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FARAFARA Cure FA

 

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.

 


 

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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Erythropoietin and Friedreich Ataxia: Time for a Reappraisal?

FA is a rare neurological disorder due to deficiency of the mitochondrial protein frataxin. Frataxin deficiency results in impaired mitochondrial function and iron deposition in affected tissues. Erythropoietin (EPO) is a cytokine which was mostly known as a key regulator of erythropoiesis until cumulative evidence showed additional neurotrophic and neuroprotective properties. These features offered the rationale for advancement of EPO in clinical trials in different neurological disorders in the past years, including FA. Several mechanisms of action of EPO may be beneficial in FA. First of all, EPO exposure results in some frataxin upregulation in vitro and in vivo. By promoting erythropoiesis, EPO influences iron metabolism and induces shifts in iron pool which may ameliorate conditions of free iron excess and iron accumulation. Furthermore, EPO signaling is crucial for mitochondrial gene activation and mitochondrial biogenesis. Up to date nine clinical trials investigated the effects of EPO and derivatives in FA. The majority of these studies had a proof-of-concept design. Considering the natural history of FA, all of them were too short in duration and not powered for clinical changes. However, these studies addressed significant issues in the treatment with EPO, such as (1) the challenge of the dose finding, (2) stability of frataxin up-regulation, (3) continuous versus intermittent stimulation with EPO/regimen, or (4) tissue changes after EPO exposure in humans in vivo (muscle biopsy, brain imaging). The recent development of small EPO mimetics which maintain cytoprotective properties without erythropoietic action may open a new era in EPO research for the treatment of FA.

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