Identification of a novel missense mutation in Friedreich's ataxia –FXNW168R

Clark, E. , Strawser, C. , Schadt, K. and Lynch, D. R. (2019), Ann Clin Transl Neurol. doi:10.1002/acn3.728

Friedreich's ataxia, characterized by decreased expression of frataxin protein, is caused by GAA trinucleotide repeats within intron 1 in 98% of patients. Two percent of patients carry GAA repeats in conjunction with a point mutation. In this work, we find that frataxinW168R, a novel disease‐causing missense mutation, is expressed predominantly as the intermediate frataxin42‐210 form, with very little expression of mature frataxin81‐210 form. Its localization to mitochondria is not impaired. Additionally, increasing frataxinW168R precursor levels do not lead to an increase in mature frataxin levels, suggesting these patients will require alternative approaches to repair frataxin processing in order to treat the disorder in a disease‐modifying manner.

Structure of the human frataxin-bound iron-sulfur cluster assembly complex provides insight into its activation mechanism

Nicholas G Fox, Xiaodi Yu, Xidong Feng, Henry J Bailey, Alain Martelli, Joseph F. Nabhan, Claire Strain-Damerell, Christine Bulawa, Wyatt W. Yue, Seungil Han; bioRxiv 561795; doi: 10.1101/561795

Our structure sheds light on how FXN facilitates ISC production through unlocking the zinc inhibition and stabilizing key loop conformations of NFS1 and ISCU at the protein-protein interfaces, and offers an explanation of how FRDA clinical mutations affect complex formation and FXN activation.

Case 3: Gait Instability and Elevated Troponin Level in a 16-year-old Boy

Carrie Johnson, Shaun Mohan; Pediatrics in Review Feb 2019, 40 (2) 85-87; DOI: 10.1542/pir.2017-0095

Given the findings of hypertrophic cardiomyopathy, ataxia, and abnormal neurologic examination findings, there was suspicion for Friedreich ataxia (FRDA). Genetics was consulted, who agreed, and recommended repeated expansion analysis. During follow-up his genetic testing results were positive for 2 alleles with GAA trinucleotide repeat expansion: allele 1 with 1070 GAA repeats and allele 2 with 830 GAA repeats, consistent with diagnosis of FRDA.

In Vitro interaction between yeast frataxin and superoxide dismutases: Influence of mitochondrial metals

Thi Hong Lien Han, Jean-Michel Camadro, Florent Barbault, Renata Santos, Jean-Michel El Hage Chahine, Nguyet-Thanh Ha-Duong; Biochimica et Biophysica Acta (BBA) - General Subjects, Volume 1863, Issue 5, 2019, Pages 883-892, ISSN 0304-4165, doi:10.1016/j.bbagen.2019.02.011.

Friedreich's ataxia results from a decreased expression of the nuclear gene encoding the mitochondrial protein, frataxin. Frataxin participates in the biosynthesis of iron-sulfur clusters and heme cofactors, as well as in iron storage and protection against oxidative stress. How frataxin interacts with the antioxidant defence components is poorly understood.

Randomized, double‐blind, placebo‐controlled study of interferon‐γ 1b in Friedreich Ataxia

Lynch, D. R., Hauser, L. , McCormick, A. , Wells, M. , Dong, Y. N., McCormack, S. , Schadt, K. , Perlman, S. , Subramony, S. H., Mathews, K. D., Brocht, A. , Ball, J. , Perdok, R. , Grahn, A. , Vescio, T. , Sherman, J. W. and Farmer, J. M. (2019); Ann Clin Transl Neurol. doi:10.1002/acn3.731

Results
No difference was noted between the groups after 6 months of treatment in the mFARS or secondary outcome measures. No change was noted in buccal cell or whole blood frataxin levels. However, during an open‐label extension period, subjects had a more stable course than expected based on natural history data.

