Muscular Dystrophy Association and Friedreich’s Ataxia Research Alliance Announce Collaborative Research Grant Using Novel Gene Editing Technology to Address Root Cause of Friedreich’s Ataxia Disease

NEW YORK, April 17, 2024 – The Muscular Dystrophy Association (MDA) and Friedreich’s Ataxia Research Alliance (FARA) announced today a collaborative grant for $300,000 awarded to Jonathan Watts, PhD, professor of RNA therapeutics; Erik Sontheimer, PhD, the Pillar Chair in Biomedical Research and professor of RNA therapeutics; Scot Wolfe, PhD, professor of molecular, cell & cancer biology; Wen Xue, PhD, associate professor of RNA therapeutics, a team of investigators at UMass Chan Medical School. This funding will further research into using novel genetic technologies to treat Friedreich’s ataxia (FA). The grant, Paired Prime Editors to treat Friedreich’s Ataxia, involves prime editing (PE), a next-generation CRISPR gene editing tool that can precisely target the removal of the GAA expansions in the frataxin (FXN) gene. 

The team will compare several PE approaches for their ability to remove the GAA repeats in FA cells with the goal to identify the optimal tool that can provide high efficiency of editing and reduced rate of off-target modifications to the genome. The investigators have also devised a system called split prime editing, in which two halves of the prime editing machinery are delivered as separate molecules. This approach allows them to rapidly test combinations of editing enzymes with desirable properties.

LEXEO THERAPEUTICS GRANTED FDA FAST TRACK DESIGNATION FOR LX2006, AN AAV-BASED GENE THERAPY CANDIDATE FOR THE TREATMENT OF FRIEDREICH’S ATAXIA CARDIOMYOPATHY

NEW YORK, April 16, 2024 (GLOBE NEWSWIRE) -- Lexeo Therapeutics, Inc. today announced the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to LX2006, the company’s AAVrh.10hFXN-based gene therapy candidate for the treatment of Friedreich’s ataxia (FA) cardiomyopathy. LX2006 is designed to deliver a functional frataxin gene to promote frataxin protein expression and restore mitochondrial function in myocardial cells.“We believe today’s Fast Track designation, along with the previously announced Rare Pediatric Disease and Orphan Drug designations granted to LX2006, will allow for enhanced regulatory interactions and the potential for this life-improving therapy to reach FA patients more quickly.” LX2006 is administered as a one-time intravenous infusion to patients in at least two ascending-dose cohorts with the potential for a third cohort. Long-term safety and efficacy will be evaluated for an additional four years following completion of the initial year of the trial, resulting in data from a total of five years post-LX2006 treatment.

Pharmacotherapeutic strategies for Friedreich Ataxia: a review of the available data

Gunther, K. and Lynch, D. R. (2024) ‘Pharmacotherapeutic strategies for Friedreich Ataxia: a review of the available data’, Expert Opinion on Pharmacotherapy. doi: 10.1080/14656566.2024.2343782. 

 The approval of omaveloxolone provides a major advance in FRDA therapeutics. Although well tolerated, it is not curative. Reversal of deficient frataxin levels with gene therapy, protein replacement, or epigenetic approaches provides the most likely prospect for enduring, disease modifying therapy in the future.

Expression and processing of mature human frataxin after gene therapy in mice

Rojsajjakul, T., Selvan, N., De, B. et al. Expression and processing of mature human frataxin after gene therapy in mice. Sci Rep 14, 8391 (2024). doi:10.1038/s41598-024-59060-0 

AAVrh.10hFXN induced mature hFXN expression in mouse heart and liver at levels that approximated endogenous mFXN levels. These results suggest that AAVrh.10hFXN can likely induce expression of therapeutic levels of mature hFXN in mice.

Chaperone function in Fe–S protein biogenesis: Three possible scenarios

Jaroslaw Marszalek, Elizabeth A. Craig, Marcin Pitek, Rafal Dutkiewicz, Chaperone function in Fe–S protein biogenesis: Three possible scenarios., Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Volume 1871, Issue 5, 2024, 119717, ISSN 0167-4889, doi:10.1016/j.bbamcr.2024.119717.

 

AAV gene therapy to treat Friedreich’s ataxia cardiomyopathy

Ferreira, J. AAV gene therapy to treat Friedreich’s ataxia cardiomyopathy. Lab Anim 53, 86 (2024). doi:10.1038/s41684-024-01351-0

NeuroVoices: Francesco Saccà, MD, PhD, on Crossing Over Dimethyl Fumarate in Friedriech Ataxia

NeurologyLive. April 3, 2024. We completed the enrollment in February. All 40 patients were enrolled. We are expecting to have the last patient last visit by the end of July. This means that we could probably get some data, at least the primary and many of the secondary endpoints, by September or October of this year. By the end of the year, we will close the entire analysis.

Approval of omaveloxolone for Friedreich ataxia

Boesch, S., Indelicato, E. Approval of omaveloxolone for Friedreich ataxia. Nat Rev Neurol (2024). doi:10.1038/s41582-024-00957-9 

The recent approval of omaveloxolone for the treatment of Friedreich ataxia in the USA and Europe represents an important milestone in the field of rare neurological diseases. However, many challenges lie ahead, including the translation of trial results into clinical practice, and the management of patients’ expectations.

Evaluating mFARS in pediatric Friedreich's ataxia: Insights from the FACHILD study

Rummey C, Perlman S, Subramony SH, Farmer J, Lynch DR. Evaluating mFARS in pediatric Friedreich's ataxia: Insights from the FACHILD study. Ann Clin Transl Neurol. 2024 Mar 31. doi: 10.1002/acn3.52057. Epub ahead of print. PMID: 38556905. 

Results confirmed the general usefulness of the mFARS score in children, but also highlighted issues, particularly with the upper limb subscore (FARS B). Increased variability, limited homogeneity across study subgroups, and potential training effects might limit mFARS application in clinical trials in pediatric populations. 

 Interpretation: The FARS E (Upright Stability) score might be a preferred outcome measure in this patient population.

Therapeutic Potential of Dimethyl Fumarate to Treat Friedreich Ataxia: Francesco Saccà, MD, PhD

NeurologyLive. March 28, 2024. Fracesco Saccà, MD, PhD In an interview with NeurologyLive®, Saccà discussed the idea behind the study and the reasons to assess dimethyl fumarate. He spoke on the mechanism of action of the therapy, the research that led up to this point, and some of the intricacies about the study. He also spoke on the fact that omaveloxolone’s ability to improve patients’ condition without impacting frataxin has opened the door for other potential therapies to hopefully do the same.