Friedreich?s ataxia (FRDA) is the most common form of hereditary ataxia, affecting approximately 1 in every 50,000 people in the United States and Europe. Symptoms typically begin between the ages of 5 and 15 years and worsen over time. The pathophysiology of FRDA reflects the deficiency of the protein frataxin. Reduced frataxin levels impair the function of mitochondrial iron- sulfur-cluster-containing enzymes and ability to produce ATP. Recently, amelioration of frataxin deficiency by gene therapy in mouse models of FRDA has produced impressive benefit in reversing the phenotype, providing an evidenced-based approach for treatment of FRDA patients. However, if attempts at reversal of frataxin deficiency were made today, they would be limited by the inability to assess frataxin levels in detail, as well as the inability to target therapies to the most biologically responsive individuals. To achieve this goal, we will validate the rigorous measurement of frataxin in larger cohorts to understand how it reflects disease activity. In the first 2 aims, we will test improved measures of frataxin deficiency and downstream metabolic function, and understand their utility in therapeutic monitoring. Peripheral samples (blood, buccal cells, isolated platelets, muscle) will be obtained from a large heterogeneous cohort of subjects with FRDA (n=200, n=20 for muscle). We will then assay the primary biomarker of disease severity, frataxin level, in the samples with a newly devised mass spectrometry based assay in order to understand the sensitivity of the assay and how such levels reflect disease status. In the second aim, we will examine mitochondrial-derived alterations in metabolic pathways in platelets and muscle to examine events downstream from frataxin deficiency.
In Aim 3, we will reevaluate long term natural history data from already established clinical instruments in the context of frataxin levels. Such data is available for a large >500 person cohort including the 200 who provide samples for the present study, and can be used to understand the relationship between frataxin levels and clinical status. Cumulatively these aims will define the utility of frataxin levels in clinical measurement of FRDA, and validate such approaches as definitive measures needed for design of informative trials of frataxin restoration.
The present proposal will characterize frataxin measurement as a biomarker in the rare disease Friedreich ataxia. This disorder is uncommon but deadly and serves as a model for many other disorders reaching clinical trials. Advances in the understanding of the features of Friedreich Ataxia (as proposed here) may affect the lives of a large number of people with and without this disease.
