Propensity matched comparison of omaveloxolone treatment to Friedreich ataxia natural history data

Lynch, D.R., Goldsberry, A., Rummey, C., Farmer, J., Boesch, S., Delatycki, M.B., Giunti, P., Hoyle, J.C., Mariotti, C., Mathews, K.D., Nachbauer, W., Perlman, S., Subramony, S.H., Wilmot, G., Zesiewicz, T., Weissfeld, L. and Meyer, C. (2023), Propensity matched comparison of omaveloxolone treatment to Friedreich ataxia natural history data. Ann Clin Transl Neurol. doi:10.1002/acn3.51897 

These results suggest a meaningful slowing of Friedreich ataxia progression with omaveloxolone, and consequently detail how propensity-matched analysis may contribute to understanding of effects of therapeutic agents. This demonstrates the direct value of natural history studies in clinical trial evaluations.

Proprioceptive and tactile processing in individuals with Friedreich Ataxia, an fMRI study

Destrebecq Virginie, Rovai Antonin, Trotta Nicola, Comet Camille, Gilles Naeije, Front. Neurol. Sec. Movement Disorders, Volume 14 - 2023, doi: 10.3389/fneur.2023.1224345

Our study captured the difference between tactile and proprioceptive impairments in FA using somatosensory fMRI paradigms. The lack of correlation between the proprioceptive paradigm and ataxia clinical parameters supports a low contribution of afferent ataxia to FA clinical severity

SIRT3 Regulates Clearance of Apoptotic Cardiomyocytes by Deacetylating Frataxin

Jing Gao, Chenglin Huang, Linghui Kong, Wugang Zhou, Mengwei Sun, Tong Wei and Weili Shen. Circulation Research. 2023;0. Originally published 30 Aug 2023 doi:10.1161/CIRCRESAHA.123.323160  

We showed that SIRT3 deficiency exacerbated Ang II–induced downregulation of the efferocytosis receptor MerTK (c-Mer tyrosine kinase) and proinflammatory cytokine production, accompanied by disrupted mitochondrial iron homeostasis in cardiac macrophages. Quantitative acetylome analysis revealed that SIRT3 deacetylated FXN (frataxin) at lysine 189. Ang II attenuated SIRT3 activity and enhanced the acetylation level of FXN K189. Acetylated FXN further reduced the synthesis of ISCs (iron-sulfur clusters), resulting in mitochondrial iron accumulation. Phagocytic internalization of apoptotic cardiomyocytes increased myoglobin content, and derived iron ions promoted mitochondrial iron overload and lipid peroxidation. An iron chelator deferoxamine improved the levels of MerTK and efferocytosis, thereby attenuating proinflammatory macrophage activation. FXNK189R mice showed improved macrophage efferocytosis, reduced cardiac inflammation, and suppressed cardiac fibrosis.

Replication Stalling at Friedreich's Ataxia (GAA)n Repeats In Vivo

Maria M. Krasilnikova & Sergei M. Mirkin (2004) Replication Stalling at Friedreich's Ataxia (GAA)n Repeats In Vivo, Molecular and Cellular Biology, 24:6, 2286-2295, DOI: 10.1128/MCB.24.6.2286-2295.2004

 We believe that repeat-caused replication attenuation in vivo is due to triplex formation. The apparent link between the replication stalling and length polymorphism of the repeat points to a new model for the repeat expansion.

Longitudinal changes of SARA scale in Friedreich ataxia: Strong influence of baseline score and age at onset

Porcu, L., Fichera, M., Nanetti, L., Rulli, E., Giunti, P., Parkinson, M.H., Durr, A., Ewenczyk, C., Boesch, S., Nachbauer, W., Indelicato, E., Klopstock, T., Stendel, C., Rodríguez de Rivera, F.J., Schöls, L., Fleszar, Z., Giordano, I., Didszun, C., Castaldo, A., Rai, M., Klockgether, T., Pandolfo, M., Schulz, J.B., Reetz, K., Mariotti, C. and (2023), Longitudinal changes of SARA scale in Friedreich ataxia: Strong influence of baseline score and age at onset. Ann Clin Transl Neurol. doi:10.1002/acn3.51886 

 Analyses of statistical properties of SARA suggest a variable sensitivity of the scale at different disease stages, and provide important information for population selection and result interpretation in future clinical trials.

