Generation and characterization of iPSC lines from Friedreich’s ataxia patient (FRDA) with GAA.TTC repeat expansion in the Frataxin (FXN) gene’s first intron (IGIBi016-A) and a non-FRDA healthy control individual (IGIBi017-A)

Istaq Ahmad, Asangla Kamai, Sana Zahra, Himanshi Kapoor, Achal Kumar Srivastava, Mohammed Faruq, Generation and characterization of iPSC lines from Friedreich’s ataxia patient (FRDA) with GAA.TTC repeat expansion in the Frataxin (FXN) gene’s first intron (IGIBi016-A) and a non-FRDA healthy control individual (IGIBi017-A), Stem Cell Research, 2024, 103382, doi:10.1016/j.scr.2024.103382.

Here, we developed iPSC lines from an FRDA patient (IGIBi016-A) and non-FRDA healthy control (IGIBi017-A). Both iPSC lines displayed typical iPSC morphology with pluripotency marker expression, regular karyotypes (46, XY; 46, XX), capacity to grow into three germ layers, and FRDA hallmark -GAA repeat expansion and decreased FXN mRNA. Through these iPSC lines, FRDA phenotypes may be replicated in the in vitro assays, by creating neuron subtypes, cardiomyocytes and 3D organoids, for molecular and cellular biomarkers and therapeutic applications.

Regulatory Pathway Widening for Cardiac Gene Therapy Hopefuls

Published: Mar 11, 2024. www.biospace.com 

Lexeo Therapeutics is developing a gene therapy, LX2006, for Friedreich’s ataxia cardiomyopathy, for which the FDA has granted Rare Pediatric Disease designation and Orphan Drug designation. 

 In its Friedreich’s ataxia program, Lexeo is using both invasive and non-invasive biomarkers pretreatment and post-treatment to evaluate the one-time gene therapy’s efficacy. Townsend said he hopes the biomarker data will lead to an accelerated approval.

Vestibular Pathology as Early Finding of Friedreich's Ataxia in a 16 Years Old Woman

Fernández AG. Vestibular Pathology as Early Finding of Friedreich's Ataxia in a 16 Years Old Woman. Indian J Otolaryngol Head Neck Surg. 2024 Feb;76(1):1247-1250. doi: 10.1007/s12070-023-04249-4. Epub 2023 Oct 5. PMID: 38440644; PMCID: PMC10908728. 

 The development of vestibular pathology is common but not completely understood. A 16 years old woman with early vestibular defects in relation to a latter Friedreich's ataxia diagnosis is reported.

Frataxin Traps Low Abundance Quaternary Structure to Stimulate Human Fe-S Cluster Biosynthesis

1. Cory S, Lin C-W, Havens S, Patra S, Putnam C, Shirzadeh M, et al. Frataxin Traps Low Abundance Quaternary Structure to Stimulate Human Fe-S Cluster Biosynthesis. ChemRxiv. 2024; doi:10.26434/chemrxiv-2024-v0gw7 

 This content is a preprint and has not been peer-reviewed. The findings support architectural switching as a regulatory mechanism linked to FXN activation of the human Fe-S cluster biosynthetic complex and provide new opportunities for therapeutic interventions of the fatal neurodegenerative disease FRDA.

Characterization of Cardiac-Onset Initial Presentation in Friedreich Ataxia

Lynch, D.R., Subramony, S., Lin, K.Y. et al. Characterization of Cardiac-Onset Initial Presentation in Friedreich Ataxia. Pediatr Cardiol (2024). doi:10.1007/s00246-024-03429-5 

The present study shows that some FRDA patients present based on cardiac features, suggesting that earlier identification of FRDA might occur through enhancing awareness of FRDA among pediatric cardiologists who see such patients. This is important in the context of newly identified therapies for FRDA

Prime Medicine Reports Full Year 2023 Financial Results and Provides Business Updat

CAMBRIDGE, Mass., March 01, 2024 (GLOBE NEWSWIRE) -- Prime Medicine, Inc. (Nasdaq: PRME), a biotechnology company committed to delivering a new class of differentiated one-time curative genetic therapies, today reported financial results for the full year ended December 31, 2023 and provided a business update. 

-Continue to advance Friedreich’s Ataxia and advance one other program into lead optimization in 2024. --In large animal studies, establish adeno-associated virus (AAV) delivery platform and route of administration for neuromuscular programs in 2024.

After pair of failures, PTC finds a path through FDA jungle for Friedreich ataxia med

https://www.fiercebiotech.com. By Annalee Armstrong; Mar 1, 2024. In a fourth-quarter earnings update Thursday afternoon, PTC executives briefed investors on the results of a type C meeting with the FDA where they pled their case for using a subscale called upright stability to show efficacy using data already collected in the phase 3 MOVE-FA trial. 

PTC’s candidate for the disorder failed to move the needle on the modified Friedreich Ataxia Rating Scale (mFARS), which measures disease progression. The therapy had little impact on the lower and upper limbs, which led to the failure. Despite the primary endpoint miss, PTC saw a glimmer of efficacy in the data, pointing to the upright stability subscales. 

PTC is expecting to file the NDA for vatiquinone in late 2024. Klein said an open-label trial is currently ongoing, which will be used to support the package and could also provide confirmatory evidence if the FDA agrees to the accelerated review. For that type of approval, companies can get an advanced go-ahead to market a drug based on biomarker data but must later provide confirmatory evidence to show benefit.

PTC Therapeutics Provides Corporate Update and Reports Fourth Quarter and Full Year 2023 Financial Results

SOUTH PLAINFIELD, N.J., Feb. 29, 2024 /PRNewswire/ -- PTC Therapeutics, Inc. PTC had a Type C meeting with the FDA in the first quarter of 2024 to discuss the vatiquinone Friedreich ataxia program. Based on discussions with the FDA, PTC has a potential path to an NDA submission in late 2024 based on the placebo-controlled results of MOVE-FA, along with data from the ongoing open-label extension study.

Voyager Therapeutics Announces Selection of Gene Therapy Development Candidate for Friedreich’s Ataxia in Collaboration with Neurocrine Biosciences

Voyager Therapeutics Announces Selection of Gene Therapy Development Candidate for Friedreich’s Ataxia in Collaboration with Neurocrine Biosciences, Triggering Milestone Payment. Voyager Therapeutics Inc. 

 LEXINGTON, Mass., Feb. 26, 2024 (GLOBE NEWSWIRE) -- Voyager Therapeutics, Inc. (Nasdaq: VYGR), a biotechnology company dedicated to advancing neurogenetic medicines, today announced that the joint steering committee with its collaborator Neurocrine Biosciences has selected a lead development candidate in the Friedreich’s ataxia (FA) program. The candidate combines a frataxin (FXN) gene replacement payload with an intravenously administered, blood-brain barrier penetrant, novel capsid derived from Voyager’s TRACER™ capsid discovery platform. The companies expect the program to advance into first-in-human clinical trials in 2025.

Phenotypic variation of FXN compound heterozygotes in a Friedreich ataxia cohort

Shen MM, Rummey C, Lynch DR. Phenotypic variation of FXN compound heterozygotes in a Friedreich ataxia cohort. Ann Clin Transl Neurol. 2024 Feb 23. doi: 10.1002/acn3.52027. Epub ahead of print. PMID: 38396238. 

These data support that the typical FRDA phenotype is driven by frataxin deficiency, especially severe in compound heterozygotes with minimal/no function mutations, whereas the heterogeneous presentations of those with partial function mutations may indicate other contributing factors to FRDA pathogenesis.