Methods to Improve Clinical Trials for A-T

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PROJECT SUMMARY / ABSTRACT : Ataxia Telangiectasia (A-T) is a rare autosomal recessive disease affecting ~420 individuals in the United States. It is characterized by cerebellar degeneration, immunodeficiency, pulmonary disease and cancer susceptibility. A-T is complex and highly variable in terms of presentation and severity, but the factors responsible for its variability are not completely understood. The small population size, combined with wide phenotypic variability, have made clinical trials challenging. The goal of this project is to make clinical trials for A-T as effective as possible. We will leverage the world’s largest clinical center for A-T, 3 major university medical centers, 2 non-profits, and a parent support group to achieve our goals. The size and diversity of the Johns Hopkins A-T patient cohort makes us well-positioned to perform this study, which requires a highly diverse patient population. We hypothesize that it is possible to stratify patients into severity groups that are more homogeneous than the two broad groups in use today (classic and mild); that A-T causes upregulation of specific stress and homeostasis genes; and that an A-T specific functional scale will capture changes in disease severity that are meaningful to patients. These hypotheses will be tested through the following Specific Aims: 1. Prospective testing of A-T severity stratification using genotypic, phenotypic and standard laboratory markers. There is a need to better define severity groups in A-T beyond the current state of the art. Stratification of A-T disease severity will utilize our very large, diverse cohort of patients with A-T and will be achieved through identification of a variety of markers that predict or define disease severity. 2. Using RNASeq to identify systemic biomarkers that will correlate with disease phenotypes in children and adults with A-T, to help further stratify patients into severity groups and identify useful biomarkers for therapeutic trials. We propose that upregulation of specific stress and homeostasis genes will be generalizable across all ages of A-T patients; that people with classic A-T will have upregulation of specific inflammatory pathway genes compared to people with mild A-T using the classification schema in Aim 1; and that socio-environmental exposures including neighborhood poverty and nicotine exposure will modify gene expression differences and DNA methylation patterns in people with A-T. 3. Validating a Functional Scale for A-T to be used as an adjunct to neurologic scoring tools in therapeutic trials. An A-T- specific functional scale with sensitivity to capture meaningful changes in activities of daily living is essential to clinical trials of drugs meant to slow the progression of symptoms. We will develop a quantitative model that will provide a simple, objective way to determine disease severity in A-T, and a capture meaningful changes in function that impact engagement and participation in activities.