Activation of Frataxin Protein Expression by Antisense Oligonucleotides Targeting the Mutant Expanded Repeat.
Li, L; Shen, X; Liu, Z; Norrbom, M; Prakash, TP; O'Reilly, D; Sharma, VK; Damha, MJ; Watts, JK; Rigo, F; Corey, DR
Nucleic Acid Ther
28
23-33
2018
Show Abstract
Friedreich's Ataxia (FA) is an inherited neurologic disorder caused by an expanded GAA repeat within intron 1 of the frataxin (FXN) gene that reduces expression of FXN protein. Agents that increase expression of FXN have the potential to alleviate the disease. We previously reported that duplex RNAs (dsRNAs) and antisense oligonucleotides (ASOs) complementary to the GAA repeat could enhance expression of FXN protein. We now explore the potential of a diverse group of chemically modified dsRNAs and ASOs to define the breadth of repeat-targeted synthetic nucleic acids as a platform for therapeutic development for FA. ASOs and dsRNAs can activate FXN protein expression in FA patient-derived cell lines that possess varied numbers of GAA repeats. Increased FXN protein expression was achieved by ASOs incorporating diverse chemical modifications with low nanomolar potencies, suggesting substantial flexibility in choosing compounds for further chemical optimization and animal studies. Our data encourage further development of ASOs as agents to treat FA. | 29341839
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Rapid and Complete Reversal of Sensory Ataxia by Gene Therapy in a Novel Model of Friedreich Ataxia.
Piguet, F; de Montigny, C; Vaucamps, N; Reutenauer, L; Eisenmann, A; Puccio, H
Mol Ther
26
1940-1952
2018
Show Abstract
Friedreich ataxia (FA) is a rare mitochondrial disease characterized by sensory and spinocerebellar ataxia, hypertrophic cardiomyopathy, and diabetes, for which there is no treatment. FA is caused by reduced levels of frataxin (FXN), an essential mitochondrial protein involved in the biosynthesis of iron-sulfur (Fe-S) clusters. Despite significant progress in recent years, to date, there are no good models to explore and test therapeutic approaches to stop or reverse the ganglionopathy and the sensory neuropathy associated to frataxin deficiency. Here, we report a new conditional mouse model with complete frataxin deletion in parvalbumin-positive cells that recapitulate the sensory ataxia and neuropathy associated to FA, albeit with a more rapid and severe course. Interestingly, although fully dysfunctional, proprioceptive neurons can survive for many weeks without frataxin. Furthermore, we demonstrate that post-symptomatic delivery of frataxin-expressing AAV allows for rapid and complete rescue of the sensory neuropathy associated with frataxin deficiency, thus establishing the pre-clinical proof of concept for the potential of gene therapy in treating FA neuropathy. | 29853274
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