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.

Utility of Optical Genome Mapping in Repeat Disorders

Mutlu MB, Karakaya T, Çelebi HBG, Duymuş F, Seyhan S, Yılmaz S, Yiş U, Atik T, Yetkin MF, Gümüş H. Utility of Optical Genome Mapping in Repeat Disorders. Clin Genet. 2024 Oct 22. doi: 10.1111/cge.14633. Epub ahead of print. PMID: 39435674. 

We evaluated 19 patients with a prediagnosis of repeat disorders and explained the molecular etiology of 9 of them with OGM (5 patients with Facioscapulohumeral Muscular Dystrophy (FSHD), 2 patients with Friedreich's Ataxia (FA), 1 patient with Fragile X Syndrome (FXS), and 1 patient with Progressive Myoclonic Epilepsy 1A (EPM1A)). We confirmed OGM results with more widely used fragment analysis techniques. This study highlights the utility of OGM as a diagnostic tool for repeat expansion and contraction diseases such as FA, FXS, EPM1A, and FSHD.