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, https://doi.org/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.