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.