PTC Therapeutics Announces Vatiquinone NDA Submission to FDA for the Treatment of Children and Adults Living with Friedreich Ataxia

WARREN, N.J., Dec. 19, 2024 /PRNewswire/ -- PTC Therapeutics, Inc. (NASDAQ: PTCT) announced today the submission of the vatiquinone New Drug Application (NDA) for the treatment of children and adults living with Friedreich ataxia (FA) to the U.S. Food and Drug Administration (FDA). 

The application is supported by data from a placebo-controlled study and two long-term studies that included pediatric and adult patients. 

Results from the three studies indicated significant, durable, and clinically meaningful evidence of slowing disease progression with vatiquinone.

Vatiquinone is known as a first-in-class selective inhibitor of 15-Lipoxygenase (15-LO), "an enzyme that is a key regulator of the energetic and oxidative stress pathways that are disrupted in Friedreich ataxia," according to PTC.

Larimar Therapeutics Announces Positive Initial Data from Ongoing Long-term Open Label Extension Study & Progress Across Nomlabofusp Program for Friedreich’s Ataxia

December 16, 2024. Source: Larimar Therapeutics BALA CYNWYD, Pa., Dec. 16, 2024 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (Larimar) (Nasdaq: LRMR), today announced positive initial data from the ongoing long-term OLE study evaluating daily subcutaneous injections of 25 mg of nomlabofusp self-administered or administered by a caregiver in participants with FA. 

The Company also provided a nomlabofusp development program update. 

We are pleased with the advancement of our OLE study that includes 14 patients dosed for up to 260 days. Importantly, 25 mg of nomlabofusp administered daily increased and maintained tissue FXN levels over time, with mean levels increasing from 15% of healthy volunteers at baseline to 30% in buccal cells and from 16% to 72% in skin cells at Day 90. At the time of data cut off for the OLE study, 14 adults with FA were included with up to 260 days (mean 99 days) of long-term daily treatment of 25 mg of nomlabofusp. Among these patients, more than 50% were non-ambulatory.

Larimar Therapeutics Reports Positive Initial Data from Nomlabofusp OLE Study for Friedreich’s Ataxia

Dec. 16, 2024. Larimar Therapeutics announced positive results from its ongoing open label extension study evaluating the daily subcutaneous administration of 25 mg nomlabofusp in participants with Friedreich’s ataxia. In a cohort of 14 patients, the treatment was generally well tolerated for up to 260 days, with tissue frataxin levels significantly increasing in both buccal and skin cells by Day 90. 

Plans for a global confirmatory study are set for mid-2025, with a Biologics License Application targeted for submission in the second half of 2025. Early trends towards improvement in clinical outcomes observed at Day 90, supporting the potential for nomlabofusp to benefit a broad spectrum of patients with Friedreich’s ataxia.

Serious adverse events occurred in two study participants during the OLE study, which, despite resolving quickly, may raise concerns about the safety profile of nomlabofusp.

Gradient of microstructural damage along the dentato- thalamo-cortical tract in Friedreich ataxia

Sirio Cocozza, Sara Bosticardo, Matteo Battocchio, Louise Corben, Martin Delatycki, Gary Egan, Nellie Georgiou-Karistianis, Serena Monti, Giuseppe Palma, Chiara Pane, Francesco Sacca, Simona Schiavi, Louisa Selvadurai, Mario Tranfa , Alessandro Daducci, Arturo Brunetti & Ian H. Harding. Gradient of microstructural damage along the dentato- thalamo-cortical tract in Friedreich ataxia. Annals of Clinical and Translational Neurology 2024; 11(7): 1691–1702. doi: 10.1002/acn3.52048

Our study further expands the current knowl- edge about brain involvement in FRDA, showing that microstructural abnormalities within the DTT are weighted to early segments of the tract (i.e., the superior cerebellar peduncle). These findings are consistent with the hypothesis of DTT undergoing anterograde degeneration arising from the dentate nuclei and progressing to the primary motor cortex.

Ignition of Small Molecule Inhibitors in Friedreich's Ataxia with Explainable Artificial Intelligence

Kübra Kirboğa, K., Küçüksille, E., & Kose, U. (2023). Ignition of Small Molecule Inhibitors in Friedreich's Ataxia with Explainable Artificial Intelligence. BRAIN. Broad Research In Artificial Intelligence And Neuroscience, 14(3), 287-313. Retrieved from https://brain.edusoft.ro/index.php/brain/article/view/1427

The results showed the importance of properties related to nitrogen-containing functional groups (SHAP value of PubchemFP656 is -0.29) and aromatic rings (SHAP value of PubchemFP12 is -0.16). As a result, we explained the effect of the molecular fingerprints on the models and the impact on possible drugs that can be developed for FA with artificial intelligence (XAI), which can be explained through SHAP (Shapley Additive Explanations) values. Model scripts and fingerprinting methods are also available at https://github.com/tissueandcells/XAI.

Altered calcium responses and antioxidant properties in Friedreich's ataxia-like cerebellar astrocytes

Marullo, Chiara & Croci, Laura & Giupponi, Iris & Rivoletti, Claudia & Zuffetti, Sofia & Bettegazzi, Barbara & Cremona, Ottavio & Giunti, Paola & Ambrosi, Alessandro & Casoni, Filippo & Consalez, Gian & Codazzi, Franca. (2024). Altered calcium responses and antioxidant properties in Friedreich's ataxia-like cerebellar astrocytes. Journal of cell science. 10.1242/jcs.263446.

Our findings shed light on cellular changes caused by FXN downregulation in cerebellar astrocytes, likely impairing their complex interaction with neurons. The potentially impaired ability to provide neuronal cells with glutathione or to release neuromodulators in a calcium-dependent manner could affect neuronal function, contributing to neurodegeneration.

Sexual dimorphism in a mouse model of Friedreich's ataxia with severe cardiomyopathy

Salinas L, Montgomery CB, Figueroa F, Thai PN, Chiamvimonvat N, Cortopassi G, Dedkova EN. Sexual dimorphism in a mouse model of Friedreich's ataxia with severe cardiomyopathy. Commun Biol. 2024 Oct 3;7(1):1250. doi: 10.1038/s42003-024-06962-4. PMID: 39363102; PMCID: PMC11449905. 

 The decrease in testosterone was related to decreased expression of proteins involved in cholesterol transfer into the mitochondria: StAR and TSPO on the outer mitochondrial membrane, and the cholesterol side-chain cleavage enzyme P450scc and ferredoxin on the inner mitochondrial membrane. Expression of excitation-contraction coupling proteins (L-type calcium channel, RyR2, SERCA2, phospholamban and CaMKIIδ) was decreased significantly more in Fxn-cKO males. This is the first study that extensively investigates the sexual dimorphism in FA mouse model with cardiac calcium signaling impairment.

Lack of Concentration-QTc Relationship and Cardiac Risk With Vatiquinone Therapeutic and Supratherapeutic Doses

Lee L, Flach S, Xue H, Arivelu L, Golden L, Kong R, Darpo B. Lack of Concentration-QTc Relationship and Cardiac Risk With Vatiquinone Therapeutic and Supratherapeutic Doses. Clin Pharmacol Drug Dev. 2024 Nov;13(11):1227-1238. doi: 10.1002/cpdd.1476. Epub 2024 Oct 17. PMID: 39415654. 

 No new safety signals were found, as safety data are consistent with the known safety profile of vatiquinone. These findings altogether demonstrated that there is a minimal cardiac risk for vatiquinone concentrations up to the supratherapeutic dose level.

Friedreich Ataxia

Bidichandani SI, Delatycki MB, Napierala M, Duquette A. Friedreich Ataxia. 1998 Dec 18 [updated 2024 Oct 31]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2024. PMID: 20301458. 

 Review (Last Update: October 31, 2024.)

Efficacy of Stabilometric Platform to Improve Standing Balance in Patients with Friedreich's Ataxia

ClinicalTrials.gov ID NCT06692296. Sponsor IRCCS Eugenio Medea. Last Update Posted 2024-11-21

The primary objective is to evaluate the potential effectiveness of an individualized intensive rehabilitation intervention using the "Prokin 252" stabilometric platform in the treatment of adolescent and adult patients with Friedreich's Ataxia. The secondary objective is to assess the retention of the rehabilitation treatment effects over time.

Omaveloxolone for the Treatment of Friedreich Ataxia: Efficacy, Safety, and Future Perspectives

Naghipour S, Corben LA, Hulme AJ, Dottori M, Delatycki MB, Lees JG, Lim SY. Omaveloxolone for the Treatment of Friedreich Ataxia: Efficacy, Safety, and Future Perspectives. Mov Disord. 2024 Nov 19. doi: 10.1002/mds.30070. Epub ahead of print. PMID: 39559924. 

The scarcity literature addressing the cardiovascular effects omaveloxolone in FRDA is concerning, especially considering that cardiomyopathy is the primary cause of mortality in affected individuals. Furthermore, the reported potential of omaveloxolone to induce mil elevations in B-natriuretic peptide (BNP), a known marker of heart failure, adds to this concern. Thus, those individuals with FRDA who have cardiomyopathy are advised to monitor BNP levels while using omaveloxolone. In this viewpoint, we examine the current literature on the efficacy and safety of omaveloxolone in treating FRDA, with a focus on its potential impact on cardiovascular health.

Assessment of the Clinical Interactions of GAA Repeat Expansions in FGF14 and FXN

Gerhart BJ, Pellerin D, Danzi MC, Zuchner S, Brais B, Matos-Rodrigues G, Nussenzweig A, Usdin K, Park CC, Napierala JS, Lynch DR, Napierala M. Assessment of the Clinical Interactions of GAA Repeat Expansions in FGF14 and FXN. Neurol Genet. 2024 Nov 20;10(6):e200210. doi: 10.1212/NXG.0000000000200210. PMID: 39574782; PMCID: PMC11581763.

Despite both molecular and clinical similarities between FRDA and SCA27B, the length of the GAA repeats in the FGF14 gene, including potentially pathogenic alleles, did not influence the clinical presentation of FRDA.

Recurrent DNA nicks drive massive expansions of (GAA)n repeats

Li L, Scott WS, Khristich AN, Armenia JF, Mirkin SM. Recurrent DNA nicks drive massive expansions of (GAA)n repeats. Proc Natl Acad Sci U S A. 2024 Dec 3;121(49):e2413298121. doi: 10.1073/pnas.2413298121. Epub 2024 Nov 25. PMID: 39585990.

