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.

 

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.

Novel approach for evaluation of mitochondrial substrate utilization in fibroblasts from patients with Friedreich’s ataxia

Ahmadian N, Dallas S, Dedkova EN. Novel approach for evaluation of mitochondrial substrate utilization in fibroblasts from patients with Friedreich’s ataxia. Biophysical Journal. 8 de febrero de 2024;123(3):523a. doi:10.1016/j.bpj.2023.11.3162

We found that FA fibroblasts had decreased utilization of alpha-ketoglutaric, succinic, fumaric and malic acids. Utilization of alpha-keto-butyric acid was not changed, however, utilization of D, L-beta-hydroxybutyric acid was decreased in FA fibroblasts as compared to control cells. At the same time utilization of acetyl-L-carnitine and palmitoyl-D,L-carnitine was increased in FA fibroblasts. Utilization of L-glutamic acid, L-glutamine, L-ornithine, glycine/alanine and tryptamine was decreased in FA fibroblasts.     

Using synthetic genome readers/regulators to interrogate chromatin processes: A brief review

Philips SJ, Danda A, Ansari AZ. Using synthetic genome readers/regulators to interrogate chromatin processes: A brief review. Methods. 1 de mayo de 2024;225:20-7. doi:10.1016/j.ymeth.2024.03.001

 A major challenge for designing small molecule therapeutics aimed at targeting desired genomic loci is the minimization of widescale disruption of genomic functions. To address this challenge, we rationally design polyamide-based multi-functional molecules, i.e., Synthetic Genome Readers/Regulators (SynGRs), which, by design, target distinct sequences in the genome. Herein, we briefly review how SynGRs access chromatin-bound and chromatin-free genomic sites, then highlight the methods for the study of chromatin processes using SynGRs on positioned nucleosomes in vitro or disease-causing repressive genomic loci in vivo.

Unique combinations of ultrasound and electrophysiological findings distinguish Friedreich’s ataxia from other inherited ataxias

Pelosi L, Mulroy E, Leadbetter R, Rodrigues M, Roxburgh R. Unique combinations of ultrasound and electrophysiological findings distinguish Friedreich’s ataxia from other inherited ataxias. Clinical Neurophysiology. 1 de mayo de 2024;161:157-8. doi:10.1016/j.clinph.2024.02.035

Larimar Triumphs: Significant Strides Made on the Road to Treating Friedreich’s Ataxia

BALA CYNWYD, PA — Larimar Therapeutics, Inc. March 19, 2024 

 In their ongoing discussions with the FDA, Larimar is working on a potential use of frataxin as a novel surrogate endpoint. This may unlock the potential for accelerated approval. Moreover, the company is planning for a global double-blind placebo-controlled confirmatory study. The study is expected to be initiated before the potential BLA (Biologics License Application) is submitted. The targeted timeline for the submission is the second half of 2025.

Design Therapeutics, Inc. (NASDAQ:DSGN) Q4 2023 Earnings Call Transcript

Published on March 19 on Seeking Alpha. Transcripts.

We learned from the human studies that the duration of adequate levels of exposure of DT-216 was much shorter than expected. While we knew that the drug was short-lived in plasma. Human studies showed by muscle biopsy that it was also short-lived in tissue and that what you observe in plasma is predictive of what is observed in tissue. 

 The tissue levels from human muscle biopsies were approximately only eight to 10 nanomolar at day two, and the drug was almost gone with levels of one nanomolar by day seven. Well, despite that, there was a clear increase in frataxin expression observed in treated patients in a dose dependent fashion with one patient frataxin level, going to clinically normal carrier levels as shown in the right. However, the effect was transient because the drug exposure was transient, so we needed to develop a new drug product that could sustain this drug exposure. While the drug was generally well tolerated, there were injection site thrombophlebitis events observed, which limited the frequency and levels of dosing with the prior product candidate. Nonclinical studies showed that these reactions were attributable to the formulation excipients in the drug product. 