Conclusions
This study provides no direct evidence for a beneficial effect of IFN‐γ1b in FRDA. The modest stabilization compared to natural history data leaves open the possibility that longer studies may demonstrate benefit.

Structure of the human frataxin-bound iron-sulfur cluster assembly complex provides insight into its activation mechanism

Nicholas G Fox, Xiaodi Yu, Xidong Feng, Henry J Bailey, Alain Martelli, Joseph F. Nabhan, Claire Strain-Damerell, Christine Bulawa, Wyatt W. Yue, Seungil Han; bioRxiv 561795; doi:10.1101/561795

Our structure sheds light on how FXN facilitates ISC production through unlocking the zinc inhibition and stabilizing key loop conformations of NFS1 and ISCU at the protein-protein interfaces, and offers an explanation of how FRDA clinical mutations affect complex formation and FXN activation.

Researchers from Lleida make advances to propose new therapies in the treatment of Friedreich's ataxia

Communication and Press IRBLleida, February 28, the World Day of Minority Diseases.

The Oxidative Stress Biochemical Research Group, of the University of Lleida (UdL) and the Biomedical Research Institute of Lleida (IRBLleida), is carrying out two projects to better understand Friedreich's ataxia - which is caused by the deficiency of Frataxin, a mitochondrial protein.
The Oxidative Stress Biochemical Research Group investigates this minority disease since 2005. In 2011, it obtained a research project from the La Marató Foundation of TV3 (led by Jordi Tamarit); In addition to the projects named above, it also has support from Ataxia UK, the United Kingdom, co-funded by the Association of Catalan Ataxias (ACAH) and a project of the Ministry -Retos- called "Targeting mitochondria in Friedreich ataxia: molecular mechanisms and therapeutic approaches ". The results of the previous projects have provided new data on the mitochondrial alterations that occur due to frataxin deficit. Therefore, in these projects, the proposed objectives seek to find answers to know which are the mechanisms that explain the neurocardiodegenerative effects of frataxin deficiency and what is the capacity of some compounds to reverse these alterations and that can be proposed as treatments of the Friedreich ataxia.

C-Path, FARA launch Friedreich's Ataxia Clinical Database for Development of Treatments

EurekAlert, PUBLIC RELEASE: 27-FEB-2019, Ariz. and DOWNINGTOWN, Penn., February 27, 2019 -- Critical Path Institute's (C-Path) Data Collaboration Center (DCC) and the Friedreich's Ataxia Research Alliance (FARA) today announced the launch of the Friedreich's Ataxia Integrated Clinical Database (FAICD). The new platform will enable collaborative research and data sharing to support the understanding of natural history, potential biomarkers and clinical endpoints, and promote research into novel clinical trial design in Friedreich's ataxia (FA). By making this data available to researchers, the organizations hope to enable the development of tools that will help design and interpret efficient clinical trials -- leading to effective treatments for FA as soon as possible.

Minoryx recibe la aprobación de la Agencia Reguladora Española para iniciar el estudio de fase 2 en la ataxia de Friedreich

