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Rating scales and biomarkers for CAG-repeat spinocerebellar ataxias: Implications for therapy development.

ABSTRACT: Spinocerebellar ataxias (SCAs) are a group of dominantly-inherited cerebellar ataxias, among which CAG expansion-related SCAs are most common. These diseases have very high penetrance with defined disease progression, and emerging therapies are being developed to provide either symptomatic or disease-modifying benefits. In clinical trial design, it is crucial to incorporate biomarkers to test target engagement or track disease progression in response to therapies, especially in rare diseases such as SCAs. In this article, we review the available rating scales and recent advances of biomarkers in CAG-repeat SCAs. We divided biomarkers into neuroimaging, body fluid, and physiological studies. Understanding the utility of each biomarker will facilitate the design of robust clinical trials to advance therapies for SCAs.

SUBMITTER: Chen ML

PROVIDER: S-EPMC8111569 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Rating scales and biomarkers for CAG-repeat spinocerebellar ataxias: Implications for therapy development.

Chen Meng-Ling ML Lin Chih-Chun CC Rosenthal Liana S LS Opal Puneet P Kuo Sheng-Han SH

Journal of the neurological sciences 20210401

Spinocerebellar ataxias (SCAs) are a group of dominantly-inherited cerebellar ataxias, among which CAG expansion-related SCAs are most common. These diseases have very high penetrance with defined disease progression, and emerging therapies are being developed to provide either symptomatic or disease-modifying benefits. In clinical trial design, it is crucial to incorporate biomarkers to test target engagement or track disease progression in response to therapies, especially in rare diseases suc ...[more]

PMID: 33836316

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Project description: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.

Dataset Information

Rating scales and biomarkers for CAG-repeat spinocerebellar ataxias: Implications for therapy development.

Publications

Rating scales and biomarkers for CAG-repeat spinocerebellar ataxias: Implications for therapy development.

Similar Datasets

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