The spinocerebellar ataxias (SCAs) comprise more than 40 autosomal dominant neurodegenerative disorders that present principally with progressive ataxia. Within the past few years, studies of pathogenic mechanisms in the SCAs have led to the development of promising therapeutic strategies, especially for SCAs caused by polyglutamine-coding CAG repeats. Nucleotide-based gene-silencing approaches that target the first steps in the pathogenic cascade are one promising approach not only for polyglutamine SCAs but also for the many other SCAs caused by toxic mutant proteins or RNA. For these and other emerging therapeutic strategies, well-coordinated preparation is needed for fruitful clinical trials. To accomplish this goal, investigators from the United States and Europe are now collaborating to share data from their respective SCA cohorts. Increased knowledge of the natural history of SCAs, including of the premanifest and early symptomatic stages of disease, will improve the prospects for success in clinical trials of disease-modifying drugs. In addition, investigators are seeking validated clinical outcome measures that demonstrate responsiveness to changes in SCA populations. Findings suggest that MRI and magnetic resonance spectroscopy biomarkers will provide objective biological readouts of disease activity and progression, but more work is needed to establish disease-specific biomarkers that track target engagement in therapeutic trials. Together, these efforts suggest that the development of successful therapies for one or more SCAs is not far away.
Bibliographical noteFunding Information:
Preclinical study is ongoing in B. Davidson’s laboratory under the NIH CREATE BIO199 grant support, which mandates rigorous preclinical study designs and go/no-go milestones200 Modest scientific premise. Needs rigorous preclinical studies. No relevant human clinical observations Modest scientific premise. Needs rigorous preclinical studies. No relevant human clinical observations Strong scientific premise. Good preclinical studies in two independent laboratories. No relevant human clinical observations Unknown mechanism(s) of the effect on the mutant ATXN3. Needs rigorous preclinical studies in SCA3 animal model(s). No relevant human clinical trials or observations Strong scientific premise for targeting the mRNA of the mutant ATXN3. Therapeutic efficacy shown in the rat model needs to be replicated in mouse models. Needs rigorous preclinical studies in SCA3 animal models. No relevant human clinical trials or observations Strong scientific premise for targeting the mRNA of the mutant ATXN3. Needs rigorous preclinical studies in SCA3 animal models. No relevant human clinical trials or observations Strong scientific premise for targeting the mRNA of the mutant ATXNs. Needs rigorous preclinical studies in animal models of SCA. No relevant human clinical trials or observations Toxic mutant mRNA is the target. Needs rigorous preclinical studies in SCA3 animal models. No relevant human clinical trials or observations
This work was supported by a grant from the US NIH (U01 NS104326-01) to T.A. (contact principal investigator), G.Ö. (multiple principal investigator) and H.L.P. (multiple principal investigator). T.A. is funded by the NIH (R01 NS083564), the National Ataxia Foundation and the Harriet and Joe B. Foster Endowment Fund on spinocerebellar ataxia (SCA) research and is collaborating with Pacific Biosciences on single-molecule real-time sequencing of the expanded SCA10 tandem repeat. G.Ö. receives grant funding from the NIH (R01 NS080816), the National Ataxia Foundation and Takeda Pharmaceuticals on SCA research. The Center for Magnetic Resonance Research is supported by the US National Institute of Biomedical Imaging and Bioengineering grant P41 EB015894 and the US Institutional Center Cores for Advanced Neuroimaging award P30 NS076408. H.L.P.’s work on SCAs is funded by the NIH (R01 NS038712), the National Ataxia Foundation, the Alfred Taubman Medical Research Institute, the University of Michigan Center for the Discovery of New Medicines, Cydan and the SCA Network of Sweden. He collaborates with Ionis Pharmaceuticals on antisense oligonucleotide therapy development for SCA3. The authors thank C. Potvin for helping with manuscript preparation and L. Eberly for assistance with sample size calculations.
T.A. has received honoraria and travel support from Pacific Biosciences. G.Ö. has received funding from Takeda Pharmaceuticals for a spinocerebellar ataxia (SCA) preclinical trial. H.L.P. recently completed a research contract with Ionis Pharmaceuticals for ASO treatments of SCA3.