 We found that DNA nicks 5' of the (GAA)100 run led to a dramatic increase in both the rate and scale of its expansion in dividing cells. Strikingly, they also promoted large-scale expansions of carrier- and large normal-size (GAA)n repeats, recreating, in a model system, the expansion events that occur in human pedigrees. DNA nicks 3' of the (GAA)100 repeat led to a smaller but significant increase in the expansion rate as well. Our genetic analysis implies that in dividing cells, conversion of nicks into double-strand breaks (DSBs) during DNA replication followed by DSB or fork repair leads to repeat expansions. Finally, we showed that 5' GAA-strand nicks increase expansion frequency in nondividing yeast cells, albeit to a lesser extent than in dividing cells.

Two-stage binding of mitochondrial ferredoxin-2 to the core iron-sulfur cluster assembly complex

Steinhilper R, Boß L, Freibert SA, Schulz V, Krapoth N, Kaltwasser S, Lill R, Murphy BJ. Two-stage binding of mitochondrial ferredoxin-2 to the core iron-sulfur cluster assembly complex. Nat Commun. 2024 Dec 4;15(1):10559. doi: 10.1038/s41467-024-54585-4. PMID: 39632806; PMCID: PMC11618653.  

The structural interaction of FDX2 with the complex remains unclear. Here, we present cryo-EM structures of the human FDX2-bound core ISC complex showing that FDX2 and FXN compete for overlapping binding sites. FDX2 binds in either a 'distal' conformation, where its helix F interacts electrostatically with an arginine patch of NFS1, or a 'proximal' conformation, where this interaction tightens and the FDX2-specific C terminus binds to NFS1, facilitating the movement of the [2Fe-2S] cluster of FDX2 closer to the ISCU2 FeS cluster assembly site for rapid electron transfer. Structure-based mutational studies verify the contact areas of FDX2 within the core ISC complex.

Stabilization of expandable DNA repeats by the replication factor Mcm10 promotes cell viability

Masnovo, C., Paleiov, Z., Dovrat, D. et al. Stabilization of expandable DNA repeats by the replication factor Mcm10 promotes cell viability. Nat Commun 15, 10532 (2024). doi:10.1038/s41467-024-54977-6  

Here, we show that deficiency of the essential replisome component Mcm10 dramatically elevates (GAA)n repeat instability in a budding yeast model by loss of proper CMG helicase interaction. When repair is inefficient, such as in the case of RPA depletion, breakage of under-replicated repetitive DNA can occur during G2/M, leading to loss of essential genes and cell death. We hypothesize that the CMG-Mcm10 interaction promotes replication through hard-to-replicate regions, assuring genome stability and cell survival.

Therapeutic hypoxia for mitochondrial disease via enhancement of hemoglobin affinity and inhibition of HIF-2α

Therapeutic hypoxia for mitochondrial disease via enhancement of hemoglobin affinity and inhibition of HIF-2α. Hong Wang, … , Fumito Ichinose, Vamsi K. Mootha. Published December 2, 2024. J Clin Invest. 2024;134(23):e185569. doi:10.1172/JCI185569. 

Our results provide preclinical proof of concept that simultaneously enhancing Hb oxygen affinity while antagonizing HIF-2α can mimic the effects of continuous hypoxic breathing for therapeutic benefit. The regimen did not confer as impressive a lifespan rescue as continuous breathing of 11% oxygen, probably because GBT440 has a short half-life (6), and for practical reasons, we treated the mice five weekdays per week. Future studies in humans are required to evaluate the safety of this combination, given that hypoxia can be associated with acute and long-term side effects. Such safety studies could pave the path for first-in-human “hypoxia-in-a-pill” trials in patients with mitochondrial disease.

Safeguarding the brain from oxidative damage

Kyung Hee Lee, Un Jeng Kim, Bae Hwan Lee, Myeounghoon Cha, Safeguarding the brain from oxidative damage, Free Radical Biology and Medicine, Volume 226, 2025, Pages 143-157, ISSN 0891-5849, doi:10.1016/j.freeradbiomed.2024.11.019. 

This paper aims to provide a concise and objective review of the oxidative and antioxidant pathways and their potential therapeutic applications in treating oxidative injury in the brain.

Exploring neuropsychiatric symptoms in Friedreich ataxia

Karamazovova, S., Stovickova, L., Jester, D.J. et al. Exploring neuropsychiatric symptoms in Friedreich ataxia. Sci Rep 14, 29076 (2024). doi:10.1038/s41598-024-80258-9 

 In conclusion, our findings show that NPS are common in FRDA and manifest not only as depression and anxiety but also as decreased motivation. It is difficult to distinguish whether these NPS are due to the neurodegenerative process or to the burden of living with a progressive, devastating disease, but in any case they need to be considered in clinical care.

Ferroptosis—disease perils and therapeutic promise

Ashley R. Brown et al. ,Ferroptosis—disease perils and therapeutic promise.Science386,848-849(2024).DOI:10.1126/science.adn703 

Identifying new strategies to inhibit ferroptosis offers therapeutic promise in contexts where ferroptotic cell death contributes to disease progression. By contrast, selective induction of ferroptosis is a promising approach in cancer therapeutics. Continuing discoveries about the mechanisms governing ferroptosis are likely to improve our understanding of disease biology and provide ideas that may assist in the diagnosis and treatment of diverse human maladies.

Therapeutic Activity of a Haematopoietic Stem Cell-Delivered Tissue-Penetrating Peptide in Friedreich's Ataxia Models

Pido, Jeffrey and Shaban, Enas and Moula, Shefta and Chritchely, Bethan and Whittaker, Thomas and Svensson, Stina and Anjomani Virmouni, Sara and Kalef-Ezra, Ester and Carr, Lucinda and Hassell, Jane and Thrasher, Adrian J. and Kurian, Manju A. and Santilli, Giorgia and Sala, Arturo and Administrator, Sneak Peek, Therapeutic Activity of a Haematopoietic Stem Cell-Delivered Tissue-Penetrating Peptide in Friedreich's Ataxia Models. doi:10.2139/ssrn.5026639 

We developed a replacement strategy for this disease by designing a fusion peptide containing secretion and tissue penetrating sequences at the amino terminus of the frataxin precursor protein. Secretion and penetration of the fusion peptide was validated in experiments that confirmed its ability to localise in the mitochondria and rescue the biochemical defects and apoptotic phenotype of FRDA patient cells, in vitro. Autologous transplantation of the modified HSPCs resulted in stable secretion of the peptide in the blood stream of recipient animals, impacting disease progression by delaying the manifestation of motor-coordination/sensory symptoms, paralleled by improved biochemical and anatomical parameters.

Additional Data from Phase 1 Studies and Phase 2 Dose Exploration Study Supporting the Nomlabofusp Clinical Program at ICAR 2024

BALA CYNWYD, Pa., Nov. 18, 2024 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (Larimar) (Nasdaq: LRMR), a clinical-stage biotechnology company focused on developing treatments for complex rare diseases, last week presented data from the Company’s Phase 1 studies and the Phase 2 dose exploration study of nomlabofusp at the International Congress for Ataxia Research (ICAR) in London, U.K. Data from a total of 61 adults with FA who participated in these studies evaluating short-term (up to 28 days) subcutaneous administration of 25, 50, 75, and 100 mg nomlabofusp were further evaluated and presented in three posters during the conference.

Posters available

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.

Design and validation of cell-based potency assays for frataxin supplementation treatments

Design and validation of cell-based potency assays for frataxin supplementation treatments; Shibani Mukherjee, Larisa Pereboeva, Daniel Fil, Achisha Saikia, Jeon Lee, Jixue Li, M. Grazia Cotticelli, Elisabetta Soragni, Robert B. Wilson, Marek Napierala, Jill S. Napierala. Molecular Therapy Methods & Clinical Development, Volume 32, Issue 4, 101347 DOI: 10.1016/j.omtm.2024.101347

Immortalized MUT MEFs are an excellent tool for developing potency assays to validate novel FRDA therapies. Care needs to be exercised while utilizing these cell lines, as extended passaging results in molecular changes that spontaneously reverse FRDA-like phenotypes without increasing Fxn expression. Based on transcriptome analyses, we identified the Warburg effect as the mechanism allowing cells expressing a minimal level of Fxn to thrive under standard cell culture conditions.

Papillon Therapeutics Receives Rare Pediatric Disease Designation from the U.S. Food and Drug Administration for PPL-001 for the Treatment of Friedreich's Ataxia

October 15, 2024. SAN DIEGO--Papillon Therapeutics Inc., today announced that the U.S. Food and Drug Administration (FDA) has granted Rare Pediatric Disease designation to Papillon’s PPL-001, an experimental treatment for Friedreich's ataxia. 

PPL-001 has previously received Orphan Drug designation. PPL-001 is an experimental gene-corrected CD34+ hematopoietic stem and progenitor cell (HSPC) therapy. This therapeutic’s novel approach utilizes targeted excision to correct the GAA repeat expansion in Intron 1 of the FXN gene.

PTC Therapeutics Announces Positive Results from Long-Term Treatment Studies and Updates on Regulatory Progress for Vatiquinone Friedreich Ataxia Program

WARREN, N.J., Oct. 8, 2024 /PRNewswire/ -- PTC Therapeutics, Inc. provided today several positive updates on the vatiquinone Friedreich ataxia (FA) program. The pre-specified endpoint for two different FA long-term extension studies was met, with highly statistically significant evidence of durable treatment benefit on disease progression. In addition, PTC recently aligned with FDA on key aspects of the planned NDA submission for vatiquinone.

Analysis of the MOVE-FA long-term extension study demonstrated that 144 weeks of vatiquinone treatment resulted in a 3.7-point benefit (p<0.0001, N=70) on the modified Friedreich Ataxia Rating Scale (mFARS) relative to a matched natural history cohort from the FACOMS (Friedreich Ataxia Clinical Outcome Measures) disease registry. This treatment difference on the primary endpoint represents a clinically meaningful 50% slowing in disease progression over 3 years. These results confirm that the slowing of disease progression recorded in the 72-week placebo-controlled MOVE-FA trial are maintained over 144 weeks of treatment. In addition, vatiquinone continued to be safe and well tolerated without any treatment-related serious adverse events reported.In addition, PTC analyzed long-term open-label data from an earlier study of vatiquinone in adults with FA. Following 24-months of treatment with vatiquinone, subjects had a 4.8-point benefit on the mFARS relative to a matched natural history population (p<0.0001, N=41).

The SIRT-1/Nrf2/HO-1 Axis: Guardians of Neuronal Health in Neurological Disorders

Pranshul Sethi, Sidharth Mehan, Zuber Khan, Pankaj Kumar Maurya, Nitish Kumar, Aakash Kumar, Aarti Tiwari, Tarun Sharma, Ghanshyam Das Gupta, Acharan S Narula, Reni Kalfin, The SIRT-1/Nrf2/HO-1 Axis: Guardians of Neuronal Health in Neurological Disorders, Behavioural Brain Research, 2024, 115280, ISSN 0166-4328, doi:10.1016/j.bbr.2024.115280. 