We have now conducted new non GLP animal studies with DT-216P2, which lead us to believe that these issues have now been solved and we can progress to confirmatory GLP studies to get back into the clinic. Furthermore, this new drug product appears suitable for IV administration, compatible with injections or infusions, peripheral or central, and also appears suitable for a subcutaneous route of administration. As we showed in the beginning, the new drug product, DT-216P2 has a much more sustained exposure profile as seen in the single dose ID PK curve from non-human primates.

Stealth BioTherapeutics Presents Data of Novel Compound, SBT-589, in Friedreich's Ataxia Cardiac Models at the Wellcome Trust Mitochondrial Medicine Conference

NEEDHAM, Mass., March 19, 2024 /PRNewswire/ -- Stealth Biotherapeutics Inc. 

SBT-589 showed mitochondrial protection across models of Friedreich's ataxia. SBT-589 displayed cardioprotective effects in aggressive mouse model of FA cardiomyopathy. Ongoing studies are expected to build on these insights as SBT-589 progresses through developmental stage-gates. Stealth Biotherapeutics Inc. announced today the presentation of new SBT-589 data demonstrating cardioprotective effects across pre-clinical models of Friedreich's ataxia (FA). 

The data were presented at the Wellcome Trust Conference on Mitochondrial Medicine – Therapeutic Development, held March 18-20, 2024, in Cambridge, England. 

SBT-589 is a promising novel molecule that acts on mitochondrial pathways essential for cellular health and energy production that are impaired in FA cardiomyopathy. To evaluate the potential of SBT-589 in FA, a series of studies were conducted in FA patient-derived cells, isolated heart mitochondria, and an aggressive mouse model of FA cardiomyopathy. SBT-589 improved bioenergetics in FA patient-derived cells and mitochondria. In an FA mouse model with prominent cardiac hypertrophy and aggressive mortality, mice treated with once-daily SBT-589 displayed significantly reduced cardiac hypertrophy and a delay in the onset of mortality compared to vehicle-treated mice. The new findings presented today support continued development of SBT-589 as a potentially disease-modifying therapy to address the unmet need in cardiomyopathy associated with Friedreich's ataxia."

Design Therapeutics Outlines Progress Across GeneTAC™ Platform and Announces Fourth Quarter and Full Year 2023 Financial Results

CARLSBAD, Calif., March 19, 2024 (GLOBE NEWSWIRE) -- Design Therapeutics, Inc.. 

New Drug Product for Friedreich Ataxia (FA) DT-216P2 with Favorable Nonclinical Pharmacokinetic and Injection Site Safety Profile; Complete GLP Studies by Year-end 2024 to Start Patient Trials in 2025. 

Friedreich Ataxia (FA) Design has developed a new drug product, DT-216P2, for patients with FA that demonstrates an improved pharmacokinetic (PK) profile and a favorable injection site safety profile in nonclinical studies. When compared to the prior formulation, DT-216P2 demonstrated greater than 10-fold exposures that are more sustained over time. DT-216P2 also appears suitable for intravenous or subcutaneous routes of administration. 

 Design previously reported Phase 1 data using its prior formulation that showed increased levels of frataxin (FXN) mRNA in peripheral blood cells and skeletal muscle, confirming activity in patients with FA. Based on these findings, Design is advancing DT-216P2 for FA, with plans to complete GLP studies by year-end 2024 to start patient trials in 2025.

Accelerometer-based measures in Friedreich ataxia: a longitudinal study on real-life activity

Accelerometer-based measures in Friedreich ataxia: a longitudinal study on real-life activity. Front. Pharmacol., 19 March 2024, Sec. Neuropharmacology, Volume 15, 2024, doi:10.3389/fphar.2024.1342965   

Real-life activity monitoring is feasible and well tolerated by patients. Accelerometer-based measures can quantify disease progression in FRDA over 1 year, providing objective information about patient’s motor activities and supporting the usefulness of these data as complementary outcome measure in interventional trials.

