PPAR gamma agonist leriglitazone improves frataxin-loss impairments in cellular and animal models of Friedreich Ataxia

Laura Rodríguez-Pascau, Elena Britti, Pablo Calap-Quintana, Yi Na Dong, Cristina Vergara, Fabien Delaspre, Marta Medina, Jordi Tamarit, Federico V. Pallardó, Pilar Gonzalez-Cabo, Joaquim Ros, David R. Lynch, Marc Martinell, Pilar Pizcueta, Neurobiology of Disease, 2020, 105162, doi:10.1016/j.nbd.2020.105162. 

Here we assess whether MIN-102 (INN: leriglitazone), a novel brain penetrant and orally bioavailable PPARγ agonist with an improved profile for central nervous system (CNS) diseases, rescues phenotypic features in cellular and animal models of FRDA. In frataxin-deficient dorsal root ganglia (DRG) neurons, leriglitazone increased frataxin protein levels, reduced neurite degeneration and α-fodrin cleavage mediated by calpain and caspase 3, and increased survival. Leriglitazone also restored mitochondrial membrane potential and partially reversed decreased levels of mitochondrial Na+/Ca2+ exchanger (NCLX), resulting in an improvement of mitochondrial functions and calcium homeostasis. In frataxin-deficient primary neonatal cardiomyocytes, leriglitazone prevented lipid droplet accumulation without increases in frataxin levels. Furthermore, leriglitazone improved motor function deficit in YG8sR mice, a FRDA mouse model. In agreement with the role of PPARγ in mitochondrial biogenesis, leriglitazone significantly increased markers of mitochondrial biogenesis in FRDA patient cells. Overall, these results suggest that targeting the PPARγ pathway by leriglitazone may provide an efficacious therapy for FRDA increasing the mitochondrial function and biogenesis that could increase frataxin levels in compromised frataxin-deficient DRG neurons. Alternately, leriglitazone improved the energy metabolism by increasing the fatty acid β-oxidation in frataxin-deficient cardiomyocytes without elevation of frataxin levels. This could be linked to a lack of significant mitochondrial biogenesis and cardiac hypertrophy. The results reinforced the different tissue requirement in FRDA and the pleiotropic effects of leriglitazone that could be a promising therapy for FRDA.

Electrocardiogram in Friedreich's ataxia: A short‐term surrogate endpoint for treatment efficacy

Sandra Mastroianno MD Michele Germano MD Angela Maggio MD Raimondo Massaro MD Domenico Rosario Potenza MD Aldo Russo MD Massimo Carella PhD Giuseppe Di Stolfo MD, PhD; Ann Noninvasive Electrocardiol. 2020; 00:e12813. doi:10.1111/anec.12813 

We describe the case of a 21‐year‐old patient affected by Friedreich's ataxia on wheel‐chair, with initial cardiac involvement and electrocardiographic features characterized by thiamine treatment‐related negative T wave and QTc variations. We discuss plausible physiopathology and potential ECG role implications as an intermediate marker of treatment response in future clinical trials considering patients affected by Friedreich's ataxia.

Effect of Mitochondrial and Cytosolic FXN Isoform Expression on Mitochondrial Dynamics and Metabolism

Agrò, M.; Díaz-Nido, J. , Int. J. Mol. Sci. 2020, 21, 8251. doi:10.3390/ijms21218251 (registering DOI)

Alternative forms of frataxin have been described, with different cellular localization and tissue distribution, including a cerebellum-specific cytosolic isoform called FXN II. Here, we explored the functional roles of FXN II in comparison to the mitochondrial FXN I isoform, highlighting the existence of potential cross-talk between cellular compartments. To achieve this, we transduced two human cell lines of patient and healthy subjects with lentiviral vectors overexpressing the mitochondrial or the cytosolic FXN isoforms and studied their effect on the mitochondrial network and metabolism. We confirmed the cytosolic localization of FXN isoform II in our in vitro models. Interestingly, both cytosolic and mitochondrial isoforms have an effect on mitochondrial dynamics, affecting different parameters. Accordingly, increases of mitochondrial respiration were detected after transduction with FXN I or FXN II in both cellular models. Together, these results point to the existence of a potential cross-talk mechanism between the cytosol and mitochondria, mediated by FXN isoforms. A more thorough knowledge of the mechanisms of action behind the extra-mitochondrial FXN II isoform could prove useful in unraveling FRDA physiopathology.

