Stabilization of expandable DNA repeats by the replication factor Mcm10 promotes cell viability

Masnovo, C., Paleiov, Z., Dovrat, D. et al. Stabilization of expandable DNA repeats by the replication factor Mcm10 promotes cell viability. Nat Commun 15, 10532 (2024). doi:10.1038/s41467-024-54977-6  

Here, we show that deficiency of the essential replisome component Mcm10 dramatically elevates (GAA)n repeat instability in a budding yeast model by loss of proper CMG helicase interaction. When repair is inefficient, such as in the case of RPA depletion, breakage of under-replicated repetitive DNA can occur during G2/M, leading to loss of essential genes and cell death. We hypothesize that the CMG-Mcm10 interaction promotes replication through hard-to-replicate regions, assuring genome stability and cell survival.

Therapeutic hypoxia for mitochondrial disease via enhancement of hemoglobin affinity and inhibition of HIF-2α

Therapeutic hypoxia for mitochondrial disease via enhancement of hemoglobin affinity and inhibition of HIF-2α. Hong Wang, … , Fumito Ichinose, Vamsi K. Mootha. Published December 2, 2024. J Clin Invest. 2024;134(23):e185569. doi:10.1172/JCI185569. 

Our results provide preclinical proof of concept that simultaneously enhancing Hb oxygen affinity while antagonizing HIF-2α can mimic the effects of continuous hypoxic breathing for therapeutic benefit. The regimen did not confer as impressive a lifespan rescue as continuous breathing of 11% oxygen, probably because GBT440 has a short half-life (6), and for practical reasons, we treated the mice five weekdays per week. Future studies in humans are required to evaluate the safety of this combination, given that hypoxia can be associated with acute and long-term side effects. Such safety studies could pave the path for first-in-human “hypoxia-in-a-pill” trials in patients with mitochondrial disease.

Safeguarding the brain from oxidative damage

Kyung Hee Lee, Un Jeng Kim, Bae Hwan Lee, Myeounghoon Cha, Safeguarding the brain from oxidative damage, Free Radical Biology and Medicine, Volume 226, 2025, Pages 143-157, ISSN 0891-5849, doi:10.1016/j.freeradbiomed.2024.11.019. 

This paper aims to provide a concise and objective review of the oxidative and antioxidant pathways and their potential therapeutic applications in treating oxidative injury in the brain.

Exploring neuropsychiatric symptoms in Friedreich ataxia

Karamazovova, S., Stovickova, L., Jester, D.J. et al. Exploring neuropsychiatric symptoms in Friedreich ataxia. Sci Rep 14, 29076 (2024). doi:10.1038/s41598-024-80258-9 

 In conclusion, our findings show that NPS are common in FRDA and manifest not only as depression and anxiety but also as decreased motivation. It is difficult to distinguish whether these NPS are due to the neurodegenerative process or to the burden of living with a progressive, devastating disease, but in any case they need to be considered in clinical care.

Ferroptosis—disease perils and therapeutic promise

Ashley R. Brown et al. ,Ferroptosis—disease perils and therapeutic promise.Science386,848-849(2024).DOI:10.1126/science.adn703 

Identifying new strategies to inhibit ferroptosis offers therapeutic promise in contexts where ferroptotic cell death contributes to disease progression. By contrast, selective induction of ferroptosis is a promising approach in cancer therapeutics. Continuing discoveries about the mechanisms governing ferroptosis are likely to improve our understanding of disease biology and provide ideas that may assist in the diagnosis and treatment of diverse human maladies.