P003: Clinical laboratory experience of frataxin quantification in blood for the diagnosis of Friedreich ataxia*

Iris Pantovich, Amy White, April Studinski, Weiyi Mu, Bonnie Kaas, Matthew Bower, Gisele Pino, Dawn Peck, Kyle Salsbery, Emily Lauer, Angela Pickart, Kandelaria Rumilla, Wei Shen, Zhiyv Niu, Patricia Hall, Matthew Schultz, Dimitar Gavrilov, Silvia Tortorelli, Dietrich Matern, Ralitza Gavrilova, Devin Oglesbee, P003: Clinical laboratory experience of frataxin quantification in blood for the diagnosis of Friedreich ataxia*, Genetics in Medicine Open, Volume 2, Supplement 1, 2024, 100880, ISSN 2949-7744, doi:10.1016/j.gimo.2024.100880. 

Since 2011, our laboratory has offered a protein-based clinical assay to quantify frataxin concentrations in blood that is useful for low-cost, rapid FA screening and diagnosis. Here, we summarize our laboratory experience.

Larimar Therapeutics Reports Fourth Quarter and Full Year 2023 Operating and Financial Results and Provides Update on Nomlabofusp Development

BALA CYNWYD, Pa., March 14, 2024 (GLOBE NEWSWIRE). 

Positive top-line data from Phase 2 dose exploration study of nomlabofusp, which was generally well-tolerated, with dose-dependent increases in tissue frataxin levels observed 

Initiated discussions with the Food and Drug Administration (FDA) on the potential use of tissue frataxin levels as a novel surrogate endpoint to support a Biologics License Application (“BLA”) submission for accelerated approval targeted for 2H 2025 

In January 2024, initiated open label extension (OLE) study with 25 mg daily dosing of nomlabofusp, with first patient dosed in March 2024; interim data expected in Q4 2024

Standing Balance Conditions and Digital Sway Measures for Clinical Trials of Friedreich's Ataxia

Casey, H.L., Shah, V.V., Muzyka, D., McNames, J., El-Gohary, M., Sowalsky, K., Safarpour, D., Carlson-Kuhta, P., Schmahmann, J.D., Rosenthal, L.S., Perlman, S., Rummey, C., Horak, F.B. and Gomez, C.M. (2024), Standing Balance Conditions and Digital Sway Measures for Clinical Trials of Friedreich's Ataxia. Mov Disord. doi:10.1002/mds.29777

 Three of the six standing conditions had completion rates over 70%. Of these three conditions, natural stance and feet together with EO showed the greatest completion rates. All six of the sway measures' mean values were significantly different between FRDA and HC. Four of these six measures discriminated between groups with >0.9 AUC in all three conditions. The Friedreich Ataxia Rating Scale Upright Stability and Total scores correlated with sway measures with P-values

Larimar Therapeutics Announces the Dosing of the First Patient in Long-term Open Label Extension Study for Nomlabofusp in Patients with Friedreich’s Ataxia

BALA CYNWYD, Pa., March 11, 2024 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (“Larimar”) (Nasdaq: LRMR), a clinical-stage biotechnology company focused on developing treatments for complex rare diseases, today announced dosing of the first patient in an open label extension (OLE) study evaluating 25 mg daily subcutaneous injections of nomlabofusp in participants with Friedreich’s ataxia (FA). Nomlabofusp (CTI-1601) is a novel protein replacement therapy designed to address the root cause of Friedreich's ataxia (FA) by delivering frataxin to mitochondria.

Lexeo Therapeutics Reports Fourth Quarter and Full Year 2023 Financial Results and Operational Highlights

NEW YORK, March 11, 2024 (GLOBE NEWSWIRE). LX2006 for the Treatment of FA Cardiomyopathy: Announced preliminary frataxin protein expression data from the second dose cohort of SUNRISE-FA showing positive change in post-treatment frataxin levels three months following administration of LX2006. Lexeo expects to report additional interim data from the SUNRISE-FA Phase 1/2 clinical trial in mid-2024 with follow-up out to one year from the low-dose and multiple timepoints of follow-up expected from at least three patients treated at the mid-dose.

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.