Mataró (Barcelona)-Charleroi (Bélgica), 27 de febrero de 2019. Minoryx Therapeutics, compañía biotecnológica especializada en el desarrollo de nuevos medicamentos para enfermedades huérfanas, anuncia hoy que la Agencia Española de Medicamentos y Productos Sanitarios (AEMPS) ha aprobado el lanzamiento de un ensayo clínico de fase II para el tratamiento de la ataxia de Friedreich (FRDA) con su fármaco candidato MIN-102.
El ensayo clínico, denominado FRAMES, iniciará el reclutamiento de pacientes en las próximas semanas en el Hospital Universitario La Paz (Madrid), bajo la dirección del Dr. Francisco Javier Rodríguez de Rivera. La compañía también trabaja en la apertura del ensayo en más centros en Bélgica, Alemania y Francia.
El ensayo será doble ciego y controlado con placebo, con el objetivo de evaluar la eficacia y seguridad del MIN-102 en los pacientes con ataxia de Friedreich. Participarán 36 pacientes mayores de 12 años.
MIN-102 es un novedoso agonista selectivo de PPAR gamma, biodisponible por vía oral, que ha mostrado un perfil superior en cuanto a penetración cerebral y seguridad. En modelos preclínicos de neurodegeneración el fármaco ha mostrado la capacidad de modular las vías que generan disfunción mitocondrial, estrés oxidativo, neuroinflamación, desmielinización y degeneración axonal. También se ha completado con éxito un estudio clínico de fase I que confirma que MIN-102 es bien tolerado y capaz de cruzar la barrera hematoencefálica a un nivel equivalente al de los estudios preclínicos. Actualmente, se encuentra en ensayo clínico de fase II/III para el tratamiento de la adrenomieloneuropatía (AMN) en Europa y Estados Unidos.

Como parte de la expansión de la compañía en nuevas indicaciones, se unen al consejo asesor científico dos líderes clave en neurología clínica: el Dr. Massimo Pandolfo, director del Laboratorio de Neurología Experimental en la Université Libre de Bruxelles que dirigió el equipo que identificó el gen de la ataxia de Friedreich en 1996, y la Dra. Fanny Mochel, líder de grupo en el Brain and Spine Institute (ICM) del hospital universitario Pitié-Salpêtrière en París y experta en resonancia magnética aplicada en neurología clínica.

Leer mas...

Minoryx Therapeutics lance une étude clinique de phase II dans l'ataxie de Friedreich avec l’autorisation de l'Agence Espagnole du Médicament

Mataró, Barcelone, Espagne et Charleroi, Belgique, le 27 février 2019 - Minoryx Therapeutics, une société spécialisée dans le développement de nouveaux médicaments contre des maladies orphelines, annonce aujourd'hui qu'elle a reçu l’autorisation de l'Agence espagnole du médicament et des dispositifs médicaux (AEMPS) pour lancer un essai clinique de phase II dans l'ataxie de Friedreich avec son principal candidat médicament, MIN-102. FRAMES, un essai clinique de phase II, va débuter dans les semaines à venir à l'hôpital La Paz (Madrid), et sera piloté par le Dr. Francisco Javier Rodríguez de Rivera. Minoryx prévoit également d’ouvrir des sites supplémentaires dans des institutions médicales en Belgique, en Allemagne et en France. L'essai, en double-aveugle avec contrôle placebo, doit permettre d'évaluer l'efficacité et l'innocuité de MIN-102 chez les patients souffrants d'ataxie de Friedreich. L’étude portera sur 36 patients âgés d’au moins 12 ans.
Le MIN-102 est un nouvel agoniste sélectif du PPAR gamma (récepteur activé par les proliférateurs des péroxisomes) avec une bonne biodisponibilité orale. Il a montré in vivo un profil de supériorité dans les maladies du système nerveux central (SNC) et une bonne efficacité. MIN-102 fait également l'objet d'un essai clinique de phase II/III pour le traitement de l'adrénomyéloneuropathie (AMN), le phénotype le plus courant de l'adrénoleucodystrophie liée à l’X (ALD).

Le Professeur Alexandra Durr, investigateur principal à l'Institut du Cerveau et de la Moëlle épinière (ICM) à l’hôpital de La Pitié-Salpêtrière à Paris sera la coordinatrice de la nouvelle étude.

La société annonce également l’arrivée de deux leaders d'opinion au sein de son conseil scientifique : le Dr. Massimo Pandolfo, directeur du Laboratoire de neurologie expérimentale de l'Université Libre de Bruxelles, et le Dr. Fanny Mochel, coordinatrice au sein de l'Institut du Cerveau et de la Moëlle épinière (ICM) à l’hôpital de La Pitié-Salpêtrière à Paris.



Lire plus...