IBRI RESEARCH PUBLISHED: Exenatide induces frataxin expression and improves mitochondrial function in Friedreich ataxia
Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease with a prevalence of 1/30,000 in Whites. Most patients are homozygous for a GAA trinucleotide repeat expansion in the first intron of the frataxin-encoding FXN gene; a few are compound heterozygous for an expanded GAA repeat and an FXN loss-of-function mutation (1). Most normal FXN alleles have 8–9 repeats, a few up to 30–35, while expanded alleles contain from 70 to over 1700 repeats that interfere with FXN transcription by heterochromatin silencing (2–4). Longer repeats lead to more severe repression of frataxin expression (65%–95% decreased compared with healthy controls), such that most residual frataxin in patients with FRDA derives from the allele with the shorter GAA repeat (GAA1), the length of which correlates inversely with age of onset and directly with disease severity (1, 5, 6). The mitochondrial protein frataxin is involved in iron-sulfur cluster (ISC) biogenesis, and reduced frataxin expression leads to impaired function and/or expression of ISC-containing enzymes, iron accumulation in the mitochondrial matrix, oxidative stress, and mitochondrial dysfunction (7, 8). Besides the neurologic manifestations that include progressive gait ataxia, dysarthria, instability, oculomotor abnormalities, and loss of proprioception (9, 10), most patients with FRDA develop impaired glucose tolerance or diabetes (11–13) and hypertrophic cardiomyopathy, the latter being the main cause of premature death (6, 10, 14). Frataxin deficiency causes early loss of large dorsal root ganglia neurons followed by neuronal loss in the cerebellar dentate nucleus and other nervous system regions (15, 16), as well as dysfunction and apoptosis of insulin-producing pancreatic β cells (13, 17). Advances in the understanding of FRDA pathophysiology have so far not translated into treatments to prevent, delay, or revert disease manifestations. Antioxidants such as high-dose coenzyme Q10 plus vitamin E or idebenone (18) failed to show efficacy in clinical trials (19–21). Other approaches tried to enhance frataxin transcription or translation. Interferon-γ (22), erythropoietin (23), or epigenetic modifiers such as histone deacetylase inhibitors (HDACis) (4, 24) showed promising frataxin induction in in vitro and in vivo models, but the former 2 failed to reach endpoints in clinical trials (25, 26) and the latter requires pharmacologic optimization to improve efficacy and reduce toxicity (27).
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