Generation of two human induced pluripotent stem cell lines, IGIBi012-A and IGIBi013-A from Friedreich's ataxia (FRDA) patients with homozygous GAA repeat expansion in FXN gene

Ahmad I, Kapoor H, Srivastava AK, Faruq M. Generation of two human induced pluripotent stem cell lines, IGIBi012-A and IGIBi013-A from Friedreich's ataxia (FRDA) patients with homozygous GAA repeat expansion in FXN gene. Stem Cell Res. 2024 Feb 10;76:103340. doi: 10.1016/j.scr.2024.103340. Epub ahead of print. PMID: 38367363. 

Both iPSC lines demonstrated characteristics of pluripotency, including expression of pluripotency markers, stable karyotypes and ability to develop into all three germ layers, and presence of GAA repeat expansion with reduced FXN mRNA expression. These iPSC lines will serve as invaluable tools for investigating the pathophysiology and phenotypes of FRDA.

Union Register of medicinal products for human use: (2024)975 of 09 Feb 2024 Skyclarys

 https://ec.europa.eu/health/documents/community-register/2024/20240209161576/dec_161576_es.pdf

https://ec.europa.eu/health/documents/community-register/2024/20240209161576/dec_161576_en.pdf

 https://ec.europa.eu/health/documents/community-register/2024/20240209161576/dec_161576_fr.pdf

FICHA TÉCNICA / SUMMARI OF PRODUCT / RÉSUMÉ

https://ec.europa.eu/health/documents/community-register/2024/20240209161576/anx_161576_es.pdf

https://ec.europa.eu/health/documents/community-register/2024/20240209161576/anx_161576_en.pdf

https://ec.europa.eu/health/documents/community-register/2024/20240209161576/anx_161576_fr.pdf

Larimar Therapeutics Reports Positive Top-line Data from Phase 2 Dose Exploration Study from 25 mg and 50 mg Cohorts of Nomlabofusp in Patients with Friedreich’s Ataxia

BALA CYNWYD, Pa., Feb. 12, 2024 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (“Larimar”) (Nasdaq: LRMR), a clinical-stage biotechnology company focused on developing treatments for complex rare diseases, today announced positive top-line data and successful completion of its four-week, placebo-controlled Phase 2 dose exploration study of nomlabofusp (CTI-1601) in participants with Friedreich’s ataxia (FA). Nomlabofusp was generally well tolerated and demonstrated dose dependent increases in frataxin (FXN) levels in all evaluated tissues (skin and buccal cells) after daily dosing of 14 days followed by every other day dosing until day 28 in the 25 mg and 50 mg cohorts. Participants in the 25 mg (n=13) and 50 mg (n=15) cohorts were randomized 2:1 to receive subcutaneous injections of nomlabofusp or placebo.

Biogen Received European Commission Approval for SKYCLARYS® (omaveloxolone), the First Therapy to Treat Friedreich’s Ataxia

CAMBRIDGE, Mass., Feb. 12, 2024 (GLOBE NEWSWIRE) -- Biogen Inc. (Nasdaq: BIIB) announced the European Commission (EC) has authorized SKYCLARYS® (omaveloxolone) for the treatment of Friedreich’s ataxia (FA) in adults and adolescents aged 16 years and older.

Real-world evidence for coverage determination of treatments for rare diseases

Dayer, V.W., Drummond, M.F., Dabbous, O. et al. Real-world evidence for coverage determination of treatments for rare diseases. Orphanet J Rare Dis 19, 47 (2024). doi.10.1186/s13023-024-03041-z

Health technology assessment (HTA) decisions for pharmaceuticals are complex and evolving. New rare disease treatments are often approved more quickly through accelerated approval schemes, creating more uncertainties about clinical evidence and budget impact at the time of market entry. The use of real-world evidence (RWE), including early coverage with evidence development, has been suggested as a means to support HTA decisions for rare disease treatments. However, the collection and use of RWE poses substantial challenges. These challenges are compounded when considered in the context of treatments for rare diseases. In this paper, we describe the methodological challenges to developing and using prospective and retrospective RWE for HTA decisions, for rare diseases in particular. We focus attention on key elements of study design and analyses, including patient selection and recruitment, appropriate adjustment for confounding and other sources of bias, outcome selection, and data quality monitoring. We conclude by offering suggestions to help address some of the most vexing challenges. The role of RWE in coverage and pricing determination will grow. It is, therefore, necessary for researchers, manufacturers, HTA agencies, and payers to ensure that rigorous and appropriate scientific principles are followed when using RWE as part of decision-making.

