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.