Comprehensive Approach to Upregulate and Stabilize Frataxin mRNA Using Antisense Oligonucleotides
Abstract
Friedreich’s ataxia (FRDA), a severe progressive neurodegenerative disorder, is caused by an increasing number of specific DNA sequences, termed GAA repeats, that are present in the Friedreich’s ataxia gene (FXN). This error in DNA causes a block in the flow of the information from DNA to RNA, and ultimately leads to a deficiency of the final FXN product, a protein called frataxin. Frataxin is a small protein that is critical for proper function of other proteins in the body, especially those involved in production of the energy needed for our organs to properly work. Consequently, shortage of frataxin results in progressive destruction of organs and systems that require a large amount of energy, such us neurons of the brain and spinal cord, or the heart. That, in turn, leads to development of debilitating movement discoordination termed ataxia along with frequent and life-threatening heart disease, diabetes, loss of vision and hearing, and ultimately premature death. This relentless disease frequently manifests initially in children, adolescents, and young adults. Our preliminary studies showed that: (i) due to the presence of the GAA repeats and block of the information flow, FRDA patients produce a large amount of an incorrect RNA (message) that cannot be made into the correct frataxin protein and (ii) all FRDA patients produce a small but detectable amount of correct frataxin that functions properly, yet the amount is not enough to maintain healthy cells. In the proposed project, we will take a new approach aimed first to increase production of the correct frataxin RNA message and subsequently to increase the amount of frataxin protein in patient cells. We will use molecules called antisense oligonucleotides, or ASOs, which are small and specific DNA fragments that can spontaneously enter diseased cells, locate frataxin RNA, block synthesis of the incorrect RNA, and stabilize the correct frataxin RNA message to increase its molecular lifespan in patient cells. This strategy targets the process of frataxin production on two stages: increases production of the correct frataxin message RNA and subsequently allows existing frataxin RNA to be available longer to make frataxin protein. We predict that the result of oligonucleotide treatment will be an increased amount of frataxin protein in FRDA patient cells. In summary, this work contributes to the development of a new strategy to treat frataxin deficiency in Friedreich’s ataxia. Importantly, while no oligonucleotide-based therapy exists for Friedreich’s ataxia, therapies using similar technology have been recently approved by the United States Food and Drug Administration for treatment of Spinal Muscular Atrophy (SMA) or Duchenne Muscular Dystrophy (DMD), paving the path for broader use of oligonucleotides for other neurodegenerative diseases, including FRDA.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310337
Entities
People
- Marek Napierala
Organizations
- United States Army
- University of Texas Southwestern Medical Center