6, 2026