Searching for Frataxin Function: Exploring the Analogy with Nqo15, the Frataxin-like Protein of Respiratory Complex I from Thermus thermophilus

Doni, D.; Cavallari, E.; Noguera, M.E.; Gentili, H.G.; Cavion, F.; Parisi, G.; Fornasari, M.S.; Sartori, G.; Santos, J.; Bellanda, M.; et al. Searching for Frataxin Function: Exploring the Analogy with Nqo15, the Frataxin-like Protein of Respiratory Complex I from Thermus thermophilus. Int. J. Mol. Sci. 2024, 25, 1912. doi:10.3390/ijms25031912

 Nqo15’s iron-binding properties were studied using NMR, fluorescence, and specific assays and its desulfurase activation by biochemical assays. We found that the recombinant Nqo15 isolated from complex I is monomeric, stable, folded in solution, and highly dynamic. Nqo15 does not share the iron-binding properties of FXN or its desulfurase activation function.

Safety, pharmacokinetics, and pharmacodynamics of nomlabofusp (CTI-1601) in Friedreich's ataxia

Clayton, R., Galas, T., Scherer, N., Farmer, J., Ruiz, N., Hamdani, M., Schecter, D. and Bettoun, D. (2024), Safety, pharmacokinetics, and pharmacodynamics of nomlabofusp (CTI-1601) in Friedreich's ataxia. Ann Clin Transl Neurol. doi:10.1002/acn3.51971 

 Patients aged 19–69 years were enrolled (SAD, N = 28; MAD, N = 27). Nomlabofusp was generally well tolerated through 13 days. Most adverse events were mild and resolved quickly. No serious adverse events or deaths were reported. Peak nomlabofusp plasma concentrations occurred 15 min after subcutaneous administration. Nomlabofusp plasma exposures increased with increasing doses and daily administration and decreased with reduced dosing frequency. Increased frataxin concentrations were observed in buccal cells, skin, and platelets with higher and more frequent nomlabofusp administration.

Absence of functional deficits in rats following systemic administration of an AAV9 vector despite moderate peripheral nerve and dorsal root ganglia findings: a clinically silent peripheral neuropathy

Cheryl Tyszkiewicz, Seo-Kyoung Hwang, Jamie K. DaSilva, Ramesh C. Kovi, Kelly A. Fader, Madhu P. Sirivelu, June Liu, Chris Somps, Jon Cook, Chang-Ning Liu, Helen Wang, Absence of functional deficits in rats following systemic administration of an AAV9 vector despite moderate peripheral nerve and dorsal root ganglia findings: a clinically silent peripheral neuropathy, NeuroToxicology, 2024, ISSN 0161-813X, doi:10.1016/j.neuro.2024.02.001. 

 These findings demonstrate that there is no detectable functional consequence to the minimal-to-moderate neurodegeneration observed with our AAV9 vector treatment in rats, suggesting a functional tolerance or reserve for loss of DRG neurons after systemic administration of AAV9 vector.

A peptide derived from TID1S rescues frataxin deficiency and mitochondrial defects in FRDA cellular models

Yi Na Dong, Lucie V. Ngaba, Jacob An, Miniat W. Adeshina, Nathan Warren, Jonathan Wong, David R. Lync, Front. Pharmacol. Sec. Neuropharmacology, Volume 15 - 2024, doi: 10.3389/fphar.2024.1352311  

The study of frataxin protein regulation might yield new approaches for FRDA treatment. Here, we report tumorous imaginal disc 1 (TID1), a mitochondrial J-protein cochaperone, as a binding partner of frataxin that negatively controls frataxin protein levels. TID1 interacts with frataxin both in vivo in mouse cortex and in vitro in cortical neurons. Acute and subacute depletion of frataxin using RNA interference markedly increases TID1 protein levels in multiple cell types. In addition, TID1 overexpression significantly increases frataxin precursor but decreases intermediate and mature frataxin levels in HEK293 cells. In primary cultured human skin fibroblasts, overexpression of TID1S results in decreased levels of mature frataxin and increased fragmentation of mitochondria. This effect is mediated by the last 6 amino acids of TID1S as a peptide made from this sequence rescues frataxin deficiency and mitochondrial defects in FRDA patient-derived cells. Our findings show that TID1 negatively modulates frataxin levels, and thereby suggests a novel therapeutic target for treating FRDA.