SIRT1 (Sirtuin 1) is a NAD+-dependent deacetylase that functions through nucleoplasmic transfer and is present in nearly all mammalian tissues. SIRT1 is believed to deacetylate its protein substrates, resulting in neuroprotective actions, including reduced oxidative stress and inflammation, increased autophagy, increased nerve growth factors, and preserved neuronal integrity in aging or neurological disease. Nrf2 is a transcription factor that regulates the genes responsible for oxidative stress response and substance detoxification. The activation of Nrf2 guards cells against oxidative damage, inflammation, and carcinogenic stimuli. Several neurological abnormalities and inflammatory disorders have been associated with variations in Nrf2 activation caused by either pharmacological or genetic factors. Recent evidence indicates that Nrf2 is at the center of a complex cellular regulatory network, establishing it as a transcription factor with genuine pleiotropy. HO-1 is most likely a component of a defense mechanism in cells under stress, as it provides negative feedback for cell activation and mediator synthesis. This mediator is upregulated by Nrf2, nitric oxide (NO), and other factors in various inflammatory states. HO-1 or its metabolites, such as CO, may mitigate inflammation by modulating signal transduction pathways. Neurological diseases may be effectively treated by modulating the activity of HO-1. Multiple studies have demonstrated that SIRT1 and Nrf2 share an important connection. SIRT1 enhances Nrf2, activates HO-1, protects against oxidative injury, and decreases neuronal death. This has been associated with numerous neurodegenerative and neuropsychiatric disorders. Therefore, activating the SIRT1/Nrf2/HO-1 pathway may help treat various neurological disorders. This review focuses on the current understanding of the SIRT1 and Nrf2/HO-1 neuroprotective processes and the potential therapeutic applications of their target activators in neurodegenerative and neuropsychiatric disorders.

Understanding the mechanisms of food effect on omaveloxolone pharmacokinetics through physiologically based biopharmaceutics modeling

Pepin XJH, Hynes SM, Zahir H, Walker D, Semmens LQ, Suarez-Sharp S. Understanding the mechanisms of food effect on omaveloxolone pharmacokinetics through physiologically based biopharmaceutics modeling. CPT Pharmacometrics Syst Pharmacol. 2024 Sep 2. doi: 10.1002/psp4.13221. Epub ahead of print. PMID: 39219492. 

Mechanistically, in vivo omaveloxolone absorption was solubility and dissolution rate limited. However, in the fed state, higher bile salt solubilization led to more rapid dissolution with predominant absorption in the upper gastrointestinal tract, resulting in increased susceptibility to first-pass gut extraction; this accounts for the lack of correlation between Cmax and AUC for omaveloxolone.

ASSAIGS CLÍNICS I REVISIÓ FARMACOLÒGICA DE L’ATÀXIA DE FRIEDREICH

Treball Final de Grau Grau de Farmàcia ASSAIGS CLÍNICS I REVISIÓ FARMACOLÒGICA.NÚRIA BAIGES BEGUER. Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona Barcelona, Juny 2024 

 Aquest treball fa una anàlisi dels assaigs clínics actius en l’actualitat, relacionant-los amb les dianes terapèutiques definides pels mecanismes d’acció dels diferents fàrmacs. En el treball s’analitzen tretze fàrmacs, incloent-hi el fàrmac recentment aprovat, i es fa una breu referència a la recerca preclínica que encara no ha estat provada en persones, fixant-me especialment en aquelles recerques en teràpies avançades, ja que són prometedores per les malalties d’origen genètic.

This paper analyses the clinical trials currently active, relating them to the therapeutic targets defined by the mechanisms of action of the different drugs. Thirteen drugs are analysed, including the recently approved drug, and a brief reference is made to preclinical research that has not yet been tested in humans, focusing especially on research into advanced therapies, as these are promising for diseases of genetic origin. 

Case Report of Friedreich's Ataxia and ALG1-Related Biochemical Abnormalities in a Patient With Progressive Spastic Paraplegia

Quinlan, A., Rodan, L., Barkoudah, E., Tam, A., Saffari, A., Shammas, I., Ranatunga, W., Morava-Kozicz, E., Oglesbee, D., Berry, G., Ebrahimi-Fakhari, D. and Srivastava, S. (2024), Case Report of Friedreich's Ataxia and ALG1-Related Biochemical Abnormalities in a Patient With Progressive Spastic Paraplegia. Am J Med Genet e63890. doi:10.1002/ajmg.a.63890 

 Our findings underscore the importance of considering FRDA as a differential diagnosis in cases of complex HSP and demonstrate the utility of unbiased genome sequencing approaches that include detection of trinucleotide repeat expansions for progressive motor disorders.

VIDEOFLUOROSCOPIC SWALLOWING STUDY FINDINGS AND RESPIRATORY FUNCTION TESTING IN PATIENTS WITH FRIEDREICH ATAXIA

VIDEOFLUOROSCOPIC SWALLOWING STUDY FINDINGS AND RESPIRATORY FUNCTION TESTING IN PATIENTS WITH FRIEDREICH ATAXIA. LEON ASTUDILLO, CARMEN E et al.. CHEST, Volume 166, Issue 4, A6528 - A6529 doi:10.1016/j.chest.2024.07.118

 Dysphagia was present in 2 subjects based on PAS score, and in 3 subjects based on DIGEST scores. Although EAT-10 was abnormal in 4 out of 5 subjects, the results did not correspond to objective findings on VFSS. Similarly, VFSS results did not correspond with other clinical metrics including pulmonary function testing, EAT-10 or IOPI. Four subjects received interventions or dietary modifications based on VFSS results. Our study is limited by the small sample. 

CLINICAL IMPLICATIONS: Dysphagia can be seen in FRDA regardless of respiratory or functional testing results. VFSS or fiberoptic endoscopic evaluation of swallowing (FEES) can be considered as an objective tool for evaluation of swallowing in this population. Further research is needed to identify risk factors, correlation with other clinical metrics and outcomes.

Early Genetic Testing Avoids Treatment Delays for Patients with Friedreich Ataxia

EMJ. 2024;9[3]:14-23. doi:10.33590/emj/RSCJ7037 

This industry-sponsored symposium took place during the European Association of Neurology (EAN) Congress held in Helsinki, Finland, 29 June−2 July, 2024.

At the 2024 European Association of Neurology (EAN) Congress, one satellite symposium discussed the recognition, diagnosis, and treatment of Friedreich ataxia (FA), the most common hereditary ataxia. This condition is characterised by progressive neurodegeneration, multisystem complications, loss of ambulation, and reductions in the ability to carry out activities of daily living (ADL). For many, there is also a premature death. FA is caused by guanine-adenine-adenine triplet (GAA) repeat expansions in the gene FXN. This codes for the protein frataxin, loss of which is associated with impaired mitochondrial function, increased sensitivity to oxidative stress and reactive oxygen species levels, increased inflammation, and cell death.

Papillon Therapeutics Receives Orphan Drug Designation from the U.S. Food and Drug Administration for PPL-001 for the Treatment of Friedreich's Ataxia

SAN DIEGO--(BUSINESS WIRE)--Sep 17, 2024-- Papillon Therapeutics Inc., today announced that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation to Papillon’s PPL-001, an experimental treatment for Friedreich's ataxia. 

PPL-001 is an experimental gene-corrected CD34+ hematopoietic stem and progenitor cell (HSPC) therapy. This therapeutic’s novel approach utilizes targeted excision to correct the GAA repeat expansion in Intron 1 of the FXN gene.

Mitotech Presents Promising Results in Friedreich's Ataxia

LONDON, Sept. 17, 2024 /PRNewswire-PRWeb/ -- Mitotech Ltd, a mitochondria-focused clinical-stage biotechnology company, presented new data for its mitochondria-targeted ferroptosis inhibitor in Friedreich's Ataxia (FA) model at the 149th annual meeting of the American Neurological Association. The conference took place on September 14-17, 2024, in Orlando, FL. 

Those new data demonstrated high level of efficacy of the company's lead compound SkQ1 – a mitochondria-targeted ferroptosis inhibitor – against ferroptosis and oxidative stress at strikingly low doses.The Friedreich's Ataxia-specific model has not only demonstrated SkQ1's great potential as a monotherapy for FA, but also highlighted its MoA as complementary to that of the currently available therapy – omaveloxolone. The latter aspect of our latest dataset opens the door for studying SkQ1 in a combination treatment in the clinic,"

Skeletal Muscle Involvement in Friedreich Ataxia

Indelicato, E.; Wanschitz, J.; Löscher, W.; Boesch, S. Skeletal Muscle Involvement in Friedreich Ataxia. Int. J. Mol. Sci. 2024, 25, 9915. doi:10.3390/ijms25189915 

 Moreover, FRDA displays skeletal muscle involvement, which contributes to the weakness and marked fatigue evident throughout the course of the disease. Herein, we review skeletal muscle findings in FRDA generated by functional imaging, histology, as well as multiomics techniques in both disease models and in patients. Altogether, these findings corroborate a disease phenotype in skeletal muscle and support the notion of progressive mitochondrial damage as a driver of disease progression in FRDA. Furthermore, we highlight the relevance of skeletal muscle investigations in the development of biomarkers for early-phase trials and future therapeutic strategies in FRDA.

Deciphering the ferroptosis pathways in dorsal root ganglia of Friedreich ataxia models. The role of LKB1/AMPK, KEAP1, and GSK3β in the impairment of the NRF2 response

Arabela Sanz-Alcázar, Marta Portillo-Carrasquer, Fabien Delaspre, Maria Pazos-Gil, Jordi Tamarit, Joaquim Ros, Elisa Cabiscol, Deciphering the ferroptosis pathways in dorsal root ganglia of Friedreich ataxia models. The role of LKB1/AMPK, KEAP1, and GSK3β in the impairment of the NRF2 response, Redox Biology, Volume 76, 2024, 103339, ISSN 2213-2317, doi:10.1016/j.redox.2024.103339

Unusual Age-Dependent Behavior of Leukocytes Telomere Length in Friedreich's Ataxia

Scarabino D, Veneziano L, Nethisinghe S, Mantuano E, Fiore A, Granata G, Solanky N, Zanni G, Cavalcanti F, Corbo RM, Giunti P. Unusual Age-Dependent Behavior of Leukocytes Telomere Length in Friedreich's Ataxia. Mov Disord. 2024 Sep 5. doi: 10.1002/mds.29976. Epub ahead of print. PMID: 39235665. 

