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.

Design Therapeutics Announces Third Quarter 2024 Financial Results and Reviews Near-term Milestones for GeneTACTM Portfolio

CARLSBAD, Calif., Nov. 07, 2024 (GLOBE NEWSWIRE) Friedreich Ataxia (FA) Design is on track to initiate the Phase 1 single ascending dose, normal healthy volunteer trial for DT-216P2 in the first half of 2025. The company anticipates beginning FA patient dosing later in 2025.

Abnormal visual cortex activity using functional magnetic resonance imaging in treatment resistant photophobia in Friedreich Ataxia

Araliya N. Gunawardene, Nicholas Reyes, David Valdes-Arias, Alpen Ortug, Jaime Martinez, Anat Galor, Eric A. Moulton, Abnormal visual cortex activity using functional magnetic resonance imaging in treatment resistant photophobia in Friedreich Ataxia, American Journal of Ophthalmology Case Reports, 2024, 102213,ISSN 2451-9936, doi:10.1016/j.ajoc.2024.102213. 

Our study highlights photophobia as one potential ocular manifestation of FDRA and suggests that one underlying contributor may be a decoupled cortical neurovascular response to light. Our study provides novel information that may guide physiologic understanding and future treatments in this disease.

Differential Gene Expression in Late-Onset Friedreich Ataxia: A Comparative Transcriptomic Analysis Between Symptomatic and Asymptomatic Sisters

Petrillo, S.; Perna, A.; Quatrana, A.; Silvestri, G.; Bertini, E.; Piemonte, F.; Santoro, M. Differential Gene Expression in Late-Onset Friedreich Ataxia: A Comparative Transcriptomic Analysis Between Symptomatic and Asymptomatic Sisters. Int. J. Mol. Sci. 2024, 25, 11615. doi:10.3390/ijms252111615  

The transcriptomic analysis revealed 398 differentially expressed genes. Notably, TLR4, IL20RB, and SLITRK5 were up-regulated, while TCF21 and GRIN2A were down-regulated, as validated by qRT-PCR. Gene ontology (GO) enrichment and network analysis highlighted significant involvement in immune response and neuronal functions. Our results, in particular, suggest that TLR4 may contribute to inflammation in FRDA, while IL20RB, SLITRK5, TCF21, and GRIN2A dysregulation may play roles in the disease pathogenesis. This study introduces new perspectives on the inflammatory and developmental aspects in FRDA, offering potential targets for therapeutic intervention.

Navigating the Orphan Medicinal Product Designation: Evidence Requirements for Gene Therapies in Europe

Palomo, G.M. et al., Navigating the Orphan Medicinal Product Designation: Evidence Requirements for Gene Therapies in Europe. Molecular Therapy, Volume 0, Issue 0. DOI: 10.1016/j.ymthe.2024.10.015 

To provide insight into regulatory decision-making at the time of granting initial orphan designation by the Committee for Orphan Medicinal Products, we have conducted a retrospective analysis for viral vector-mediated gene therapies in rare non-oncological conditions with respect to the data provided to support the criteria to be met in successful applications.

At-home wearable-based monitoring predicts clinical measures and biological biomarkers of disease severity in Friedreich’s Ataxia

Mishra, R.K., Nunes, A.S., Enriquez, A. et al. At-home wearable-based monitoring predicts clinical measures and biological biomarkers of disease severity in Friedreich’s Ataxia. Commun Med 4, 217 (2024). Doi:10.1038/s43856-024-00653-1 

This results establish the initial clinical validity of using wearable sensors in assessing disease severity and monitoring motor dysfunction in FRDA.

Uniparental IsoDisomy: a case study on a new mechanism of Friedreich ataxia

Sperelakis-Beedham, B., Gitiaux, C., Rajaoba, M. et al. Uniparental IsoDisomy: a case study on a new mechanism of Friedreich ataxia. Eur J Hum Genet (2024). Doi:10.1038/s41431-024-01728-2 

The identification of a deletion in the primer-annealing region of the TP-PCR explained the initial TP-PCR failure. This is the first documented case of FRDA caused by segmental UPiD. This case highlights the complexity of the molecular diagnosis of FRDA, and emphasises the importance of integrating results from various technical diagnostic approaches.