Nerve Ultrasound in Friedreich’s Ataxia: enlarged nerves as a Biomarker of disease severity

G. Di Pietro, E. Cioffi, P. Falco, E. Galosi, G. De Stefano, G. Di Stefano, C. Leone, V. Martines, S. Perotti, C. Casali, A. Truini, Nerve Ultrasound in Friedreich’s Ataxia: enlarged nerves as a Biomarker of disease severity, Clinical Neurophysiology, 2024, ISSN 1388-2457, doi:10.1016/j.clinph.2024.01.004 

 Our study now shows that high-resolution nerve ultrasound examination can detect nerve enlargements in patients with Friedreich's ataxia (mostly at the level of upper limbs). Neve ultrasound abnormalities correlate with clinically established variables in patients with Friedreich's ataxia. This technique, therefore, might be a promising biomarker for measuring disease severity and treatment effects in this rare and severely disabling condition.

Protective effect of FXN overexpression on ferroptosis in L-Glu-induced SH-SY5Y cells

Mengran Wang, Tingting Xuan, Haining Li, Jing An, Tianhui Hao, Jiang Cheng, Protective effect of FXN overexpression on ferroptosis in L-Glu-induced SH-SY5Y cells, Acta Histochemica, Volume 126, Issue 1, 2024, 152135, ISSN 0065-1281, doi:10.1016/j.acthis.2024.152135. 

 To conclude, our research demonstrates that an elevated expression of FXN effectively demonstrates a robust neuroprotective effect against oxidative damage induced by L-Glu. Moreover, it mitigates mitochondrial dysfunction and lipid metabolic dysregulation associated with ferroptosis. FXN overexpression holds promise in potential therapeutic strategies for AD by inhibiting ferroptosis in nerve cells and fostering their protection.

Anti-gene oligonucleotides targeting Friedreichs ataxia expanded GAA:TTC repeats increase Frataxin expression

Anti-gene oligonucleotides targeting Friedreichs ataxia expanded GAA:TTC repeats increase Frataxin expression, Negin Mozafari, Salome Isabel Marques Milagres, Cristina Simoes Jesus Rocha, Claudia Marina Vargiu, Fiona Freyberger, Osama Saher, Tea Umek, Pontus Blomberg, Per Trolle Jorgensen, Edvard Carl Igne Smith, Jesper Wengel, Rula L Zain, bioRxiv 2024.01.25.577034; doi:10.1101/2024.01.25.577034 

We examined numerous LNA-DNA AGOs and found that the design, length and their LNA composition have a high impact on the effectiveness of the treatment. Collectively, our results demonstrate the unique capability of specifically designed ONs targeting the GAA:TTC DNA repeats to upregulate FXN gene expression.

Omaveloxolone for the treatment of Friedreich Ataxia: clinical trial results and practical considerations

David R Lynch, Susan Perlman & Kim Schadt (2024) Omaveloxolone for the treatment of Friedreich Ataxia: clinical trial results and practical considerations, Expert Review of Neurotherapeutics, DOI: 10.1080/14737175.2024.2310617 

Omaveloxolone provides a significant advance in treatment of FRDA that is likely to be beneficial in a majority of the FRDA population. The data suggesting a benefit is consistent, and adverse issues are relatively modest. The major remaining questions are the subgroups that are most responsive and how long the beneficial effects will remain significant in FRDA patients.

