Frataxin deficiency in FA leads to changes in iron handling by the body as well as changes in metabolic pathways, the way chemicals are broken down in the body. Clinical research in FA has advanced rapidly in recent years, with the development of clinical measures and successful execution of clinical trials such as MOXIe (omaveloxolone). Still, future clinical trials need novel ways based on biology to assess outcomes in clinical studies and to understand better how new drugs alter the causes of disease in patients with FA. At present, Spectroscopy (a type of MRI scan) can provide utility in some situations, but ongoing studies of brain structure and chemicals reflect the late pathophysiology of FA and thus are unlikely to be early markers of disease or early effects of treatment. In this proposal, Dr. Lynch, Dr. Gaetz, and Dr. Roberts will use advanced, edited magnetic resonance spectroscopy to assess brain levels of glutathione (a molecule that is an indicator of the presence of free radicals and oxidative stress) and the neurotransmitter γ-aminobutyric acid (GABA) (a compound involved in nerve communication in the brain), two potential markers of the proximal pathophysiology of FRDA. The hypothesis of this proposal is that the assessment of brain glutathione and GABA levels provides accurate biomarkers of disease status in FA. In this pilot proposal, using advanced edited magnetic resonance spectroscopy, the investigators will assess GABA and glutathione in the brain motor cortex of 10 FA subjects and 10 age-matched controls. They will also assess the relationship of glutathione and GABA motor cortex levels to markers of FA disease severity. Finally, 5 FA subjects will be tested after initiation of omaveloxolone therapy (as it becomes clinically available). This will allow us to determine whether glutathione spectroscopy responds to the new drug omaveloxolone and whether imaging of glutathione and/or GABA will advance monitoring of FA.
General Research Grant | Outcome Measures & Biomarkers
Imaging of glutathione and GABA in the brain as biomarkers of Friedreich Ataxia
Grant Awarded | Dec 2022
David Lynch, MD, PhD, William Gaetz, PhD, & Timothy Roberts, PhD
Children’s Hospital of Philadelphia
Active
The FARA Grant Program is proud to award a General Research Grant to David Lynch, MD, PhD, William Gaetz, PhD, & Timothy Roberts, PhD at Children’s Hospital of Philadelphia.
LAY SUMMARY