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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.



Agilis Biotherapeutics Updates on Progress in CNS Gene Therapy Programs

Agilis Therapeutics announced the completion of the Company's Phase IIb clinical study of gene therapy for the treatment of Aromatic L-amino acid decarboxylase (AADC) deficiency and the preparation of a Biologics License Application (BLA) for submission to the FDA. In addition to being a milestone for the AADC community, advances in the AADC program are informative for the company's Friedreich's ataxia (FA) program. The Company also announced that the program in FA, AGIL-FA, an AAV-based vector for delivery of the human FXN gene intended to address the CNS manifestations of FA, is advancing rapidly through nonclinical, manufacturing and regulatory activities toward human clinical study.

Read the entire article HERE

Molecular Alterations in a Mouse Cardiac Model of Friedreich's Ataxia: An Impaired Nrf2 Response Mediated via Up-Regulation of Keap1 and Activation of the Gsk3β Axis

Nuclear factor-erythroid 2-related factor-2 (Nrf2) is a master regulator of the anti-oxidant response. However, studies in models of Friedreich's ataxia (FA), a neuro- and cardio-degenerative disease associated with oxidative stress, reported decreased Nrf2 expression due to unknown mechanisms. Using a mouse conditional frataxin knockout (KO) model in the heart and skeletal muscle, we examined the Nrf2 pathway in these tissues. Frataxin KO results in fatal cardiomyopathy, while skeletal muscle was asymptomatic. In the KO heart, protein oxidation and a decreased GSH:GSSG ratio was observed, but the opposite was found in skeletal muscle. Decreased total and nuclear Nrf2 and increased levels of its inhibitor, Keap1, were evident in the KO heart, but not skeletal muscle. Moreover, a mechanism involving activation of the nuclear Nrf2 export/degradation machinery via Gsk3β-signaling was demonstrated in the KO heart. This process involved: (i) increased Gsk3β activation; (ii) β-TrCP nuclear accumulation; and (iii) Fyn phosphorylation. A corresponding decrease in Nrf2-DNA-binding activity and a general decrease in Nrf2-target mRNA was observed in KO hearts. Paradoxically, protein levels of some Nrf2 anti-oxidant targets were significantly increased in KO mice. Collectively, cardiac frataxin-deficiency reduces Nrf2 levels via two potential mechanisms: increased levels of cytosolic Keap1, and activation of Gsk3β-signaling that decreases nuclear Nrf2. These findings are in contrast to the frataxin-deficient skeletal muscle, where Nrf2 was not decreased.

Read the entire article HERE

Lipophilic methylene violet analogues as modulators of mitochondrial function and dysfunction

In an effort to identify methylene blue analogues having improved antioxidant activity, a series of new methylene violet analogues have been designed and synthesized. The analogues were prepared following a synthetic route that is more efficient than the previously reported methods, both in terms of yield and purity of the final products. The methylene violet analogues were evaluated for their ability to preserve mitochondrial function in Friedreich's ataxia (FRDA) lymphocytes. The analogues were shown to be efficient ROS scavengers, and able to protect cultured FRDA lymphocytes from oxidative stress resulting from inhibition of complex I. The analogues also preserved mitochondrial membrane potential and augmented ATP production. The analogues were found to be better antioxidants than the parent compounds methylene blue and methylene violet.

Read the entire article HERE

Reversible Axonal Dystrophy by Calcium Modulation in Frataxin-Deficient Sensory Neurons of YG8R Mice

Friedreich's ataxia (FRDA) is a peripheral neuropathy involving a loss of proprioceptive sensory neurons. Studies of biopsies from patients suggest that axonal dysfunction occurs before the death of proprioceptive neurons in a dying-back process. This group investigated how the deficiency of frataxin in sensory neurons of dorsal root ganglia (DRG) of the YG8R mouse model causes a sequence of events that lead to neuronal death. These observations support the author's proposed model of FRDA distal axonopathy based on axonal focal damage. The group link this damage to the formation of "axonal spheroids," formation of which also correlated with oxidative stress and changes in calcium signaling. The authors suggest that axonal spheroids may be a consequence of calcium imbalance, thus that the quenching or removal extracellular Ca2+ to prevent spheroids formation might reduce disease progression. In their neuronal model, treatments with BAPTA and o-phenanthroline reverted the axonal dystrophy and the mitochondrial dysmorphic parameters. These results support the hypothesis that axonal pathology is reversible in FRDA by pharmacological manipulation of intracellular Ca2+ with Ca2+ chelators or metalloprotease inhibitors, preventing Ca2+-mediated axonal injury. Thus, the modulation of Ca2+ levels may be a relevant therapeutic target to develop early axonal protection and prevent dying-back neurodegeneration.

Read the entire article HERE

Impact of diabetes in the Friedreich ataxia clinical outcome measures study

OBJECTIVE: Friedreich ataxia (FA) is a progressive neuromuscular disorder caused by GAA triplet repeat expansions or point mutations in the FXN gene. FA is associated with increased risk of diabetes mellitus (DM). This study assessed the age-specific prevalence of FA-associated DM and its impact on neurologic outcomes.

RESEARCH DESIGN AND METHODS: Participants were 811 individuals with FA from 12 international sites in a prospective natural history study (FA Clinical Outcome Measures Study, FACOMS). Physical function was assessed, using validated instruments. Multivariable regression analyses examined the independent association of DM with outcomes.

RESULTS: Mean age of participants was 30.1 years (SD 15.3, range: 7-82), 50% were female, and 94% were non-Hispanic white. 9% (42/459) of adults and 3% (10/352) of children had DM. Individuals with FA-associated DM were older (P < 0.001), had longer GAA repeat length on the least affected FXN allele (P = 0.037), and more severe FA (P = 0.0001). Of individuals with DM, 65% (34/52) were taking insulin. Even after accounting statistically for both age and GAA repeat length, DM was independently associated with greater FA symptom burden (P = 0.010), reduced capacity to perform activities of daily living (P = 0.021), and a decrease of 0.33 SDs on a composite performance measure (95% CI: -0.56-0.11, P = 0.004); the relative impact of DM was most apparent in younger individuals.

CONCLUSIONS: DM-associated FA has an independent adverse impact on well-being in affected individuals, particularly at younger ages. In future, evidence-based approaches for identification and management of FA-related DM may improve both health and function.

Read the entire article HERE

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