Emerging antioxidant therapies in Friedreich's ataxia

Fred J. Edzeamey, Zenouska Ramchunder, Charareh Pourzand, Sara Anjomani Virmoun, Front. Pharmacol. Sec. Experimental Pharmacology and Drug Discovery, Volume 15 - 2024 | doi: 10.3389/fphar.2024.1359618 

The confirmation of oxidative stress as one of the pathological signatures of FRDA led to the search for antioxidants which can be used as therapeutic modality. Based on this observation, antioxidants with different mechanisms of action have been explored for FRDA therapy since the last two decades. In this review, we bring forth all antioxidants which have been investigated for FRDA therapy and have been signed off for clinical trials. We summarise their various target points in FRDA disease pathway, their performances during clinical trials and possible factors which might have accounted for their failure or otherwise during clinical trials. We also discuss the limitation of the studies completed and propose possible strategies for combinatorial therapy of antioxidants to generate synergistic effect in FRDA patients. treatment modality for FRDA.

Omaveloxolone: a groundbreaking milestone as the first FDA-approved drug for Friedreich ataxia

Pilotto, Federica et al., Trends in Molecular Medicine, Volume 0, Issue 0. doi:10.1016/j.molmed.2023.12.002 

 Omaveloxolone represents the first FDA-approved drug for Friedreich’s ataxia (FA). Omaveloxolone targets nuclear factor erythroid 2-related factor 2 (NRF2), which is a master regulator in the antioxidant pathway. The omaveloxolone clinical trial serves as an example for future design of clinical trials. A resolutive cure for FA would probably be achieved only via combinatorial therapy.

AAV8 gene therapy reverses cardiac pathology and prevents early mortality in a mouse model of friedreich’s ataxia

Chang, J. C., Ryan, M. R., Stark, M. C., Liu, S., Purushothaman, P., Bolan, F., Johnson, C. A., Champe, M., Meng, H., Lawlor, M. W., Halawani, S., Ngaba, L. V., Lynch, D. R., Davis, C., Gonzalo-Gil, E., Lutz, C., Urbinati, F., Medicherla, B., & Fonck, C. (2024). AAV8 gene therapy reverses cardiac pathology and prevents early mortality in a mouse model of friedreich’s ataxia. Molecular Therapy. Methods & Clinical Development, 101193, 101193. doi:10.1016/j.omtm.2024.101193

 Frataxin protein expression in heart tissue was detected in a dose-dependent manner, exhibiting wide distribution throughout the heart similar to wild-type, but more speckled. These results support an AAV8-based approach to treat FRDA-associated cardiomyopathy.

METTL17 is an Fe-S cluster checkpoint for mitochondrial translation

METTL17 is an Fe-S cluster checkpoint for mitochondrial translation. Tslil Ast,Yuzuru Itoh,Shayan Sadre,Jason G. McCoy,Gil Namkoong,Jordan C. Wengrod,Ivan Chicherin,Pallavi R. Joshi,Piotr Kamenski,Daniel L.M. Suess,Alexey Amunts,Vamsi K. Mootha. Molecular Cell 84, 359–374, January 18, 2024. Doi:10.1016/j.molcel.2023.12.016 

METTL17 overexpression rescued the mitochondrial translation and bioenergetic defects, but not the cellular growth, of FXN-depleted cells. These findings suggest that METTL17 acts as an Fe-S cluster checkpoint, promoting translation of Fe-S cluster-rich oxidative phosphorylation (OXPHOS) proteins only when Fe-S cofactors are replete.

Gene editing improves Endoplasmic reticulum-mitochondrial contacts and Unfolded Protein Response in Friedreich's Ataxia iPSC-derived neurons

Priyanka Mishra, Anusha Sivakumar, Avalon Johnson, Carla Pernaci, Anna S. Warden, Lilas Rony El- Hachem, Emily Hansen1, Rafael A. Badell-Grau, VEENITA KHARE, Gabriela Ramirez, Sydney Gillette, Peng Guo, Nicole Coufal, Stephanie Cherqui. Front. Pharmacol., Sec. Neuropharmacology, Volume 15 - 2024 | doi: 10.3389/fphar.2024.1323491

Taken together, these results represent a novel finding for disease pathogenesis showing dramatic ER structural damage in FRDA, validate the efficacy profile of our FXN gene editing approach in a disease relevant model, and support our approach as an effective strategy for therapeutic intervention for Friedreich's ataxia.

