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. ​