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Scientific News

FARA funds research progress

In this section, you will find the most recent FA research publications, many of which are funded by FARA, as well as information on upcoming conferences and symposiums. You can search for articles by date using the archive box in the right hand column. To locate FARA Funded or Supported Research, click the hyperlink in the right hand column. You may also search for specific content using key words or phrases in the search button at the top right of your screen. Please be sure to visit other key research sections of our website for information on FARA’s Grant Program and the Treatment Pipeline.



Microvascular pathology in Friedreich cardiomyopathy

Heart disease is an integral part of Friedreich ataxia (FA). In addition to cardiomyocytes getting bigger, death of muscle fibers, and inflammatory infiltration, heart tissues show fibrosis and disorganized capillaries. This group examined the left ventricular wall (LVW) of 41 homozygous and 2 compound heterozygous FA patients aged 10-87 and 21 controls aged 2-69. They quantified the numbers of capillaries for comparison with the number of cardiac cells in the same field. The median ratio of capillaries to cardiomyocytes in samples from unaffected individuals was 1.0. In FA, the number of cardiomyocytes/mm² was significantly less, and the median ratio of capillaries to heart fibers was 2.0. There was a significant correlation of the expanded guanine-adenine-adenine trinucleotides (shorter allele, GAA1) with a younger age of onset, shorter disease duration, and lower cardiomyocyte counts. The ratio of capillaries to heart fibers was higher in patients with long GAA1 repeat expansions. Data supports endothelial-to-mesenchymal transition in the pathogenesis of cardiac fibrosis in FA. We propose that the pathogenesis of FA heart disease includes primary fibrosis.

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p53 Binds Preferentially to Non-B DNA Structures Formed by the Pyrimidine-Rich Strands of GAA·TTC Trinucleotide Repeats Associated with Friedreich's Ataxia

Expansions of trinucleotide repeats are associated with genetic disorders such as Friedreich's ataxia. The tumor suppressor p53 is a central regulator of cell fate in response to different types of insults. p53 protein recognizes specific structures in the DNA, dependent on sequence and structure. The focus of this work was analysis of the p53 structure-selective recognition of repeat sequences associated with human neurodegenerative diseases. The group studied how p53 and several deletion variants bound to repeat sequences folded into different shapes that occur in cells. They show that p53 binds to all studied DNA structures that are not the standard helical structure (non-B DNA structure), with a preference for structures formed by pyrimidine rich strands. They found a specific part of p53 to be crucial for recognition of such non-B DNA structures. They also observed that p53 prefers binding to the Pyrimidine-rich strand over the purine rich strand in non-B DNA from the repeat sequence in the first intron of the frataxin gene. The binding of p53 to this region was confirmed in human Friedreich's ataxia fibroblast and adenocarcinoma cells. Altogether these observations provide further evidence that p53 binds to non-B DNA structures in trinucleotide repeat sequences.

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Dimethyl fumarate dosing in humans increases frataxin expression: A potential therapy for Friedreich's Ataxia

High throughput screening of clinically used drugs identified Dimethyl fumarate (DMF) as protective in FA patient cells. This group demonstrates that DMF significantly increases frataxin gene (FXN) expression in FA cell models, FA mouse models and in DMF treated humans. DMF also rescues mitochondrial biogenesis deficiency in FA-patient derived cell models. In FA patient cells, they demonstrate that DMF significantly increases initiation of new FXN transcripts and reduction in DNA structures thought to slow FXN production, significantly increasing FXN expression. Lastly, DMF dosed Multiple Sclerosis (MS) patients showed significant increase in FXN expression by ~85%. As deficiency in FXN is the primary cause of FA, and DMF is demonstrated to increase FXN expression in humans, with further work DMF could be a possible therapy for FA.

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Efficient Electroporation of Neuronal Cells Using Synthetic Oligonucleotides: Identifying Duplex RNA and Antisense Oligonucleotide Activators of Human Frataxin Expression

Oligonucleotide drugs are experiencing greater success in the clinic, encouraging the initiation of new projects. Resources are insufficient to develop every potentially important project and persuasive experimental data using cell lines close to disease target tissue is needed to prioritize candidates. This group has previously shown that synthetic nucleic acids can activate FXN expression in human patient-derived cells. They further tested these compounds in patient derived cells formed into cells that develop into neurons (iPSC-NPCs). Here we describe methods to deliver oligonucleotides and duplex RNAs into iPSC-NPC's cells using electroporation. Activation of FXN expression is potent, easily reproducible, and potencies parallel those determined using previous cell types. Oligonucleotides with various chemical modifications were active, providing multiple starting points for further development and highlighting improved potency as an important goal for preclinical development. This data support the conclusion that ASO-mediated activation of FXN is a feasible approach for treating FA and that electroporation is a robust method for introducing ASOs to modulate gene expressions in neuronal cells.

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Pharmacokinetics and pharmacodynamics of the novel Nrf2 activator omaveloxolone in primates

Omaveloxolone is a potential therapy thatactivates Nrf2, a master transcription factor that regulates genes with antioxidative, anti-inflammatory, and mitochondrial bioenergetic properties, and is being evaluated in patients with Friedreich's ataxia. This study evaluated the pharmacokinetics (PK), pharmacodynamics (PD) and tissue distribution of omaveloxolone in monkeys after single and multiple oral doses, and then compared these data to initial results in Friedreich's ataxia patients. A PK/PD model was generated with the monkey data, and used to further evaluate the Friedreich's ataxia patient PK profile. The authors found that oral administration of omaveloxolone to monkeys was associated with dose-linear plasma PK and readily measurable and dose-proportional concentrations in liver, lung, and brain. Dose-dependent induction of Nrf2 target genes was also observed. Clinically, oral administration of omaveloxolone to Friedreich's ataxia patients at incremental doses from 2.5 to 300 mg produced dose-proportional systemic exposures. Clinical doses of at least 80 mg were associated with meaningful improvements in neurological function in patients and generated plasma omaveloxolone concentrations consistent with those significantly inducing Nrf2 target genes in monkeys, as shown with the monkey PK/PD model. Overall, the monkey data demonstrate a well-characterized and dose-proportional PK and tissue distribution profile after oral administration of omaveloxolone, which was associated with Nrf2 activation. Further, systemic exposures to omaveloxolone that produce Nrf2 activation in monkeys were readily achievable in Friedreich's ataxia patients after oral administration.

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