Iron imbalance in neurodegeneration

Levi, S., Ripamonti, M., Moro, A.S. et al. Iron imbalance in neurodegeneration. Mol Psychiatry (2024). doi:10.1038/s41380-023-02399-z 

 This protein plays a key role in delivering iron to the ISC complex machinery. A second example is a rare disease known as sideroblastic anemia with X-linked ataxia (XLSA/A), which is caused by defects in ABCB7, the mitochondrial transporter of the cytosolic ISC precursor [141], which is essential for the maturation of cytosolic ISC proteins. This condition reflects the importance of the mitochondrion in the synthesis of ISC and in maintaining cellular homeostasis.

Evaluating the therapeutic efficacy of SKYCLARYS: a promising FDA-approved drug for Friedreich ataxia treatment

 Ahmed, Usaid MBBSa; Afaq, Laiba MBBSa; Muhammad, Aqeel MBBSa; Riaz, Rumaisa MBBSa; Akilimali, Aymar MDb. Evaluating the therapeutic efficacy of SKYCLARYS: a promising FDA-approved drug for Friedreich ataxia treatment. International Journal of Surgery: Global Health 7(1):e0394, January 2024. | DOI: 10.1097/GH9.0000000000000394 

 Omaveloxone’s activation of the Nrf2 pathway, responsible for combating oxidative stress, has shown significant promise, especially in enhancing neurological function. Continuous research and the accumulation of clinical knowledge will play a crucial role in fine-tuning its best practices and investigating potential synergies with other treatments, all with the goal of further advancing the outcomes for those living with FRDA.

Tissue Iron in Friedreich Ataxia

Arnulf H Koeppen. Tissue Iron in Friedreich Ataxia. J. Integr. Neurosci. 2024, 23(1), 4. Doi:10.31083/j.jin2301004 (registering DOI) 

 Iron dysmetabolism in DRG is complex and consists of prominent expression of ferritin in hyperplastic satellite cells and residual nodules, also a loss of the iron export protein ferroportin from the cytoplasm of the remaining DRG nerve cells.

PTC Therapeutics Provides an Update on Commercial Progress and R&D Pipeline at 42nd Annual J.P. Morgan Healthcare Conference

SOUTH PLAINFIELD, N.J., Jan. 8, 2024 /PRNewswire/ -- PTC Therapeutics, Inc. 

FDA meeting for vatiquinone to discuss how the MOVE-FA data along with additional clinical and preclinical data could support an NDA submission in FA is scheduled for the first quarter. 

Scientific advice feedback from the EMA on a potential submission of vatiquinone for conditional marketing authorization for Friedreich ataxia is expected in the first quarter.

Perspectives of the Friedreich ataxia community on gene therapy clinical trials

Shandra J. Trantham,Mackenzi A. Coker,Samantha Norman,Emma Crowley,Julie Berthy,Barry J. Byrne,Sub Subramony,XiangYang Lou,Manuela Corti; Molecular Therapy Methods & Clinical Development, Volume 32, Issue 1, 101179, doi:10.1016/j.omtm.2023.101179 

 This study provides valuable information on priorities, beliefs, and expectations regarding gene therapy and serves to guide future gene therapy opinion studies and gene therapy trial design.

Omaveloxolone ameliorates isoproterenol-induced pathological cardiac hypertrophy in mice

Xianchao Li, Yang Wu, Yunzhao Yang, Yaohua Wu, Xi Yu & Wenjuan Hu (2023) Omaveloxolone ameliorates isoproterenol-induced pathological cardiac hypertrophy in mice, Free Radical Research, DOI: 10.1080/10715762.2023.2299359 

The cardioprotective effect of omaveloxolone was directly related to the activation of the Nrf2 signaling. In summary, our study identified that omaveloxolone may be a promising therapeutic agent to mitigate pathological cardiac hypertrophy.