Collaborative Efforts for Spinocerebellar Ataxia Research in the United States: CRC-SCA and READISCA

Abstract

Spinocerebellar ataxias are progressive neurodegenerative disorders primarily affecting the cerebellum. Although the first disease-causing gene was identified nearly 30 years ago, there is no known cure to date, and only a few options exist for symptomatic treatment, with modest effects. The recently developed tools in molecular biology, such as CRISPR/Cas9 and antisense oligonucleotides, can directly act on the disease mechanisms at the genomic or RNA level in disease models. In a nutshell, we are finally just one step away from clinical trials with therapies targeting the underlying genetic cause. However, we still face the challenges for rare neurodegenerative diseases: difficulty in obtaining a large cohort size for sufficient statistical power and the need for biomarkers and clinical outcome assessments (COA) with adequate sensitivity to reflect progression or treatment responses. To overcome these obstacles, ataxia experts form research networks for clinical trial readiness. In this review, we retrace our steps of the collaborative efforts among ataxia researchers in the United States over the years to study and treat these relentless disorders and the future directions of such research networks.

Spinocerebellar ataxia clinical trials: opportunities and challenges

“…Structural abnormalities are accompanied by disturbances in white matter tracts as demonstrated by diffusion tensor imaging (DTI), with abnormalities discernible not just in the cerebellum and cerebellar peduncles but also in the brainstem and cerebral white matter. 3,96,97 These imaging abnormalities align 91 inferior, 91 and superior 91 frontal lobe, 91 lateral temporal lobe, 91 parietal lobe, and vermis 91 [ 99 mTc]ECD SPECT:↓perfusion in bilateral cerebellum 92 and vermis 92 [ 123 I]iomazenil SPECT:↓binding in cerebellum, 93 cerebral cortex, 93 thalamus, 93 41,98,100 Furthermore, the glial marker myoinositol has been shown to increase with gliosis. 100 Other metabolites that can be monitored include the metabolic marker creatine/phosphocreatine and the membrane marker choline.…”

“…Multiple successful international research cohorts have been developed (Table 3 ). 2 , 47 , 62 , 97 , 136 , 137 For instance, In the United States, there is a large consortium for the SCAs called the Clinical Research Consortium for Spinocerebellar Ataxias (CRC‐SCA), while in Europe, the Ataxia Study Group has organized multiple international collaborative research projects including the European Integrated Project on Spinocerebellar Ataxia (EuroSCA) and the European Spinocerebellar Ataxia Type 3/Machado‐Joseph Disease Initiative (ESMI). Looking forward, there are on‐going global initiatives like SCA Global, which aims to accelerate biomarker discovery and treatment development via standardization of research procedures and expansion of research efforts around the world.…”

Serum NfL in spinocerebellar ataxia type 1 is increased already at the preataxic stage, correlating with proximity to clinical onset

“…Secondly, validation of our findings (in particular of e.g. the MRI findings) is needed in independent larger multicentric cohorts of SCA1 subjects, like the READISCA cohort 31 .…”

The History of Gene Hunting in Hereditary Spinocerebellar Degeneration: Lessons From the Past and Future Perspectives

“…International registries, such as SCA Global and ARCA Global 2 and SPATAX, 3 have been launched to meet the need for better documentation of SCD cases. A prerequisite for international patient registries, besides appropriate research ethics policies, is the development of unified common disability scales to facilitate analysis and comparison ( Trouillas et al, 1997 ; Lin et al, 2020 ). Many disability scales have been developed for SCD, the most commonly used scales being the scale for the assessment and rating of ataxia (SARA) and the International Cooperative Ataxia Rating Scale (ICARS; Perez-Lloret et al, 2020 ).…”