Sarepta Therapeutics to Collaborate With Lexeo on Heart Disease Gene Therapy Pipeline

Aug 28, 2023, NEW YORK – Sarepta Therapeutics has invested an undisclosed sum in Lexeo Therapeutics, and the two companies on Monday said they will explore opportunities to further develop gene therapies in Lexeo's preclinical pipeline for cardiovascular disease.

Halogens engineering-based design of agonists for boosting expression of frataxin protein in Friedreich's ataxia

Naveed, M., Ali, I., Aziz, T., Ain, N., Shabbir, M. A., Javed, K., Alharbi, M., Alshammari, A., Alasmari, A. F., Alharbi, S. A., & Alharbi, M. S. (2023). Halogens engineering-based design of agonists for boosting expression of frataxin protein in Friedreich's ataxia. European review for medical and pharmacological sciences, 27(15), 6972–6984. doi:10.26355/eurrev_202308_33269 

 The selected agonist is one of the most potent compounds in increasing Frataxin protein expression. Furthermore, optimization with halogens can be a productive approach to improve the candidate's drug efficacy. The development of effective medications for the treatment of Friedreich ataxia would be aided by the results of these computational investigations.

The optimized agonist 9-[1-[(1S, 5R)-8, 8-dimethyl-8-azoniabicyclo[3.2.1]octan-3-yl]triazol-4-yl]fluoren-9-ol has higher binding energy of -10.4Kcal/mol with molecular weight of 705.63 g/mol. Drug-like properties are identified through ADMET profiling, having water solubility of about -7.59, skin permeation -7.08 cm/s, bioavailability score 0.17, and high GI absorption. The candidate fulfills the Lipinski rule of five and portrays efficient molecular dynamic stimulations.

Design Therapeutics Reports Initial Results from Phase 1 Multiple-Ascending Dose Study of DT-216 for the Treatment of Friedrich Ataxia

CARLSBAD, Calif., Aug. 14, 2023 (GLOBE NEWSWIRE) -- Design Therapeutics, Inc. (Nasdaq: DSGN), a clinical-stage biotechnology company developing treatments for serious degenerative genetic diseases, today reported initial results from the company’s Phase 1 multiple-ascending dose (MAD) clinical trial of DT-216 in patients with Friedrich ataxia (FA). As of a data cutoff date of August 7, 2023, results showed that DT-216 was generally well-tolerated and achieved a statistically significant and dose-related increase in frataxin (FXN) mRNA levels in skeletal muscle biopsies.

Epidemiological research on rare diseases using large-scale online search queries and reported case data

Zhang, L., Jin, Y., Li, J. et al. Epidemiological research on rare diseases using large-scale online search queries and reported case data. Orphanet J Rare Dis 18, 236 (2023). doi:10.1186/s13023-023-02839-7

 Rare diseases have become a major public health concern worldwide. However, detailed epidemiological data are lacking. With the development of the Internet, search queries have played an important role in disease surveillance. In this study, we explored a new method for the epidemiological research on rare diseases, using large-scale online search queries and reported case data. We distilled search logs related to rare diseases nationwide from 2016 to 2019. The case data were obtained from China’s national database of rare diseases during the same period.

Finding an Appropriate Mouse Model to Study the Impact of a Treatment for Friedreich Ataxia on the Behavioral Phenotype

Bouchard, C.; Gérard, C.; Yanyabé, S.G.-f.; Majeau, N.; Aloui, M.; Buisson, G.; Yameogo, P.; Couture, V.; Tremblay, J.P. Finding an Appropriate Mouse Model to Study the Impact of a Treatment for Friedreich Ataxia on the Behavioral Phenotype. Genes 2023, 14, 1654. doi:10.3390/genes14081654

 The YG8sR mice are Knock-Out (KO) for their murine frataxin gene but contain a human frataxin transgene derived from an FRDA patient with 300 GAA repeats. These mice are used as a FRDA model but even with a low frataxin concentration, their phenotype is mild. We aimed to find an optimized mouse model with a phenotype comparable to the human patients to study the impact of therapy on the phenotype. We compared two mouse models: the YG8sR injected with an AAV. PHP.B coding for a shRNA targeting the human frataxin gene and the YG8-800, a new mouse model with a human transgene containing 800 GAA repeats.