 The results showed that before 35 years of age, leukocyte telomeres were longer in patients than in controls, whereas the reverse applies in patients above 36 years of age. Interestingly, LTL was greater than controls at any age in heterozygous subjects. Overall, the present study indicates that telomere length analysis in FRDA may be a relevant biomarker for following the stages of the disease.

A Pilot Phase 2 Randomized Trial to Evaluate the Safety and Potential Efficacy of Etravirine in Friedreich Ataxia Patients

Paparella, G.; Stragà, C.; Pesenti, N.; Dal Molin, V.; Martorel, G.A.; Merotto, V.; Genova, C.; Piazza, A.; Piccoli, G.; Panzeri, E.; et al. A Pilot Phase 2 Randomized Trial to Evaluate the Safety and Potential Efficacy of Etravirine in Friedreich Ataxia Patients. Children 2024, 11, 958, doi:10.3390/children11080958.

Etravirine was well tolerated. Etravirine completely stopped the progression of the SARA score during the 4-months treatment period, compared to the 4 months pre and post treatment. It increased peak workload, while the improvement of peak oxygen uptake was not statistically significant. No changes in the cardiac measures were observed. Health and QoL measures showed a worsening at the suspension of the drug. In this open trial etravirine significantly improved neurological function and was generally safe and reasonably tolerated. This suggests that etravirine represents a potential therapeutic agent in FRDA deserving testing in a randomized placebo controlled clinical trial.

Interplay of FXN expression and lipolysis in white adipocytes plays a critical role in insulin sensitivity in Friedreich’s ataxia mouse model

Wu, L., Huang, F., Yang, L. et al. Interplay of FXN expression and lipolysis in white adipocytes plays a critical role in insulin sensitivity in Friedreich’s ataxia mouse model. Sci Rep 14, 19876 (2024). doi:10.1038/s41598-024-71099-7

We uncovered the interplay between FXN expression and lipolysis and found that impairment of lipolysis, particularly the white adipocytes, is an early event, likely, as a primary cause for insulin resistance in FRDA patients at later age.

A multiple animal and cellular models approach to study frataxin deficiency in Friedreich Ataxia

Valentine Mosbach, Hélène Puccio, A multiple animal and cellular models approach to study frataxin deficiency in Friedreich Ataxia, Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Volume 1871, Issue 7, 2024, 119809, ISSN 0167-4889, doi:10.1016/j.bbamcr.2024.119809. 

 Over the years, several cellular and animal models for FA have been developed. These models are all complementary and possess their own strengths to investigate different aspects of the disease, such as the epigenetics of the locus or the pathophysiology of the disease, as well as being used to developed novel therapeutic approaches. This review will explore the recent advancements in the different mammalian models developed for FA.

NAD+ precursors prolong survival and improve cardiac phenotypes in a mouse model of Friedreich’s Ataxia

NAD+ precursors prolong survival and improve cardiac phenotypes in a mouse model of Friedreich’s Ataxia, Caroline E. Perry, … , David R. Lynch, Joseph A. Baur. Published August 22, 2024, Citation Information: JCI Insight. 2024;9(16):e177152. doi:10.1172/jci.insight.177152. 

Administering nicotinamide mononucleotide or riboside to shFxn mice increases survival, modestly improves cardiac hypertrophy, and limits increases in ejection fraction. Mechanistically, most of the transcriptional and metabolic changes induced by frataxin knockdown are insensitive to NAD+ precursor administration, but glutathione levels are increased, suggesting improved antioxidant capacity. Overall, our findings indicate that NAD+ precursors are modestly cardioprotective in this model of FRDA and warrant further investigation.

Emerging therapies in hereditary ataxias

Eisel MLS, Burns M, Ashizawa T, Byrne B, Corti M, Subramony SH. Emerging therapies in hereditary ataxias. Trends Mol Med. August 16, 2024 ;0(0). doi:10.1016/j.molmed.2024.07.008 

In this review, we focus on Friedreich ataxia (FRDA) and the polyglutamine ataxias in which translational research is active. However, much remains to be done to identify safe and effective molecules, create ideal delivery methods, and perform innovative clinical trials to prove the safety and efficacy of treatments for these rare but devastating diseases.

The importance of synthetic pharmacotherapy for recessive cerebellar ataxias

Beaudin, M., Dupre, N., & Manto, M. (2024). The importance of synthetic pharmacotherapy for recessive cerebellar ataxias. Expert Review of Neurotherapeutics, 24(9), 897-912.  doi:10.1080/14737175.2024.2376840

This article reviews the currently approved and most promising candidate pharmacotherapies in relation to the known disease mechanisms of the most prevalent autosomal recessive ataxias. Omaveloxolone is an Nrf2 activator that increases antioxidant defense and was recently approved for treatment of Friedreich ataxia. Its therapeutic effect is modest, and further research is needed to find synergistic treatments that would halt or reverse disease progression. Promising approaches include upregulation of frataxin expression by epigenetic mechanisms, direct protein replacement, and gene replacement therapy.

Lexeo Therapeutics Reports Second Quarter 2024 Financial Results and Operational Highlights

NEW YORK, Aug. 12, 2024 (GLOBE NEWSWIRE) -- Lexeo Therapeutics, Inc. “Based on the favorable evidence to date, we have initiated engagements with FDA on surrogate endpoints for a registrational study so we can work to bring this potentially transformative gene therapy to patients as quickly as possible.” 

LX2006 for the Treatment of FA Cardiomyopathy: In July 2024, Lexeo announced positive interim data of LX2006 across both the Lexeo SUNRISE-FA Phase 1/2 clinical trial (NCT05445323) and the Weill Cornell Medicine investigator-initiated Phase 1A trial (NCT05302271). Safety and Tolerability: Interim safety results showed LX2006 was well tolerated with no treatment-related serious adverse events in either study. Efficacy and Protein Expression: Sustained and consistent improvements were observed across multiple cardiac biomarkers associated with outcomes in FA cardiomyopathy, and increased frataxin protein levels were observed in all SUNRISE-FA participants post-treatment. Regulatory Plans: In light of the evidence of treatment effect with improvements across multiple cardiac measures, Lexeo recently initiated formal engagements with FDA to discuss surrogate endpoints for a future registrational study and expects to provide an update on ongoing regulatory engagements by end of 2024. LX2006 was also granted Orphan Medicinal Product designation for the treatment of Friedreich ataxia by the European Commission in July 2024. 

Expected Upcoming Milestones LX2006 for the treatment of Friedreich ataxia cardiomyopathy Previously disclosed data, and one additional cardiac biopsy from Cohort 2, will be shared at a scientific conference in Fall 2024 Update on ongoing regulatory engagements expected by end of 2024

Everything You Need to Know About Larimar Therapeutics' Nomlabofusp and the FDA's START Program

August 7, 2024 By Andrew Cox, Pharm.D., MBA. www.managedhealthcareexecutive.com 

Nomlabofusp is a protein replacement therapy designed to deliver frataxin to mitochondria, addressing the root cause of Friedreich's Ataxia. It has received various designations from regulatory bodies, such as Rare Pediatric Disease designation, Fast Track designation, Orphan Drug designation, and PRIME designation. ​ The selection of nomlabofusp for the START program allows Larimar Therapeutics to communicate more effectively with the FDA to expedite the development program towards the pre-BLA meeting stage. Interim data from an ongoing open-label extension (OLE) study are expected in the fourth quarter of 2024. ​ The study assesses the long-term safety, tolerability, pharmacokinetics, and frataxin levels in peripheral tissues of Friedreich's ataxia patients. ​

Lexeo Therapeutics' LX2006 Shows Promise in Treating Friedreich Ataxia Cardiomyopathy

August 9, 2024. By Andrew Cox, Pharm.D., MBA. Managed Healthcare Executive.

Although the initial results are promising, LX2006's ultimate success will depend on ongoing safety evaluations, long-term efficacy data, and the ability to navigate the regulatory landscape. Lexeo Therapeutics' interim clinical data for LX2006 represents a potentially transformative advancement in treating Friedreich Ataxia cardiomyopathy. While the early results are encouraging, ongoing clinical evaluations and regulatory engagements will be vital in determining the future of this promising gene therapy.

New and Emerging Drug and Gene Therapies for Friedreich Ataxia

Scott V, Delatycki MB, Tai G, Corben LA. New and Emerging Drug and Gene Therapies for Friedreich Ataxia. CNS Drugs. 2024 Aug 8. doi: 10.1007/s40263-024-01113-z. Epub ahead of print. PMID: 39115603. 

 This review provides a contemporary position of drug and gene therapies for FRDA currently in phase 1 clinical trials and beyond. Despite significant scientific advances in the specificity of both compounds and targets developed and investigated, challenges remain for the advancement of treatments in a limited recruitment population. Currently therapies focus on reducing oxidative stress and improving mitochondrial function, modulating frataxin controlled metabolic pathways and gene replacement and editing. Approval of omaveloxolone, the first treatment for individuals with FRDA aged 16 years and over, has created much excitement for both those living with FRDA and those that care for them.

Glial cell activation precedes neurodegeneration in the cerebellar cortex of the YG8–800 murine model of Friedreich ataxia

Andrés Vicente-Acosta, Saúl Herranz-Martín, María Ruth Pazos, Jorge Galán-Cruz, Mario Amores, Frida Loria, Javier Díaz-Nido, Glial cell activation precedes neurodegeneration in the cerebellar cortex of the YG8–800 murine model of Friedreich ataxia, Neurobiology of Disease, 2024, 106631, doi:10.1016/j.nbd.2024.106631.

Together, our results show that the YG8–800 mouse model exhibits a stronger phenotype than previous experimental murine models, reliably recapitulating some of the features observed in humans. Accordingly, this humanized model could represent a valuable tool for studying Friedreich ataxia molecular disease mechanisms and for preclinical evaluation of possible therapies.

Insulin sensitivity and insulin secretion in adults with Friedreich’s Ataxia: the role of skeletal muscle

Jaclyn Tamaroff, Sara Nguyen, Neil E Wilson, Darko Stefanovski, Rui Xiao, Theresa Scattergood, Christopher Capiola, Gayatri Maria Schur, Julia Dunn, Anna Dedio, Kristin Wade, Hardik Shah, Rohit Sharma, Vamsi K Mootha, Andrea Kelly, Kimberly Y Lin, David R Lynch, Ravinder Reddy, Michael R Rickels, Shana E McCormack, Insulin sensitivity and insulin secretion in adults with Friedreich’s Ataxia: the role of skeletal muscle, The Journal of Clinical Endocrinology & Metabolism, 2024;, dgae545, doi:10.1210/clinem/dgae545 

 Lower mitochondrial OXPHOS capacity, inactivity, and visceral adiposity contribute to lower insulin sensitivity in FRDA. Higher insulin secretion appears compensatory, and when inadequate, could herald DM. Further studies are needed to determine if muscle- or adipose-focused interventions could delay FRDA-related DM.

