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.

Alterity Therapeutics Presents New Data Demonstrating Potential of ATH434 to Treat Rare Neurodegenerative Disease Friedreich’s Ataxia

MELBOURNE, Australia and SAN FRANCISCO, April 29, 2024 (GLOBE NEWSWIRE) -- Alterity Therapeutics (ASX: ATH, NASDAQ: ATHE) (“Alterity” or “the Company”), a biotechnology company dedicated to developing disease modifying treatments for neurodegenerative diseases, today announced that important new data on its lead drug candidate ATH434 was presented at the World Orphan Drug Congress USA 2024 in Boston, MA. 

The poster, entitled, “Biophysical Characteristics of ATH434, a Unique Iron-Targeting Drug for Treating Friedreich’s Ataxia”, was presented by Ashley Pall, Department of Pharmaceutical Sciences at Wayne State University. The study evaluated the ability of ATH434 to target the toxic form of iron that drives the pathology of Friedreich’s Ataxia

Opinion: Larimar Could Compete with Biogen in Friedreich’s Ataxia

BioSpace. Published: Apr 29, 2024. n February 2024, Larimar Therapeutics released positive Phase II data for its injectable subcutaneous investigational agent nomlabofusp in treating Friedreich’s ataxia, a rare disease that causes neuromuscular degeneration. The data indicate that Larimar could go head-to-head in the market with Biogen's Skyclarys, the only disease-specific therapy for Friedreich’s ataxia to so far receive FDA approval.

Inherited metabolic disorders in Cyprus

Theodoros Georgiou, Petros P. Petrou, Anna Malekkou, Ioannis Ioannou, Marina Gavatha, Nicos Skordis, Paola Nicolaidou, Irini Savvidou, Emilia Athanasiou, Sofia Ourani, Elena Papamichael, Marios Vogazianos, Maria Dionysiou, Gabriella Mavrikiou, Olga Grafakou, George A. Tanteles, Violetta Anastasiadou, Anthi Drousiotou, Inherited metabolic disorders in Cyprus, Molecular Genetics and Metabolism Reports, Volume 39, 2024, 101083, ISSN 2214-4269, doi:10.1016/j.ymgmr.2024.101083. 

The Cypriot population has a unique genetic composition which differs significantly from that of its neighbours. This was the result of enrichment of the local genetic pool by the genes of numerous “visitors” to the island, whether as conquerors (Persians, Arabs, Franks, Venetians and Turks) or as immigrants (Maronites, Armenians). Founder effects have been described for many genetic disorders in addition to Sandhoff's and GM1 gangliosidosis: familial Mediterranean fever, cystic fibrosis, Friedreich's ataxia and 21-hydroxylase deficiency.