clinical trial readiness for sca1 and sca3

Conditions: Spinocerebellar Ataxia Type 1; Spinocerebellar Ataxia 3

Summary: the investigators plan to fill the gap between the current state of clinical trial readiness and the optimal one for sca1 and sca3, which are fatal rare diseases with no treatments. through us-european collaborations, the investigators will establish the world's largest cohorts of subjects at the earliest disease stages, who will benefit most from treatments, validate an ability to detect disease onset and early progression by imaging markers, even prior to ataxia onset, and identify clinical trial designs that will generate the most conclusive results on treatment efficacy with small populations of patients.

spinocerebellar ataxia types 1 (sca1) and 3 (sca3) are rare, inherited neurodegenerative disorders that relentlessly progress to total disability and death. sca1 is the fastest progressing sca while sca3 is the most common sca in us and europe. expanded (cag)n repeats encoding polyglutamines (polyq) in the respective genes, ataxin 1 (atxn1) and ataxin 3 (atxn3), cause sca1 and sca3. disease-modifying therapies that target the pathway upstream of the complex pathogenic cascade will offer ultimate treatment. scientific premise and preclinical animal data strongly support msk1 inhibitors for sca1, citalopram for sca3, and nucleotide-based gene silencing for both scas as drugs to be examined in clinical trials in five years. however, the challenge that investigators face in current clinical trial readiness for such disease-modifying therapies is that the modest effect size of candidate drugs as measured by the scale for the assessment and rating of ataxia (sara; the most robust and well-validated clinical outcome assessment measure) requires large cohorts of study subjects to achieve sufficient statistical power. to accomplish the goal of establishing clinical trial readiness, the investigators propose to launch an international, multi-site effort focusing on premanifest mutation carriers and patients in an early disease stage, who are likely responders to the disease-modifying interventions prior to irreversible brain damage. based on the investigators' studies funded by nih and the national ataxia foundation (naf), the us ataxia consortium has developed an unprecedented opportunity for tight collaborations with the european ataxia study group to jointly address this challenge and establish clinical trial readiness for sca1 and sca3. to achieve this goal, the investigators propose the following specific aims: aim 1. establish the world's largest cohorts of premanifest/early sca1 and sca3 by combining cohorts, clinical outcome assessment data and biofluid samples (blood, cerebrospinal fluid) from us and europe aim 2. validate mr morphological, biochemical and functional biomarkers in premanifest and early sca1 and sca3 aim 3. adapt recent developments on statistical design and analysis of small population trials to scas.

Eligibility criteria:
inclusion criteria: 1. signed informed consent (no study-related procedures may be performed before the subject has signed the consent form). 2. subjects of either sex aged 18 to 65 with presence of symptomatic ataxic disease or asymptomatic mutation carrier or 3. subjects with definite molecular diagnosis of sca1 or sca3 or another affected family member 4. subjects of any age with previous diagnosis of early stage sca1 and sca3 5. subjects capable of understanding and complying with protocol requirements 6. no changes in physical/occupational therapy status within two months prior to enrollment exclusion criteria: 1. subjects currently receiving, or having received within 2 months prior to enrollment into this study, any investigational drug. 2. subjects who do not wish to or cannot comply with study procedures. 3. genotype consistent with other inherited ataxias 4. changes in coordinative physical and occupational therapy for ataxia 2 months prior to study participation 5. concomitant disorder(s) or condition(s) that affects assessment of ataxia or severity of ataxia during this study 6. aim 2 exclusion criteria also includes the inability to undergo mri scanning and weight over 300lbs, presence of structural abnormalities such as subdural hematoma or primary or metastatic neoplasms and concurrent illnesses or treatment interfering with cognitive function such as stroke or normal pressure hydrocephalus.

Keywords: spinocerebellar ataxia ataxia ataxias sca1 sca3 spinocerebellar ataxia type 1 spinocerebellar ataxia type 3 readisca sca scas clinical trial readiness