Larimar Therapeutics Reports Second Quarter 2024 Operating and Financial Results

BALA CYNWYD, Pa., Aug. 07, 2024 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (Larimar) “We made significant achievements in our nomlabofusp program this quarter that strongly position us for successful execution across important catalysts over the next 12 months. We were honored to be selected by the FDA to participate in the START pilot program which may be invaluable in helping us achieve our timeline for BLA submission targeted for the second half of 2025 to support accelerated approval. We are actively pursuing clinical sites in the U.S., Europe, U.K. Canada, and Australia in anticipation of initiating a global confirmatory study in mid-2025. We are excited to have recently joined the TRACK-FA Neuroimaging Consortium as an industry partner to support research to define disease-specific neuroimaging biomarkers for potential use in clinical trials.” said Carole Ben-Maimon, MD, President, and Chief Executive Officer of Larimar. “Our OLE study continues to progress with all seven sites now activated and interim data planned for the fourth quarter of this year. We plan to initiate a PK run-in study in adolescents with Friedreich’s ataxia (FA) by year-end, with option for study participants to transition to the OLE study after completing the run-in study. Expanding our clinical program into younger patients will allow us to evaluate the effect of nomlabofusp earlier in the disease process which may help further address the effect of the underlying frataxin deficiency in patients with FA.”

mTORC1 Signaling Inhibition Modulates Mitochondrial Function in Frataxin Deficiency

mTORC1 Signaling Inhibition Modulates Mitochondrial Function in Frataxin Deficiency, Madison Lehmer, Roberto Zoncu, bioRxiv 2024.08.06.606942; doi:10.1101/2024.08.06.606942

 We find that acute chemical modulation of mTORC1 signaling decreased mitochondrial oxygen consumption, increased mitochondrial membrane potential and reduced susceptibility to stress-induced mitophagy. In cellular models of Friedreich Ataxia (FA), where loss of the Frataxin (FXN) protein suppresses Fe-S cluster synthesis and mitochondrial respiration, the changes induced by mTORC1 inhibitors lead to improved cell survival. Proteomic-based profiling uncover compositional changes that could underlie mTORC1-dependent modulation of FXN-deficient mitochondria.

Rare disease clinical trials in the European Union: navigating regulatory and clinical challenges

Mishra, S., Venkatesh, M. Rare disease clinical trials in the European Union: navigating regulatory and clinical challenges. Orphanet J Rare Dis 19, 285 (2024). doi:10.1186/s13023-024-03146-5

Collaboration among academic institutions, pharmaceutical companies (both small and major), patient groups, and health authorities is crucial in overcoming obstacles related to clinical trials and providing assistance and creative ideas. The ultimate objective of granting rare disease patients timely and affordable access to medications with a positive balance between benefits and risks is to be met.

GLP-1R mediates idebenone-reduced blood glucose in mice

Xin Zhao, Qingxuan Zeng, Siting Yu, Xiaochan Zhu, Bin Hu, Lijiao Deng, Yi Zhang, Yunfeng Liu,, GLP-1R mediates idebenone-reduced blood glucose in mice, Biomedicine & Pharmacotherapy, Volume 178, 2024, 117202, ISSN 0753-3322, doi:10.1016/j.biopha.2024.117202. 

( GLP-1 receptor agonists (GLP-1RAs) are an innovative class of drugs with significant therapeutic value for type 2 diabetes mellitus (T2DM). The GLP-1RAs currently available on the market are biologic macromolecular peptide agents that are expensive to treat and not easy to take orally. Therefore, the development of small molecule GLP-1RAs is becoming one of the most sought-after research targets for hypoglycemic drugs. In this study, we sought to find a potential oral small molecule GLP-1RA and to evaluate its effect on insulin secretion in rat pancreatic β cells and on blood glucose in mice. We downloaded the mRNA expression profiles of GSE102194 and GSE37936 from the Gene Expression Omnibus database. Subsequently, the small molecule compound idebenone was screened through the connectivity map database. The results of molecular docking, biolayer interferometry, and cellular thermal shift assay indicated that idebenone could bind potently with GLP-1R. Furthermore, ibebenone elevated intracellular cAMP levels. The radioimmunoassay data showed that idebenone enhanced glucose-stimulated insulin secretion via agonism of GLP-1R. Moreover, the results of oral glucose tolerance tests in C57BL/6, Glp-1r-/-, and hGlp-1r mice demonstrated that the glucose-lowering effects of idebenone were mediated by GLP-1R and that there were no species differences in the agonistic effect of idebenone on GLP-1R. In summary, idebenone reduces blood glucose in mice by promoting insulin release through agonism of GLP-1R, suggesting that idebenone is probably a potential GLP-1RA, which is expected to provide a new therapeutic strategy for the prevention and treatment of metabolic diseases such as T2DM.

Microfluidic formulation of diazoxide-loaded solid lipid nanoparticles as a Novel approach for Friedreich's ataxia treatment

Ilaria Arduino, Antonella Santoro, Silvia De Santis, Rosa Maria Iacobazzi, Angela Assunta Lopedota, Eleonora Paradies, Giuseppe Merla, Sara Anjomani Virmouni, Luigi Palmieri, Carlo Marya Thomas Marobbio, Nunzio Denora, Microfluidic formulation of diazoxide-loaded solid lipid nanoparticles as a Novel approach for Friedreich's ataxia treatment, Journal of Drug Delivery Science and Technology, Volume 97, 2024, 105837, ISSN 1773-2247, doi:10.1016/j.jddst.2024.105837. 

 This study aimed to create solid lipid nanoparticles (SLNs) loaded with DZX by microfluidic technique to improve blood-brain barrier (BBB) penetration and reduce side effects. Employing an in vitro BBB model, SLN-DZX demonstrated enhanced permeability compared to plain DZX. Cell viability assays carried out on FRDA fibroblast cells indicated enhanced viability with 1 μM SLN-DZX. Cellular uptake studies confirmed SLN internalization in FRDA fibroblasts, and subsequent treatment with SLN-DZX significantly reduced both total and mitochondrial ROS levels compared to control and empty SLN-treated cells. These findings suggest SLN-DZX as a potential therapeutic approach for FRDA, mitigating oxidative stress with improved BBB penetration and reduced toxicity.

Phase 2 Trial of Dimethyl Fumarate for Friedrich Ataxia

NeurologyLive. July 17, 2024. Updates in Therapeutic Development: Clinical Trial Readouts to Watch in the Second Half of 2024 

According to a recent interview with Francesco Saccà, MD, PhD, an associate professor of neurology at the University of Naples, the phase 2 study assessing the use of dimethyl fumarate (DMF), an approved product for relapsing multiple sclerosis and psoriasis in Europe, in patients with Friedreich ataxia (FA), potentially anticipates some data, at least the primary and many of the secondary endpoints, by September or October of this year. Saccà also noted that potentially by the end of the year, investigators will close the entire analysis. 

The study, which two sequential 12-week phases, assesses whether DMF can increase the expression of the FXN gene and frataxin protein and ameliorate in-vivo detectable measures of mitochondrial dysfunction in FA. FA, which is typically associated with several developmental features, is caused by a genetic deficiency of frataxin, a small, nuclear-encoded mitochondrial protein. Frataxin deficiency leads to impairment of iron-sulphur cluster synthesis, and consequently ATP production abnormalities.

Lexeo Therapeutics Announces Positive Interim Phase 1/2 Clinical Data of LX2006 for the Treatment of Friedreich Ataxia Cardiomyopathy

NEW YORK, July 15, 2024 (GLOBE NEWSWIRE) -- Lexeo Therapeutics, Inc. (Nasdaq: LXEO), announced positive interim data of LX2006 for the treatment of Friedreich ataxia (FA) cardiomyopathy. Across both the Lexeo SUNRISE-FA Phase 1/2 clinical trial (NCT05445323) and the Weill Cornell Medicine investigator-initiated Phase 1A trial (NCT05302271), LX2006 was well tolerated with no treatment-related serious adverse events, and clinically meaningful improvements in cardiac biomarkers were observed with increasing improvement over time.

Interim Safety Results

• LX2006 was well tolerated with no treatment-related serious adverse events to date in either study
• No signs of complement activation or other immunogenicity observed
• No cardiac or hepatic safety signals observed
• All adverse events were transient and resolved
• No participants discontinued from either study
  

Interim Clinical Results (from 8 participants with > 6-months of follow-up)

• Left ventricular mass index (LVMI): Of participants with elevated LVMI at baseline, 75% achieved >10% reduction at 12 months (n=4). Of all participants, 50% achieved >10% reduction in LVMI at 12 months (n=6).
  • Among the participants with elevated LVMI at baseline, mean reduction in LVMI was 11.4% at 12 months (n=4) and 18.3% at 18 months (n=2).
• Left ventricular (LV) lateral wall thickness: wall thickening, an early indicator of left ventricular hypertrophy, was reduced by 13.6% on average in all participants at 12 months (n=6).
• High-sensitivity Troponin I (hsTnI): troponin I, a biomarker of myocardial injury, was reduced by 53.3% on average in all participants at 12 months (n=5).
• Frataxin protein expression evaluated via myocardial biopsy: observed increased frataxin levels compared to baseline following treatment with LX2006 in all participants evaluated to date utilizing two distinct measurements:
  • LCMS: frataxin increase observed in 3 of 3 evaluable participants.
  • IHC: frataxin increase observed in 2 of 2 evaluable participants.
    

Dosing Update and Next Steps

• As of July 15, 2024, 13 participants dosed to date across two trials:
  • Cohort 1 (1.8x10¹¹vg/kg): n=6
  • Cohort 2 (5.6x10¹¹ vg/kg): n=6
  • Cohort 3 (1.2x10¹² vg/kg): n=1
• SUNRISE-FA independent Data and Safety Monitoring Board endorsed proceeding to Cohort 3 dose level (1.2x10¹²vg/kg). This cohort has started enrollment with 1 participant dosed to date and will include at least 3 participants.
• The Weill Cornell investigator-initiated trial is currently enrolling in Cohort 2.
• Lexeo expects to share further details of these interim results, including an additional cardiac biopsy from Cohort 2, at a scientific conference in Fall 2024.

