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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.

Thioredoxin and Glutaredoxin Systems as Potential Targets for the Development of New Treatments in Friedreich's Ataxia

The thioredoxin family consists of a small group of redox proteins present in all organisms and composed of thioredoxins (TRXs), glutaredoxins (GLRXs) and peroxiredoxins (PRDXs) which are found in the extracellular fluid, the cytoplasm, the mitochondria and in the nucleus with functions that include antioxidation, signaling and transcriptional control, among others. The importance of thioredoxin family proteins in neurodegenerative diseases is gaining relevance because some of these proteins have demonstrated an important role in the central nervous system by mediating neuroprotection against oxidative stress, contributing to mitochondrial function and regulating gene expression. Specifically, in the context of Friedreich's ataxia (FRDA), thioredoxin family proteins may have a special role in the regulation of Nrf2 expression and function, in Fe-S cluster metabolism, controlling the expression of genes located at the iron-response element (IRE) and probably regulating ferroptosis. Therefore, comprehension of the mechanisms that closely link thioredoxin family proteins with cellular processes affected in FRDA will serve as a cornerstone to design improved therapeutic strategies.

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Minoryx's clinical candidate leriglitazone shows clinical benefit in a proof of concept Phase 2 study in Friedreich's ataxia

MIN-102 (leriglitazone) is an orally bioavailable selective PPAR gamma agonist that is one of the metabolites of pioglitazone and has been shown to have improved access to the central nervous system and better safety profile. Several research studies in both animal and cell models have identified that the peroxisome-proliferator activator receptor gamma (PPARγ)/PPARγ coactivator 1 alpha (Pgc1a) pathway is dysregulated when there is frataxin deficiency thus making this pathway a potential therapeutic target for FA.

Minoryx Therapeutics conducted a clinical trial that was a multicenter, double-blind and placebo-controlled study with leriglitazone. 39 Friedreich's ataxia patients were enrolled, with 32 completing the study. Today they announced that topline results show improvement of relevant disease biomarkers in the brain and spinal cord in this proof of concept Phase 2 study. Treatment with leriglitazone resulted in PPARg engagement, within the target range, in all patients as assessed by the relevant biomarker (adiponectin). Results of the trial show modulation of the Frataxin pathway and restoration of the bioenergetics deficits by leriglitazone in Friedreich's ataxia patients. They also reported that leriglitazone was well tolerated with some anticipated adverse events (side-effects) known to drugs with this mechanism of action.

Minoryx indicates that based on these results they are advancing the program and will be meeting with regulatory agencies, FDA and EMA, and planning a confirmatory study in FA.

Thank you to all of the individuals with FA who volunteered, investigators, and study sites for your participation and conduct of this important research trial and to Minoryx for their commitment to developing treatments for FA and their efficiency and transparency in sharing results from the trial. In the coming months, as Minoryx Therapeutics determines the next steps for the clinical development of this program, we will share that information with the community.

Click here to read the full press release

Calcitriol increases frataxin levels and restores mitochondrial function in cell models of Friedreich Ataxia

In primary cultures of dorsal root ganglia neurons, frataxin depletion results in decreased levels of the mitochondrial calcium exchanger NCLX, neurite degeneration and apoptotic cell death. This study shows that frataxin-deficient dorsal root ganglia neurons display low levels of ferredoxin 1, a mitochondrial Fe/S cluster-containing protein that interacts with frataxin and, interestingly, is essential for the synthesis of calcitriol, the active form of vitamin D. Calcitriol supplementation, used at nanomolar concentrations, is able to reverse the molecular and cellular markers altered in DRG neurons. Calcitriol is able to recover both ferredoxin 1 and NCLX levels and restores mitochondrial membrane potential indicating an overall mitochondrial function improvement. Accordingly, reduction of apoptotic markers and neurite degeneration was observed and, as a result, cell survival was also recovered. All these beneficial effects would be explained by the finding that calcitriol is able to increase the mature frataxin levels in both frataxin-deficient DRG neurons and cardiomyocytes; remarkably, this increase also occurs in lymphoblastoid cell lines derived from Friedreich Ataxia (FA) patients. In conclusion, these results provide molecular bases to consider calcitriol as an easy and affordable therapeutic approach for FA patients.

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Larimar Therapeutics Announcement/Program Update

BALA CYNWYD, Pa., Dec. 08, 2020 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (“Larimar”) (Nasdaq: LRMR), a clinical-stage biotechnology company focused on developing treatments for complex rare diseases, today announced the completion of dosing from the Company’s Phase 1 single ascending dose (SAD) clinical trial (n=28) evaluating CTI-1601 as a treatment for Friedreich’s ataxia (FA) and provided additional updates regarding the status of an ongoing multiple ascending dose (MAD) clinical trial, the timing of Phase 1 topline results, and future activities planned for 2021.

A Safety Review Committee reviewed preliminary blinded data after each cohort of the placebo-controlled SAD clinical trial and recommended continuation of the trial. Dosing has been completed and based on preliminary data, single subcutaneous injections of CTI-1601 at doses up to 100 mg are thought to have been well tolerated. Injection site adverse events were mild and transient, and no serious adverse events were reported. Analysis of clinical trial results remains ongoing...

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Mitochondrial dysfunction in the development and progression of neurodegenerative diseases

In addition to ATP synthesis, mitochondria are highly dynamic organelles that modulate apoptosis, ferroptosis, and inflammasome activation. Through executing these varied functions, the mitochondria play critical roles in the development and progression of neurodegenerative diseases including Alzheimer disease, Parkinson disease, Huntington disease, and Friedreich ataxia, among others. Impaired mitochondrial biogenesis and abnormal mitochondrial dynamics contribute to mitochondrial dysfunction in these diseases. Additionally, dysfunctional mitochondria play critical roles in signaling for both inflammasome activation and ferroptosis. Therapeutics are being developed to circumvent inflammasome activation and ferroptosis in dysfunctional mitochondria. Targeting these aspects of mitochondrial dysfunction may present viable therapeutic strategies for combating the neurodegenerative diseases. This review aims to summarize the role of the mitochondria in the development and progression of neurodegenerative diseases and to present current therapeutic approaches that target mitochondrial dysfunction in these diseases.

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