European Investment Bank provides Minoryx with up to €25 million to support development of breakthrough therapies in orphan neurodegenerative diseases

Press release, 30 October 2020, Barcelona.

 The European Investment Bank (EIB) today announced that it has approved €25 million financing for Minoryx Therapeutics, a Phase 3 clinical stage biotech company focused on the development of differentiating treatment options for orphan central nervous system (CNS) disorders.

The EU bank will grant long-term financing to Minoryx to drive the company's research activities in orphan genetic diseases for which there are currently no approved drugs available. The EIB investments will specifically support the development of Minoryx's leriglitazone, a disease-modifying treatment (PPAR-γ agonist) currently being evaluated in three late-stage clinical trials:......Phase 2 FRAMES study in Friedreich's Ataxia (FRDA), a life threatening disease characterised by neurodegeneration resulting in loss of coordination, muscle strength, and cardiomyopathy.

EL BANCO EUROPEO DE INVERSIONES PROPORCIONA €25M A MINORYX PARA APOYAR EL DESARROLLO DE TERAPIAS INNOVADORAS EN ENFERMEDADES RARAS NEURODEGENERATIVAS.

Mataró (Barcelona, España) y Charleroi (Bélgica), 30 de octubre de 2020. Minoryx Therapeutics, una empresa biotecnológica en fase clínica III especializada en el desarrollo de tratamientos diferenciales para enfermedades raras del sistema nervioso central (CNS), ha anunciado hoy que el Banco Europeo de Inversiones (BEI) ha aprobado una financiación de 25 millones de euros. El banco de la UE concederá financiación a largo plazo a Minoryx para impulsar las actividades de investigación y desarrollo de la entidad en enfermedades genéticas huérfanas para las que actualmente no se dispone de medicamentos aprobados.

 Las inversiones del BEI apoyarán específicamente el desarrollo de la leriglitazona, un agonista PPAR gamma diferenciado y con potencial de modificar el curso de la enfermedad que actualmente se está evaluando en tres ensayos clínicos en fase avanzada. Estudio FRAMES de fase II en ataxia de Friedreich (FRDA).

30/10/2020. ACN Mataró.-El Banc Europeu d’Inversions (BEI) ha anunciat l’aprovació de 25 milions d’euros en finançament per a Minoryx Therapeutics, una empresa de biotecnologia amb seu a Mataró que es dedica al desenvolupament de noves opcions terapèutiques per a malalties del sistema nerviós central per a les que no hi ha medicaments aprovats, com l’adrenomieloneuropatia, l’adrenoleucodistròfia o l’atàxia de Friedreich. BEI da 25 millones a firma que desarrolla terapia para enfermedades genéticas. Barcelona, 30 oct (EFE).- 

El Banco Europeo de Inversiones (BEI) ha anunciado que financiará con 25 millones de euros a Minoryx Therapeutics, una empresa de biotecnología centrada en el desarrollo de nuevas terapias para enfermedades genéticas huérfanas del sistema nervioso central y con sede en el Tecnocampus de Mataró (Barcelona). El ensayo (FRAMES) estudia la ataxia de Friedreich (AF), una enfermedad potencialmente mortal caracterizada por una neurodegeneración que provoca pérdida de coordinación y de fuerza muscular y cardiomiopatía.

