Myelinating Glia: Potential Therapeutic Targets in Polyglutamine Spinocerebellar Ataxias

Putka, Alexandra F.; Mato, Juan P.; McLoughlin, Hayley S.

doi:10.3390/cells12040601

Cited by 4 publications

References 121 publications

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Sensitivity of Advanced Magnetic Resonance Imaging to Progression over Six Months in Early Spinocerebellar Ataxia

Rezende,

Petit,

Park

et al. 2024

Movement Disorders

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BackgroundClinical trials for upcoming disease‐modifying therapies of spinocerebellar ataxias (SCA), a group of rare movement disorders, lack endpoints sensitive to early disease progression, when therapeutics will be most effective. In addition, regulatory agencies emphasize the importance of biological outcomes.ObjectivesREADISCA, a transatlantic clinical trial readiness consortium, investigated whether advanced multimodal magnetic resonance imaging (MRI) detects pathology progression over 6 months in preataxic and early ataxic carriers of SCA mutations.MethodsA total of 44 participants (10 SCA1, 25 SCA3, and 9 controls) prospectively underwent 3‐T MR scanning at baseline and a median [interquartile range] follow‐up of 6.2 [5.9–6.7] months; 44% of SCA participants were preataxic. Blinded analyses of annual changes in structural, diffusion MRI, MR spectroscopy, and the Scale for Assessment and Rating of Ataxia (SARA) were compared between groups using nonparametric testing. Sample sizes were estimated for 6‐month interventional trials with 50% to 100% treatment effect size, leveraging existing large cohort data (186 SCA1, 272 SCA3) for the SARA estimate.ResultsRate of change in microstructural integrity (decrease in fractional anisotropy, increase in diffusivities) in the middle cerebellar peduncle, corona radiata, and superior longitudinal fasciculus significantly differed in SCAs from controls (P < 0.005), with high effect sizes (Cohen's d = 1–2) and moderate‐to‐high responsiveness (|standardized response mean| = 0.6–0.9) in SCAs. SARA scores did not change, and their rate of change did not differ between groups.ConclusionsDiffusion MRI is sensitive to disease progression at very early‐stage SCA1 and SCA3 and may provide a >5‐fold reduction in sample sizes relative to SARA as endpoint for 6‐month‐long trials. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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Sensitivity of Advanced Magnetic Resonance Imaging to Progression over Six Months in Early Spinocerebellar Ataxia

Rezende,

Petit,

Park

et al. 2024

Movement Disorders

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ASOs are an effective treatment for disease-associated oligodendrocyte signatures in premanifest and symptomatic SCA3 mice

Schuster,

Zalon,

DiFranco

et al. 2024

Molecular Therapy

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ASOs are an effective treatment for disease-associated oligodendrocyte signatures in premanifest and symptomatic SCA3 mice

Schuster

Zalon

DiFranco

et al. 2022

Preprint

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Spinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited ataxia. Currently, no preventative or disease-modifying treatments exist for this progressive neurodegenerative disorder, although efforts using gene silencing approaches are under clinical trial investigation. The disease is caused by a CAG repeat expansion in the mutant gene, ATXN3, which produces an abnormally enlarged polyglutamine tract in the mutant ATXN3 protein. Similar to other paradigmatic neurodegenerative diseases, studies evaluating the pathogenic mechanism focus primarily on neuronal implications. Consequently, therapeutic interventions generated to target these deficiencies often overlook non-neuronal contributions to disease. Our lab recently reported that oligodendrocytes display some of the earliest and most progressive dysfunction in SCA3 mice. Evidence of disease-associated oligodendrocyte signatures has also been reported in other neurodegenerative diseases, including Alzheimer’s disease, ALS, Parkinson’s disease, and Huntington’s disease. Here, we assess the effects of anti-ATXN3 antisense oligonucleotide (ASO) treatment on oligodendrocyte dysfunction in both premanifest and symptomatic SCA3 mouse models. We report a severe, but modifiable, deficit in oligodendrocyte maturation caused by the toxic gain-of-function of mutant ATXN3 early in SCA3 disease progression that is transcriptionally, biochemically, and functionally rescued with anti-ATXN3 ASO. Our results establish the necessity of considering non-neuronal targets in future neurodegenerative disease therapies.

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Myelinating Glia: Potential Therapeutic Targets in Polyglutamine Spinocerebellar Ataxias

Cited by 4 publications

References 121 publications

Sensitivity of Advanced Magnetic Resonance Imaging to Progression over Six Months in Early Spinocerebellar Ataxia

Sensitivity of Advanced Magnetic Resonance Imaging to Progression over Six Months in Early Spinocerebellar Ataxia

ASOs are an effective treatment for disease-associated oligodendrocyte signatures in premanifest and symptomatic SCA3 mice

ASOs are an effective treatment for disease-associated oligodendrocyte signatures in premanifest and symptomatic SCA3 mice

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