Anatomical and functional analysis of the corticospinal tract in an FRDA mouse model

Anatomical and functional analysis of the corticospinal tract in an FRDA mouse model. Misa Nishiyama, John Kalambogias, Fumiyasu Imai, Emily Yang, Sonia Lang, Joriene C de Nooij, Yutaka Yoshida bioRxiv 2024.06.28.601178; doi:10.1101/2024.06.28.601178 

Yet, it remains poorly understood how early in the disease cortical spinal neurons (CSNs) show these alterations, or whether CSN/CST pathology resembles the abnormalities observed in other tissues affected by FXN loss. To address these questions, we examined CSN driven motor behaviors and pathology in the YG8JR FRDA mouse model. We find that FRDA mice show impaired motor skills, exhibit significant reductions in CSN functional output, and, among other pathological changes, show abnormal mitochondrial distributions in CSN neurons and CST axonal tracts. Moreover, some of these alterations were observed as early as two months of age, suggesting that CSN/CST pathology may be an earlier event in FRDA disease than previously appreciated. These studies warrant a detailed mechanistic understanding of how FXN loss impacts CSN health and functionality.

Challenges for gene therapy in the financial sustainability of health systems: a scoping review

Ossandon, H., Armijo, N., Vargas, C. et al. Challenges for gene therapy in the financial sustainability of health systems: a scoping review. Orphanet J Rare Dis 19, 243 (2024). doi:10.1186/s13023-024-03249-z

The study identified 279 publications, and after removing duplicates and screening for eligibility, 10 were included in the study. The results show that various financing models have been proposed, including subscription-based payment models, outcome-based payment models, and amortization strategies. However, several barriers to implementing these models were identified, such as deficiencies in informatics systems for data collection, changes in laws or regulations, the lack of accessible clinical endpoints and administrative costs.

SYSTEMIC FRATAXIN DEFICIENCY CAUSES TISSUE-DEPENDENT IRON HOMEOSTASIS ALTERATIONS: IMPLICATIONS FOR FRIEDREICH ATAXIA

SYSTEMIC FRATAXIN DEFICIENCY CAUSES TISSUE-DEPENDENT IRON HOMEOSTASIS ALTERATIONS: IMPLICATIONS FOR FRIEDREICH ATAXIA Maria Pazos-Gil, Marta Medina-Carbonero, Arabela Sanz-Alcázar, Marta Portillo-Carrasquer, Luiza Oliveira, Gonzalo Hernandez, Mayka Sánchez, Fabien Delaspre, Elisa Cabiscol, Joaquim Ros, Jordi Tamarit bioRxiv 2024.07.05.602088; doi:10.1101/2024.07.05.602088 

Our findings demonstrate that frataxin deficiency affects iron homeostasis in a time dependent and tissue-specific manner, and that the pathological mechanisms in FA comprise both iron accumulation and limited iron availability. Understanding this specificity is crucial for the design of iron-related therapeutic interventions aiming to improve FA symptomatology.

Altered calcium responses and antioxidant properties in Friedreich’s ataxia-like cerebellar astrocytes

Altered calcium responses and antioxidant properties in Friedreich’s ataxia-like cerebellar astrocytes Chiara Marullo, Laura Croci, Iris Giupponi, Claudia Rivoletti, Sofia Zuffetti, Barbara Bettegazzi, Filippo Casoni, Ottavio Cremona, Gian Giacomo Consalez, Franca Codazzi bioRxiv 2024.07.19.604129; doi: 10.1101/2024.07.19.604129 

Our findings shed light on cellular changes caused by FXN downregulation in cerebellar astrocytes, which can interfere with their physiological and complex interaction with neurons. The potentially impaired ability to provide neuronal cells with glutathione or to release neuromodulators and bioactive molecules in a calcium-dependent manner could impact neuronal function and contribute to neurodegeneration.

Relative Bioavailability of Omaveloxolone When Capsules Are Sprinkled Over and Mixed in Applesauce Compared With Administration as Intact Omaveloxolone Capsules: A Phase 1, Randomized, Open-Label, Single-Dose, Crossover Study in Healthy Adults

Hynes SM, Goldsberry A, Henneghan PD, et al. Relative bioavailability of omaveloxolone when capsules are sprinkled over and mixed in applesauce compared with administration as intact omaveloxolone capsules: A phase 1, randomized, open-label, single-dose, crossover study in healthy adults. J Clin Pharm. 2024;: 00-00. doi:10.1002/jcph.2482 

Some patients with FA may have oropharyngeal dysphagia or difficulty swallowing whole capsules; therefore, alternate method(s) of administration are needed. A Phase 1 clinical study in 32 healthy volunteers evaluated the relative bioavailability, safety, and tolerability of a single dose of omaveloxolone when capsule contents were sprinkled on and mixed in applesauce compared to when taken as intact capsules. Palatability when sprinkled on and mixed in applesauce was assessed with a questionnaire.

Advancing Understanding of Predictive Factors for Survival in Friedreich's Ataxia: A Review of Current Evidence and Future Directions

Xia F, Su C. Advancing Understanding of Predictive Factors for Survival in Friedreich's Ataxia: A Review of Current Evidence and Future Directions. Mov Disord. 2024 Jun;39(6):1081-1082. doi: 10.1002/mds.29869. PMID: 38923013.

Indelicato E, Boesch S. Reply to: "Advancing Understanding of Predictive Factors for Survival in Friedreich's Ataxia: A Review of Current Evidence and Future Directions". Mov Disord. 2024 Jun;39(6):1082. doi: 10.1002/mds.29873. PMID: 38924164.   

C-Path partners with FARA to fortify RDCA-DAP and further accelerate drug development with new Friedreich’s Ataxia Data

TUCSON, Ariz., June 18, 2024 — Critical Path Institute (C-Path), a leader in accelerating drug development for rare diseases, today announced the targeted integration of additional Friedreich’s ataxia (FA) datasets into C-Path’s Rare Disease Cures Accelerator-Data and Analytics Platform (RDCA-DAP®) as part of a partnership with Friedreich’s Ataxia Research Alliance (FARA). 

“RDCA-DAP’s extensive resources can amplify the impact of the existing data and foster new discoveries in FA research. This collaboration will build upon our strong, sustained, and productive partnership with the C-Path team,” said Farmer.

Friedreich’s Ataxia and Cesarean Delivery: A Case Report of Epidural Anesthesia With Ropivacaine

Theodosopoulou P, Mavromati M, Paraskeva A (June 06, 2024) Friedreich’s Ataxia and Cesarean Delivery: A Case Report of Epidural Anesthesia With Ropivacaine. Cureus 16(6): e61776. doi:10.7759/cureus.61776 

Overall management and the choice to proceed with neuraxial anesthesia in a woman with FRDA should be based on comprehensive consultations in both cardio-obstetrics and pre-anesthetic evaluations.

Microfluidic Formulation of Diazoxide-Loaded Solid Lipid Nanoparticles as a Novel Approach for Friedreich's Ataxia Treatment

Ilaria Arduino, Antonella Santoro, Silvia De Santis, Rosa Maria Iacobazzi, Angela Assunta Lopedota, Eleonora Paradies, Giuseppe Merla, Sara Anjomani Virmouni, Luigi Palmieri, Carlo Marya Thomas Marobbio, Nunzio Denora, Microfluidic Formulation of Diazoxide-Loaded Solid Lipid Nanoparticles as a Novel Approach for Friedreich's Ataxia Treatment, Journal of Drug Delivery Science and Technology, 2024, 105837, ISSN 1773-2247, doi: 10.1016/j.jddst.2024.105837. 

 These findings suggest SLN-DZX as a potential therapeutic approach for FRDA, mitigating oxidative stress with improved BBB penetration and reduced toxicity.

The Mechanism of Folding of Human Frataxin in Comparison to the Yeast Homologue - Broad Energy Barriers and the General Properties of the Transition State

Pietrangeli P, Marcocci L, Pennacchietti V, Diop A, Di Felice M, Pagano L, Malagrinò F, Toto A, Brunori M, Gianni S. The Mechanism of Folding of Human Frataxin in Comparison to the Yeast Homologue - Broad Energy Barriers and the General Properties of the Transition State. J Mol Biol. 2024 May 15;436(10):168555. doi: 10.1016/j.jmb.2024.168555. Epub 2024 Mar 27. PMID: 38552947. 

 We compared results from yeast and human frataxin providing insights into the impact of native topology on the folding mechanism and elucidating the properties of the underlying free energy landscape. The findings are discussed in the context of the funneled energy landscape theory of protein folding.

The genetic basis of early-onset hereditary ataxia in Iran: results of a national registry of a heterogeneous population

Mahdieh N, Heidari M, Rezaei Z, et al. The genetic basis of early-onset hereditary ataxia in Iran: results of a national registry of a heterogeneous population. Human Genomics. 2024 Apr;18(1):35. DOI: 10.1186/s40246-024-00598-5. PMID: 38570878; PMCID: PMC10988936.

 Friedreich ataxia (FA), ataxia telangiectasia (AT), ataxia with oculomotor apraxia (AOA), and autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) are among the most common forms of ARCA. These conditions typically present with a complicated phenotype. For instance, FA, the most prevalent recessive ataxia affecting 1 in 50,000 individuals in white populations, is caused by homozygous expansions of an intronic GAA trinucleotide repeat in the FXN gene

Mitochondrial calcium regulation of cardiac metabolism in health and disease

Balderas E, Lee SH, Rai NK, et al. Mitochondrial calcium regulation of cardiac metabolism in health and disease. Physiology (Bethesda, Md.). 2024 May. DOI: 10.1152/physiol.00014.2024. PMID: 38713090. 

In this review, we delve into recent insights further defining the relationship between mitochondrial Ca2+ dynamics and oxidative phosphorylation. Our focus is on how such regulation affects cardiac function in health and disease, including heart failure, ischemia-reperfusion, arrhythmias, catecholaminergic polymorphic ventricular tachycardia, mitochondrial cardiomyopathies, Barth syndrome, and Friedreich's ataxia.

Revisiting Friedreich's Ataxia: Phenotypic and Imaging Characteristics

Mahale R, Purushottam M, Singh R, Yelamanchi R, Kamble N, Holla V, Pal PK, Jain S, Yadav R. Revisiting Friedreich's Ataxia: Phenotypic and Imaging Characteristics. Ann Indian Acad Neurol. 2024 Mar-Apr;27(2):152-157. doi: 10.4103/aian.aian_1001_23. Epub 2024 Apr 12. PMID: 38751907; PMCID: PMC11093178.

A retrospective cross-sectional, descriptive analysis of genetically proven FRDA patients was performed. A detailed review of all the hospital case records was done to analyze the clinical, radiologic, and electrophysiologic details.

Mapping Novel Frataxin Mitochondrial Networks Through Protein- Protein Interactions

Etienne Gnimpieba, D M Diing, Jared Ailts et al. Mapping Novel Frataxin Mitochondrial Networks Through Protein- Protein Interactions, 26 April 2024, PREPRINT (Version 1) available at Research Square doi: 10.21203/rs.3.rs-4259413/v1] 

Our data has demonstrated the strengths of employing complementary methods to identify a unique interactome for FXN. Our data provides new insights into FXN function and regulation, a potential direct interaction between FXN and NFS1, and pathway interactions between FXN and Prdx3.

