[R01] Probing mechanisms of frataxin repression in Friedreich’s ataxia
Ente: National Institute of Neurological Disorders and Stroke
Scadenza: 2031-03-31
Importo max: 696.710 EUR
Paese: US
Descrizione
PROJECT SUMMARY/ABSTRACT
Friedreich’s ataxia (FRDA/FA) is the most commonly inherited autosomal recessive neurodegenerative disease
for which there is no cure. This debilitating and life-limiting disease occurs due to significant reduction in frataxin
(FXN), a nuclear encoded protein that plays a role in iron metabolism in mitochondria. Homozygous expansion
of GAA triplet repeats in the first intron of FXN repress mRNA synthesis in FRDA cells. The resulting FXN protein
deficiency leads to progressive neurodegeneration, hypertrophic cardiomyopathy and diabetes mellitus. A novel
class of synthetic gene regulators (SynGRs) that target GAA repeat expansions in FXN and actively stimulate
Pol II function across the silenced gene are being developed by our group. In patient-derived cells, the prototype
SynGR1 (SynTEF1) and its next-generation derivatives, restore FXN to levels observed in healthy individuals.
The premise that underlies this proposal is that rigorous evaluation of the SynGR1-mediated changes in the
epigenetic landscape and/or the formation of repressive DNA structures will reveal the extent to which of these
mechanisms contribute to FXN silencing in patient-derived cells. This understanding will result in more
mechanistically guided design of precision-tailored SynGRs. Moreover, testing next generation SynGRs in
disease-relevant cell types where frataxin deficiency results in ataxia and morbidity is an essential step toward
the development of gene-tailored precision therapeutics. In support of that overarching goal, modular design of
SynGRs readily lends itself to the design and development of bespoke molecules that would target other
microsatellite repeat expansions and remedy the expression of dysregulated genes that contribute to the etiology
of a growing list of diseases and disorders, including Fragile-X syndrome, SCA27B ataxia, Myotonic Dystrophy
type 1, and Ewing’s sarcoma.
Istituzione: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
PI: ASEEM Z ANSARI
Progetto: 2R01NS108376-12
Settori: National Institute of Neurological Disorders and Stroke
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