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.

Genetic Determined Iron Starvation Signature in Friedreich's Ataxia

Grander, M., Haschka, D., Indelicato, E., Kremser, C., Amprosi, M., Nachbauer, W., Henninger, B., Stefani, A., Högl, B., Fischer, C., Seifert, M., Kiechl, S., Weiss, G. and Boesch, S. (2024), Genetic Determined Iron Starvation Signature in Friedreich's Ataxia. Mov Disord. doi:10.1002/mds.29819

In conclusion, we collected multiple findings suggestive of a systemic and cellular iron starvation signature in FA whose severity is determined by the genotype. We provided for the first-time quantitative MRI data on iron storages and parenchyma state in liver, spleen, and pancreas in FA in vivo. Our findings argue against the use of surrogate measures of iron reduction as endpoints in clinical trials. They furthermore show that a stratification according to the genotype is necessary when addressing iron metabolism in FA. Overall, the present findings provide an indispensable clinical ground for the development of iron-targeting therapeutics in FA.

One-to-one Benefit provided by Antioxidants to cultured skin Fibroblasts from Friedreich Ataxia patients

One-to-one Benefit provided by Antioxidants to cultured skin Fibroblasts from Friedreich Ataxia patients, Paule Bénit, Malgorzata Rak, Pierre Rustin, bioRxiv 2024.04.25.591088; doi: 10.1101/2024.04.25.591088 

Under conditions that force the cells to rely on mitochondrial activity, we observed significant yet variable FRDA cell proliferation. These conditions were thereafter used to screen the effectiveness of a set of antioxidant molecules targeting different steps of the pro-oxidant cascade previously documented in FRDA, i.e. Uridine, Pyruvate, and Pioglitazone, to prevent or slow down cell mortality. We observed a surprising variability of response to antioxidant molecules even under the similar, controlled conditions used to culture patient’s fibroblasts. We conclude that the specific response of each individual already discernable at cellular level may well play an important role in the frequent difficulties encounter to reach firm conclusions when testing the capacity of antioxidants to counteract the consequences of frataxin depletion, including in clinical trials.

Astellas' Friedreich’s ataxia gene therapy cleared for clinical study after earlier version stumbled

April 25, 2024. Astellas' Friedreich’s ataxia gene therapy cleared for clinical study after earlier version stumbled. On Thursday, the Japanese drugmaker announced the FDA has cleared its IND for ASP2016.

Friedreich’s ataxia, a rare disease caused by the mutations in the gene for the protein frataxin, can cause both cardiac and neuromuscular complications, Wilson said. Addressing both in a single shot, as Astellas and several other companies had tried to do, turned out to be an “incredibly complicated problem” because of challenges in distribution, expression levels and therapeutic window, he said. 

 Frataxin, as Wilson put it, is “one of those Goldilocks proteins” — either having too much or too little would be dangerous. With ASP2016, which targets the cardiac complications of the condition, Astellas employed a mild promoter so that the AAV8-delivered gene therapy produces “just enough” protein in the target tissue.

“Our intention really has been to try and get as many cardiomyocytes transduced as we can, but not to produce such an overwhelming amount of frataxin protein that it would produce toxicity".

 The company is hoping to dose the first patient in the second half of 2024.