Efficacy and Safety of Coenzyme Q10 Supplementation in Neonates, Infants and Children: An Overview

Mantle D, Hargreaves IP. Efficacy and Safety of Coenzyme Q10 Supplementation in Neonates, Infants and Children: An Overview. Antioxidants (Basel, Switzerland). 2024 Apr;13(5):530. DOI: 10.3390/antiox13050530. PMID: 38790635; PMCID: PMC11117623. 

 Contradictory outcomes have been described regarding the effect of supplementation with the CoQ10 analogue idebenone on cardiac function or neurological function in younger Friedreich’s ataxia patients. Thus, in an open study, supplementation with idebenone (5 mg/kg/day for 6 months) in eight children (age range 4–12 years) with Friedreich’s ataxia resulted in improved cardiac indices (left ventricular mass, left ventricular posterior wall thickness, shortening fraction). An open study of Friedreich’s ataxia patients, including 15 children (ages 4–12 years), found improved cardiac indices (left ventricular posterior wall thickness, interventricular septum thickness) following supplementation with idebenone (20 mg/kg/day). However, in a randomised controlled trial comprising 70 paediatric patients, supplementing idebenone (450–2250 mg/day for 6 months) did not result in any significant benefit on left ventricular hypertrophy or other cardiac function parameters. Similarly, with regard to neurological function, an open study by Pineda et al. comparing younger (ages 8–18 years) and adult (ages 18–46 years) patients with Friedreich’s ataxia found supplementation with idebenone (5–20 mg/kg/day for 3–5 years) stabilised neurological function in younger subjects, but not in adults. However, a randomised controlled trial supplementing idebenone (450–2250 mg/day for 6 months) in a series of 70 children/adolescents (aged 8–18 years) did not result in any significant improvement in neurological function. In addition, a randomised controlled trial, supplementation with idebenone (5–45 mg/kg/day for 6 months) in a cohort of 42 children/adolescents (aged 9–17 years) with Friedreich’s ataxia did not result in any improvement in exercise capacity.

CRPD frontiers in movement disorders Therapeutics: From evidence to treatment and applications: Addressing Patients' Needs in the Management of the Ataxias

Perlman SL. CRPD frontiers in movement disorders Therapeutics: From evidence to treatment and applications: Addressing Patients' Needs in the Management of the Ataxias. Clinical Parkinsonism & Related Disorders. 2024 ;10:100255. DOI: 10.1016/j.prdoa.2024.100255. PMID: 38798918; PMCID: PMC11126860. 

The genetic ataxias have no cures and no proven ways to delay progression (no disease-modifying therapies). The acquired ataxias may have treatments that address the underlying cause and may slow or stop progression, but will not reverse damage already sustained. The idiopathic ataxias (of unknown genetic or acquired cause) also have no proven disease-modifying therapies. However, for all patients with ataxia of any cause, there is always something that can be done to improve quality of life-treat associated symptoms, provide information and resources, counsel patient and family, help with insurance and disability concerns, be available to listen and answer the many questions they will have.

Requirements for the biogenesis of [2Fe-2S] proteins in the human and yeast cytosol

Braymer JJ, Stehling O, Stümpfig M, et al. Requirements for the biogenesis of [2Fe-2S] proteins in the human and yeast cytosol. Proceedings of the National Academy of Sciences of the United States of America. 2024 May;121(21):e2400740121. DOI: 10.1073/pnas.2400740121. PMID: 38743629; PMCID: PMC11126956. 

The most critical GSH requirement was assigned to Atm1-dependent export, i.e. a step before GSH-dependent cGrxs function. Our findings extend the general model of eukaryotic Fe/S protein biogenesis by adding the molecular requirements for cytosolic [2Fe-2S] protein maturation.

Insights into the effects of Friedreich ataxia on the left ventricle using T1 mapping and late gadolinium enhancement

Peverill RE, Lin KY, Fogel MA, Cheung MMH, Moir WS, Corben LA, et al. (2024) Insights into the effects of Friedreich ataxia on the left ventricle using T1 mapping and late gadolinium enhancement. PLoS ONE 19(5): e0303969. https://doi.org/10.1371/journal.pone.0303969

In conclusion, there is an association between diffuse interstitial LV myocardial fibrosis and genetic severity in FRDA, with this effect being independent of the FRDA-associated LV changes in LVEDVI and LVMI. Localised replacement fibrosis was found in a minority of subjects with FRDA, this minority including both children and adults, and subjects with and without a reduction of LVEF. In contrast to T1 mapping variables, LGE in subjects with a normal LVEF was not associated with genetic severity, and was also not associated with LVM or LVEDV, consistent with the development of LGE in FRDA having an idiosyncratic element. There is the potential for roles of both T1 mapping and LGE in the assessment and monitoring of the cardiomyopathy of FRDA, but information will be required about their prognostic significance, and more data will also be required regarding the reproducibility of T1 mapping variables.

Larimar Therapeutics Selected by FDA to Participate in START Pilot Program for Nomlabofusp in Friedreich’s Ataxia

BALA CYNWYD, Pa., May 30, 2024 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (Larimar).United States Food and Drug Administration (FDA) has selected nomlabofusp to participate in the Support for Clinical Trials Advancing Rare Disease Therapeutics (START) pilot program. 

The START pilot program was launched by the FDA in September 2023 to further accelerate the pace of development, with an initial selection of up to six novel drugs, three by the Center for Drug Evaluation and Research (CDER) and three by the Center for Biologics Evaluation and Research (CBER), intended to treat a rare disease or other serious condition with high unmet medical need through an enhanced mechanism for communication with the FDA. Sponsors selected can benefit from more frequent and rapid ad-hoc interactions with the FDA to help facilitate the development of programs to the pivotal clinical study or pre-BLA meeting stage, and to generate high-quality and reliable data intended to support a BLA or New Drug Application (NDA). 

 Nomlabofusp is currently being evaluated in an ongoing open label extension (OLE) study to assess the long-term safety and tolerability, pharmacokinetics, and frataxin levels in peripheral tissues in patients with FA. Interim data from the OLE study is expected in the fourth quarter of 2024.

An In Silico Analysis of Genetic Variants and Structural Modeling of the Human Frataxin Protein in Friedreich’s Ataxia

Da Conceição, L.M.A.; Cabral, L.M.; Pereira, G.R.C.; De Mesquita, J.F. An In Silico Analysis of Genetic Variants and Structural Modeling of the Human Frataxin Protein in Friedreich’s Ataxia. Int. J. Mol. Sci. 2024, 25, 5796. doi:10.3390/ijms25115796 

Overall, 226 missense mutations in human frataxin were compiled from the literature and databases, which underwent a thoroughly functional characterization in silico. This study also provided an unprecedented, complete, and accurate three-dimensional model of human frataxin, serving as a basis for constructing the structure of clinically relevant variants, I154F and W155R. Our MD findings suggest that these mutations disturb FXN’s inherent structure and dynamics, primarily within the N-terminal domain. This behavior could compromise the protein’s ability to adopt functional conformations, potentially leading to impaired recognition and cleavage by the MPP protein, which is directly involved in FXN maturation, as outlined in previous studies. Thus, our findings provide valuable insights into the molecular basis of FXN dysfunction in FRDA, shedding light on future directions that could be explored for developing new therapeutic strategies.

Patient experiences of interprofessional collaboration and intersectoral communication in rare disease healthcare in Germany – a mixed-methods study

Inhestern, L., Otto, R., Brandt, M. et al. Patient experiences of interprofessional collaboration and intersectoral communication in rare disease healthcare in Germany – a mixed-methods study. Orphanet J Rare Dis 19, 197 (2024). doi:10.1186/s13023-024-03207-9 

Our findings indicate the high relevance of transferring affected patients to specialized care as fast as possible to provide best medical treatment and increase patient satisfaction. Intersectoral collaboration should exceed written information exchange and should unburden patients of being and feeling responsible for communication between sectors and specialists. Results indicate a lack of inclusion of psychosocial aspects in routine care, which suggests opportunities for necessary improvements.

Friedreich Ataxia Caregiver-Reported Health Index: Development of a Novel, Disease-Specific Caregiver-Reported Outcome Measure

Seabury J, Varma A, Weinstein J, Rosero SJ, Engebrecht C, Khosa S, Zizzi C, Wagner ES, Alexandrou D, Cohen BL, Dilek N, Heatwole JM, Lynch DR, Park CC, Wells M, Subramony SH, Heatwole CR. Friedreich Ataxia Caregiver-Reported Health Index: Development of a Novel, Disease-Specific Caregiver-Reported Outcome Measure. Neurol Clin Pract. 2024 Jun;14(3):e200303. doi: 10.1212/CPJ.0000000000200300. Epub 2024 May 10. PMID: 38751829; PMCID: PMC11092940. 

Initial evaluation of the FACR-HI supports its content validity, test-retest reliability, and construct validity as a caregiver-reported outcome measure for assessing how pediatric individuals with FRDA feel and function. The FACR-HI provides a potential mechanism to quantify changes in multifactorial FRDA disease burden during future clinical trials.

Glial cell activation precedes neurodegeneration in the cerebellar cortex of the YG8-800 murine model of Friedreich’s ataxia

Glial cell activation precedes neurodegeneration in the cerebellar cortex of the YG8-800 murine model of Friedreich’s ataxia. Andrés Vicente-Acosta, Saúl Herranz-Martín, María Ruth Pazos, Jorge Galán-Cruz, Mario Amores, Frida Loria, Javier Díaz-Nido bioRxiv 2024.05.17.594658;  doi:10.1101/2024.05.17.594658 

Our results show how the YG8-800 mouse model exhibits a stronger phenotype than previous experimental murine models, reliably recapitulating some of the features observed in the human condition. Accordingly, this humanized model could represent a valuable tool to study Friedreich’s ataxia molecular disease mechanisms and for preclinical evaluation of possible therapies.

Glial overexpression of Tspo extends lifespan and protects against frataxin deficiency in Drosophila

Estelle Jullian, Maria Russi, Ema Turki, Margaux Bouvelot, Laura Tixier, Sandrine Middendorp, Elodie Martin, Véronique Monnier, Glial overexpression of Tspo extends lifespan and protects against frataxin deficiency in Drosophila, Biochimie, 2024, ISSN 0300-9084, doi:10.1016/j.biochi.2024.05.003. 

 We further overexpressed Tspo specifically in glial cells and observed improved survival. Finally, we investigated the effects of Tspo overexpression in healthy flies. Increased longevity was conferred by glial-specific overexpression, with opposite effects in neurons. Overall, this study highlights protective effects of glial TSPO in Drosophila both in a neurodegenerative and a healthy context.

