Localized Changes in Dentate Nucleus Shape and Magnetic Susceptibility in Friedreich Ataxia

Harding, I.H., Nur Karim, M.I., Selvadurai, L.P., Corben, L.A., Delatycki, M.B., Monti, S., Saccà, F., Georgiou-Karistianis, N., Cocozza, S. and Egan, G.F. (2024), Localized Changes in Dentate Nucleus Shape and Magnetic Susceptibility in Friedreich Ataxia. Mov Disord. doi:10.1002/mds.29816 

 Changes in the structure of the dentate nuclei in FRDA are not spatially uniform. Atrophy is greatest in areas with high gray matter density, whereas increases in susceptibility—reflecting iron concentration, demyelination, and/or gliosis—predominate in the medial white matter.

Vesigen to Present New Preclinical Data on Engineered ARMMs Technology at 2024 ASGCT Annual Meeting

Provided by Business Wire. Apr 22, 2024. Engineering ARMMs with Engagers to Direct Biodistribution to Specific Neurons as a Therapeutic Strategy for Friedreich Ataxia.

Lexeo Enters License Agreement for Friedreich Ataxia Treatment

04.22.24. LEXEO Therapeutics, Inc., a clinical stage genetic medicine company, entered an in-license agreement with Cornell University to expedite development of the investigational gene therapy candidate LX2006 for the treatment of Friedreich ataxia (FA) cardiomyopathy. Under the license agreement, Lexeo has acquired certain rights, including rights to current and future data generated in an ongoing investigator-initiated Phase 1A trial of AAVrh.10hFXN to treat FA cardiomyopathy (NCT05302271). 

The agreement will support Lexeo’s efforts to develop a potentially life-changing therapy for this unmet need. Lexeo previously licensed know-how relating to AAVrh.10hFXN from Weill Cornell Medicine and collaborated with researchers there to further study the candidate, which Lexeo refers to as LX2006. Lexeo is studying LX2006 in the company-sponsored, open label, dose-ascending, multicenter SUNRISE-FA Phase 1/2 trial (NCT05445323).

Recent Advances in the Treatment Strategies of Friedreich’s Ataxia: A Review of Potential Drug Candidates and their Underlying Mechanisms

S. Saini, Kumar Aman,A nil, Neha,Vijay, N. Ardra,Mangla, Bharti,Javed, Shamama,Kumar, Pankaj,Ahsan, Waquar, Recent Advances in the Treatment Strategies of Friedreich’s Ataxia: A Review of Potential Drug Candidates and their Underlying Mechanisms,Current Pharmaceutical Design, volume 30, issue , pages 1-18, year 2024, issn 1381-6128/1873-4286, doi 10.2174/0113816128288707240404051856  

While there has been significant progress in the development of treatment strategies for FRDA, further research is needed to optimize these approaches and identify the most effective and safe treatment options for patients. The integration of multiple therapeutic strategies may be necessary to achieve the best outcomes in FRDA management.

The Role of Verbal Fluency in the Cerebellar Cognitive Affective Syndrome Scale in Friedreich Ataxia

Corben LA, Blomfield E, Tai G, Bilal H, Harding IH, Georgiou-Karistianis N, Delatycki MB, Vogel AP. The Role of Verbal Fluency in the Cerebellar Cognitive Affective Syndrome Scale in Friedreich Ataxia. Cerebellum. 2024 Apr 20. doi: 10.1007/s12311-024-01694-x. Epub ahead of print. PMID: 38642239. 

 The presence of dysarthria in many individuals with ataxia, particularly FRDA, may confound results on some items of the CCAS-S resulting in false-positive scores. This study explored the relationship between performance on the CCAS-S and clinical metrics of disease severity in 57 adults with FRDA. In addition, this study explored the relationship between measures of intelligibility and naturalness of speech and scores on the CCAS-S in a subgroup of 39 individuals with FRDA. We demonstrated a significant relationship between clinical metrics and performance on the CCAS-S.

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.