Therapeutic Activity of a Haematopoietic Stem Cell-Delivered Tissue-Penetrating Peptide in Friedreich's Ataxia Models

Pido, Jeffrey and Shaban, Enas and Moula, Shefta and Chritchely, Bethan and Whittaker, Thomas and Svensson, Stina and Anjomani Virmouni, Sara and Kalef-Ezra, Ester and Carr, Lucinda and Hassell, Jane and Thrasher, Adrian J. and Kurian, Manju A. and Santilli, Giorgia and Sala, Arturo and Administrator, Sneak Peek, Therapeutic Activity of a Haematopoietic Stem Cell-Delivered Tissue-Penetrating Peptide in Friedreich's Ataxia Models. doi:10.2139/ssrn.5026639 

We developed a replacement strategy for this disease by designing a fusion peptide containing secretion and tissue penetrating sequences at the amino terminus of the frataxin precursor protein. Secretion and penetration of the fusion peptide was validated in experiments that confirmed its ability to localise in the mitochondria and rescue the biochemical defects and apoptotic phenotype of FRDA patient cells, in vitro. Autologous transplantation of the modified HSPCs resulted in stable secretion of the peptide in the blood stream of recipient animals, impacting disease progression by delaying the manifestation of motor-coordination/sensory symptoms, paralleled by improved biochemical and anatomical parameters.

Additional Data from Phase 1 Studies and Phase 2 Dose Exploration Study Supporting the Nomlabofusp Clinical Program at ICAR 2024

BALA CYNWYD, Pa., Nov. 18, 2024 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (Larimar) (Nasdaq: LRMR), a clinical-stage biotechnology company focused on developing treatments for complex rare diseases, last week presented data from the Company’s Phase 1 studies and the Phase 2 dose exploration study of nomlabofusp at the International Congress for Ataxia Research (ICAR) in London, U.K. Data from a total of 61 adults with FA who participated in these studies evaluating short-term (up to 28 days) subcutaneous administration of 25, 50, 75, and 100 mg nomlabofusp were further evaluated and presented in three posters during the conference.

Posters available

Precision medicine and Friedreich ataxia: promoting equity, beneficence, and informed consent for novel gene therapies

Kwa, F., Kendal, E. Precision medicine and Friedreich ataxia: promoting equity, beneficence, and informed consent for novel gene therapies. Int J Equity Health 23, 230 (2024). doi:10.1186/s12939-024-02318-w 

This article will use FA as an example to explore some of the practical and ethical issues emerging in precision medicine for rare diseases. It will first describe the existing management strategies available for FA patients, before considering the potential impact of gene therapy trials on the prevention and treatment of disease symptoms. Finally, ethical considerations will be discussed, including equity of access and managing resource allocation dilemmas; balancing benefits, burdens and harms; and gaining informed consent for novel treatments.

frataxin is essential for zebrafish embryogenesis and pronephros formation

frataxin is essential for zebrafish embryogenesis and pronephros formation. Wesley S. Ercanbrack, Austin Dungan, Ella Gaul, Mateo Ramirez, Rebecca A. Wingert; Front. Cell Dev. Biol. Sec. Embryonic Development Volume 12 - 2024 | doi: 10.3389/fcell.2024.1496244

Here, we developed a zebrafish loss of function model to study the role of Fxn during early embryogenesis. fxn-deficient zebrafish exhibited failure to thrive, edema, elevated cell death in the central nervous system, craniofacial defects, as well as stunted renal development and reduced kidney function that was associated with alterations in nephron lineage formation. Our findings reveal that Fxn is crucial for the normal development of multiple embryonic tissues, and disclose for the first time that Fxn plays important roles in supporting the pattern formation of the embryonic kidney.

PTC Therapeutics Provides Corporate Update and Reports Third Quarter 2024 Financial Results

WARREN, N.J., Nov. 7, 2024 /PRNewswire/ -- PTC Therapeutics, Inc. "We continue to achieve excellent revenue performance allowing us to raise full-year revenue guidance. In addition, we have submitted three approval applications to FDA so far this year, all of which have been accepted for review, and plan a fourth submission for vatiquinone for Friedreich ataxia in December. 

PTC plans to submit an NDA for vatiquinone for the treatment of Friedreich ataxia in December 2024.