Characterizing the molecular basis of Friedreich's ataxia using molecular dynamics

Characterizing the molecular basis of Friedreich's ataxia using molecular dynamics. Fox, David J., David R. Koes. Biophysical Journal, Volume 123, Issue 3, 138a, doi:10.1016/j.bpj.2023.11.950

Using weighted ensemble molecular dynamics, we are able to simulate the dynamics of this process both with and without FXN. From these simulations we are able to derive models of the mobile loop dynamics, FXN’s function, and how the lack of FXN in this process may cause FRDA. This work provides novel and necessary information for the understanding of FRDA as well as the development of treatments for FRDA.

An RNA-seq study in Friedreich ataxia patients identified hsa-miR-148a-3p as a putative prognostic biomarker of the disease

Vancheri, C., Quatrana, A., Morini, E. et al. An RNA-seq study in Friedreich ataxia patients identified hsa-miR-148a-3p as a putative prognostic biomarker of the disease. Hum Genomics 18, 50 (2024).doi:10.1186/s40246-024-00602-y

 Our findings support the evaluation of combined expression levels of different circulating miRNAs as potent epi-biomarkers in FRDA. Moreover, we found hsa-miR-148a-3p significantly over-expressed in Intermediate and Late-Onset Friedreich Ataxia patients’ group (IOG and LOG, respectively) compared to healthy individuals, indicating it as a putative prognostic biomarker in this pathology.

Larimar Therapeutics Announces FDA has Removed Partial Clinical Hold for Nomlabofusp Program in Friedreich’s Ataxia

BALA CYNWYD, Pa., May 20, 2024 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (Larimar) (Nasdaq: LRMR), a clinical-stage biotechnology company focused on developing treatments for complex rare diseases, today announced the U.S. FDA has removed the partial clinical hold previously placed on the company's nomlabofusp (CTI-1601) clinical program.

Long non-coding RNA TUG1 is down-regulated in Friedreich’s ataxia

Mert Koka, Hui Li, Rumana Akther, Susan Perlman, Darice Wong, Brent L Fogel, David R Lynch, Vijayendran Chandran, Long non-coding RNA TUG1 is down-regulated in Friedreich’s ataxia, Brain Communications, 2024;, fcae170, doi:10.1093/braincomms/fcae170 

This study identifies TUG1 as a potential blood-based biomarker for FRDA, showing consistent expression variance in human and mouse tissues related to disease severity and key FRDA pathways. It correlates with frataxin levels, indicating its promise as an early, non-invasive marker. TUG1 holds potential for FRDA monitoring and therapeutic development, meriting additional research.

Characterization of clinical serum cardiac biomarker levels in individuals with Friedreich ataxia

David R. Lynch, Sonal Sharma, Patrick Hearle, Nathaniel Greeley, Katherine Gunther, Medina Keita, Cassandra Strawser, Lauren Hauser, Courtney Park, Kimberly Schadt, Kimberly Y. Lin, Characterization of clinical serum cardiac biomarker levels in individuals with Friedreich ataxia, Journal of the Neurological Sciences, 2024, 123053, doi:10.1016/j.jns.2024.123053 

In subjects with multiple assessments, mean unprovoked troponin I levels decreased slightly over time. The presence of abnormal troponin I values and their levels were predicted by echocardiographic measures of hypertrophy. In addition, troponin I levels predicted long-term markers of clinical cardiac dysfunction over time to a modest degree. Consequently, troponin I values provide a marker of hypertrophy but only a minimally predictive biomarker for later cardiac manifestations of disease such as systolic dysfunction or arrhythmia.

Deciphering the ferroptosis pathways in dorsal root ganglia of Friedreich ataxia models. The role of LKB1/AMPK, KEAP1, and GSK3beta in the impairment of the NRF2 response

Deciphering the ferroptosis pathways in dorsal root ganglia of Friedreich ataxia models. The role of LKB1/AMPK, KEAP1, and GSK3beta in the impairment of the NRF2 response. Arabela Sanz-Alcazar, Marta Portillo-Carrasquer, Fabien Delaspre, Maria Pazos-Gil, Jordi Tamarit, Joaquim Ros, Elisa Cabiscol. bioRxiv 2024.05.10.593481; doi: 10.1101/2024.05.10.593481 

This study demonstrated that frataxin deficiency in DRG neurons disrupts iron homeostasis and the intricate regulation of molecular pathways affecting NRF2 activation and the cellular response to oxidative stress, leading to ferroptosis.

1. WO2024097772 - COMPOSITIONS AND METHODS FOR TREATMENT OF FRIEDREICH'S ATAXIA

N.º de publicación WO/2024/097772. Fecha de publicación 10.05.2024. Nº de la solicitud internacional PCT/US2023/078373. Fecha de presentación internacional 01.11.2023.

The present application provides compositions for treatment of Friedreich's Ataxia (FA). These include, but are not limited to, nucleic acid constructs and recombinant AAV7 vectors comprising a human frataxin 5' untranslated region (5'UTR FXN) and a human frataxin (FXN).

Ferrostatin-1 specifically targets mitochondrial iron-sulfur clusters and aconitase to improve cardiac function in Sirtuin 3 cardiomyocyte knockout mice

Ferrostatin-1 specifically targets mitochondrial iron-sulfur clusters and aconitase to improve cardiac function in Sirtuin 3 cardiomyocyte knockout mice, Cantrell, Aubrey C. et al. Journal of Molecular and Cellular Cardiology, Volume 0, Issue 0. DOI:10.1016/j.yjmcc.2024.05.003 

Inhibition of ferroptosis ameliorated cardiac dysfunction by specifically targeting mitochondrial aconitase and iron‑sulfur clusters. Blockade of mitochondrial ferroptosis may be a novel therapeutic target for mitochondrial cardiomyopathies.

Larimar Therapeutics Reports First Quarter 2024 Operating and Financial Results

BALA CYNWYD, Pa., May 09, 2024 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. In March 2024, the first patient was dosed in the OLE study evaluating daily subcutaneous injections of 25 mg of nomlabofusp self-administered or administered by a caregiver. Participants who completed treatment in the Phase 2 dose exploration study, or who previously completed a prior clinical trial of nomlabofusp, are potentially eligible to screen for the OLE study. The OLE study will evaluate the safety and tolerability, pharmacokinetics, and frataxin levels in peripheral tissues as well as other exploratory pharmacodynamic markers (lipid profiles and gene expression data) following long-term subcutaneous administration of nomlabofusp. Dose escalation in the OLE study is contingent on the FDA’s review of data from the 50 mg cohort of the Phase 2 study and available data from the OLE study, due to the continued partial clinical hold. Interim data is expected in the fourth quarter of 2024. In addition, clinical assessments collected during the study will be compared to data from a matched control arm derived from participants in the Friedreich’s Ataxia Clinical Outcomes Measures Study (FACOMS) database.

Stealth BioTherapeutics’ SBT-589 Shows Cardioprotective Effects in Preclinical Models of Friedreich Ataxia

May 3, 2024. New data on SBT-589 (Stealth BioTherapeutics) presented at the 2024 Wellcome Trust Conference on Mitochondrial Medicine – Therapeutic Development, held March 18-20, in Cambridge, England, demonstrated cardioprotective effects across preclinical models of Friedreich ataxia (FA).1,2 These findings support further development of SBT-589, a novel molecule that can act on mitochondrial pathways that are impaired, and suggest the compound could be a disease-modifying therapy in FA cardiomyopathy. 

Our major finding was that the novel compound, SBT-589, improved metrics of adverse cardiac growth (hypertrophy) in a highly aggressive mouse model of FA cardiomyopathy. Transgenic FA mice showed increased left ventricular mass (normalized to body weight) and increased left ventricular wall thickness compared with control mice. We found that 3 weeks of daily SBT-589 treatment prevented cardiac hypertrophy

Design Therapeutics Announces First Quarter 2024 Financial Results and Highlights Upcoming Program Milestones

CARLSBAD, Calif., May 08, 2024 (GLOBE NEWSWIRE) -- Design Therapeutics, Inc.Friedreich Ataxia (FA) Design’s new drug product for FA, DT-216P2, demonstrates an improved pharmacokinetic (PK) profile, injection site profile and sustained drug exposure in nonclinical studies compared to the prior formulation. Design is on track to complete GLP studies for DT-216P2 by year-end 2024 to start patient trials in 2025.

Elevated Bile Acid 3β,5α,6β-Trihydroxycholanoyl Glycine in a Subset of Adult Ataxias Including Niemann–Pick Type C

Motamed-Gorji, N.; Khalil, Y.; Gonzalez-Robles, C.; Khan, S.; Mills, P.; Garcia-Moreno, H.; Ging, H.; Tariq, A.; Clayton, P.T.; Giunti, P. Elevated Bile Acid 3β,5α,6β-Trihydroxycholanoyl Glycine in a Subset of Adult Ataxias Including Niemann–Pick Type C. Antioxidants 2024, 13, 561. doi:10.3390/antiox13050561 

Patient No. 155 had a 3β,5α,6β-triOH-Gly of 159 nM. Analysis of the Frataxin gene (FXN) showed that the patient was compound heterozygous for two GAA expansions (length 75 and 101 bp), indicating a diagnosis of Friedreich’s ataxia (FRDA). This raises the question as to whether oxidation of cholesterol by ROS could play a role in the pathogenesis of FRDA, or at least, provide a marker of ROS damage.

Calcitriol Treatment Is Safe and Increases Frataxin Levels in Friedreich Ataxia Patients

Alemany-Perna, B., Tamarit, J., Cabiscol, E., Delaspre, F., Miguela, A., Huertas-Pons, J.M., Quiroga-Varela, A., Merchan Ruiz, M., López Domínguez, D., Ramió i Torrentà, L., Genís, D. and Ros, J. (2024), Calcitriol Treatment Is Safe and Increases Frataxin Levels in Friedreich Ataxia Patients. Mov Disord. doi:10.1002/mds.29808 

Although the patients did not experience any observable neurological improvement, there was a statistically significant increase in frataxin levels from initial values, 5.5 to 7.0 pg/μg after 12 months. Differences in frataxin levels referred to total protein levels were observed among sex- and age-matched controls (18.1 pg/μg), relative controls (10.1 pg/μg), and FRDA patients (5.7 pg/μg). The treatment was well tolerated by most patients, and only some of them experienced minor adverse effects at the beginning of the trial. 

Calcitriol dosage used (0.25 mcg/24 h) is safe for FRDA patients, and it increases frataxin levels. We cannot rule out that higher doses administered longer could yield neurological benefits.