 

[4Fe-4S] cluster trafficking mediated by Arabidopsis mitochondrial ISCA and NFU proteins

Tamanna Azam, Jonathan Przybyla-Toscano, Florence Vignols, Jérémy Couturier, Nicolas Rouhier, and Michael K. Johnson, J. Biol. Chem. jbc.RA120.015726. doi:10.1074/jbc.RA120.015726

 The results demonstrate rapid, unidirectional and quantitative [4Fe-4S]2+ cluster transfer from ISCA1a/2 to NFU4 or NFU5 that further delineates their respective positions in the plant ISC machinery and their contributions to the maturation of client [4Fe-4S] cluster-containing proteins.

An Overview of the Ferroptosis Hallmarks in Friedreich’s Ataxia

Turchi, R.; Faraonio, R.; Lettieri-Barbato, D.; Aquilano, K. Biomolecules 2020, 10, 1489. doi:10.3390/biom10111489 

 Even though ferroptosis has been associated with various neurodegenerative diseases including FRDA, the mechanisms leading to disease onset/progression have not been demonstrated yet. We describe the molecular alterations occurring in FRDA that overlap with those characterizing ferroptosis. Major conclusions: The study of ferroptotic pathways is necessary for the understanding of FRDA pathogenesis, and anti-ferroptotic drugs could be envisaged as therapeutic strategies to cure FRDA.

Gene Therapy Company AavantiBio Launches With $107 Million Series A Financing From Perceptive Advisors, Bain Capital Life Sciences, RA Capital Management and Sarepta Therapeutics

CAMBRIDGE, Mass., Oct. 22, 2020 (GLOBE NEWSWIRE). 

 A premier syndicate of life sciences investors including Perceptive Advisors, Bain Capital Life Sciences (“Bain Capital”), and RA Capital Management (“RA Capital”) (collectively the “Investor Group”) together with Sarepta Therapeutics, Inc. (“Sarepta”) (NASDAQ: SRPT), a leader in precision genetic medicine for rare diseases, today announced a $107 million Series A financing to create AavantiBio, a gene therapy company focused on transforming the lives of patients with rare genetic diseases. The private financing round includes a $15 million equity investment from Sarepta.

Headquartered in the greater Boston area, UF startup and UF Innovate | The Hub resident client AavantiBio, is co-founded by renowned gene therapy researchers Barry Byrne, M.D., Ph.D., and Manuela Corti, P.T., Ph.D., who together bring thirty years of experience to the company. AavantiBio’s lead program is in Friedreich’s Ataxia (FA), a rare inherited genetic disease that causes cardiac and central nervous system dysfunction. AavantiBio’s research efforts expand on foundational research conducted by Drs. Byrne and Corti in Friedreich’s Ataxia, among other rare genetic disorders. AavantiBio will benefit from strategic partnerships with the University of Florida’s renowned Powell Gene Therapy Center and the MDA Care Center at UF Health where Drs. Byrne and Corti maintain their research and clinical practices. Initial funding in AavantiBio was provided by GoFAR, an Italian patient advocacy group, and the Muscular Dystrophy Association Venture Philanthropy Fund.

The French Association of Ataxia in Friedreich renews its 25,000 euro grant to validate the therapeutic potential of calcitriol for treating this rare malaltia

IRBLleida, Friday, October 23, 2020. The French Association of Ataxia of Friedreich has renewed the aid of 25,000 euros to the Oxidative stress biochemistry Research Group of the Biomedical Research Institute of Lleida (IRBLleida) and the University of Lleida (UdL) to validate the therapeutic potential of calcitriol, the active form of vitamin D, to treat this disease. "The entity has decided to continue collaborating due to the advances in research carried out in Lleida, despite the difficulties of working in the laboratory during the confinement and the new normality" explained the principal investigator of this project, Fabien Delaspre.

Sarepta, continuing its gene therapy push, helps launch a startup

BIOPHARMA DIVE, Oct. 22, 2020. AavantiBio joins a couple large, powerful companies in the hunt for a gene therapy to treat Friedreich's ataxia. Pfizer and Novartis are each working on their own programs. Outside of gene therapy, Reata Pharmaceuticals disclosed last year positive data from a study that tested an oral drug, known as omaveloxolone, in patients with Friedreich's ataxia. Reata said it intends to file the drug for approval based on those results.