Minoryx’s clinical candidate leriglitazone shows clinical benefit in a proof of concept Phase 2 study in Friedreich´s ataxia

Mataró, Barcelona, Spain, December 15, 2020 - Minoryx Therapeutics, a Phase 3 clinical stage biotech company focused on the development of differentiating treatment options in orphan central nervous system (CNS) disorders, today announces topline results from the Phase 2 FRAMES clinical trial. “Clinical results from the Minoryx Phase 2 FRAMES clinical trial are promising. Specifically, the reduction in decline in upper limb ataxia in Friedreich's ataxia patients demonstrate the potential of meaningful benefit in tackling this neurodegenerative condition,” said Professor Alexandra Durr, the principal investigator and coordinator of the FRAMES study, from the Brain and Spine Institute of La Pitié-Salpêtrière University Hospital (ICM), Paris.

Calcitriol increases frataxin levels and restores mitochondrial function in cell models of Friedreich Ataxia

Elena Britti; Fabien Delaspre; Arabela Sanz; Marta Medina-Carbonero; Marta Llovera; Rosa Purroy; Stefka Mincheva-Tasheva; Jordi Tamarit; Joaquim Ros; Biochem J BCJ20200331. doi: 10.1042/BCJ20200331

We provide data that calcitriol supplementation, used at nanomolar concentrations, is able to reverse the molecular and cellular markers altered in DRG neurons. Calcitriol is able to recover both ferredoxin 1 and NCLX levels and restores mitochondrial membrane potential indicating an overall mitochondrial function improvement. Accordingly, reduction of apoptotic markers and neurite degeneration was observed and, as a result, cell survival was also recovered. All these beneficial effects would be explained by the finding that calcitriol is able to increase the mature frataxin levels in both, frataxin-deficient DRG neurons and cardiomyocytes; remarkably, this increase also occurs in lymphoblastoid cell lines derived from FA patients. In conclusion, these results provide molecular bases to consider calcitriol for an easy and affordable therapeutic approach for FA patients.

Thioredoxin and Glutaredoxin Systems as Potential Targets for the Development of New Treatments in Friedreich’s Ataxia

Seco-Cervera, M.; González-Cabo, P.; Pallardó, F.V.; Romá-Mateo, C.; García-Giménez, J.L. ; Antioxidants 2020, 9, 1257. doi:10.3390/antiox9121257 The thioredoxin family consists of a small group of redox proteins present in all organisms and composed of thioredoxins (TRXs), glutaredoxins (GLRXs) and peroxiredoxins (PRDXs) which are found in the extracellular fluid, the cytoplasm, the mitochondria and in the nucleus with functions that include antioxidation, signaling and transcriptional control, among others. The importance of thioredoxin family proteins in neurodegenerative diseases is gaining relevance because some of these proteins have demonstrated an important role in the central nervous system by mediating neuroprotection against oxidative stress, contributing to mitochondrial function and regulating gene expression. Specifically, in the context of Friedreich’s ataxia (FRDA), thioredoxin family proteins may have a special role in the regulation of Nrf2 expression and function, in Fe-S cluster metabolism, controlling the expression of genes located at the iron-response element (IRE) and probably regulating ferroptosis. Therefore, comprehension of the mechanisms that closely link thioredoxin family proteins with cellular processes affected in FRDA will serve as a cornerstone to design improved therapeutic strategies.

Friedreich’s Ataxia Center of Excellence at CHOP Awarded $1.275 Million to Advance Medical Research

Published on Dec 10, 2020 in CHOP News. The Friedreich’s Ataxia Center of Excellence (COE) at Children’s Hospital of Philadelphia (CHOP) was awarded $1.275 million by the Friedreich’s Ataxia Research Alliance (FARA), along with the Hamilton and Finneran families and the CureFA Foundation, to support the development of breakthrough therapies to improve the quality of life for individuals with Friedreich’s ataxia. The Friedreich’s Ataxia COE at CHOP was established in March 2014 by CHOP, Penn Medicine and FARA, and was a result of a $3.25 million gift from FARA in partnership with the Hamilton and Finneran families. Since 2014, more than $8 million in research funding has been committed to the COE to create a multi-disciplinary, translational research and clinical care center devoted to FA. Its mission is to expedite basic science and drug discovery to treatments and dedicate resources to clinical research and care to improve outcomes for individuals living with FA.

Safety and feasibility of upper limb cardiopulmonary exercise test in Friedreich ataxia

Chiara Pane, Andrea Salzano, Assunta Trinchillo, Claudia Del Prete, Carlo Casali, Christian Marcotulli, Giovanni Defazio, Vincenzo Guardasole, Rossella Vastarella, Francesco Giallauria, Giorgia Puorro, Angela Marsili, Giovanna De Michele, Alessandro Filla, Antonio Cittadini, Francesco Saccà; European Journal of Preventive Cardiology, zwaa134, doi:10.1093/eurjpc/zwaa134 

 Upper limb CPET is useful in the assessment of exercise tolerance and a possible tool to determine the functional severity of the mitochondrial oxidative defect in patients with FRDA. The cardiopulmonary exercise test is an ideal functional endpoint for Phases II and III trials through a simple, non-invasive, and safe exercise test.

Larimar Therapeutics Announces Completion of Dosing of the Single Ascending Dose Clinical Trial in Friedreich’s Ataxia Patients and Provides Program Update

BALA CYNWYD, Pa., Dec. 08, 2020 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (“Larimar”) (Nasdaq: LRMR), a clinical-stage biotechnology company focused on developing treatments for complex rare diseases, today announced the completion of dosing from the Company’s Phase 1 single ascending dose (SAD) clinical trial (n=28) evaluating CTI-1601 as a treatment for Friedreich’s ataxia (FA) and provided additional updates regarding the status of an ongoing multiple ascending dose (MAD) clinical trial, the timing of Phase 1 topline results, and future activities planned for 2021.

A Safety Review Committee reviewed preliminary blinded data after each cohort of the placebo-controlled SAD clinical trial and recommended continuation of the trial. Dosing has been completed and based on preliminary data, single subcutaneous injections of CTI-1601 at doses up to 100 mg are thought to have been well tolerated. Injection site adverse events were mild and transient, and no serious adverse events were reported. Analysis of clinical trial results remains ongoing.

Patients completing the SAD and/or MAD clinical trials are eligible to screen for an open-label extension clinical trial, which is expected to initiate in the second half of 2021. Larimar also expects to initiate a MAD clinical trial in patients under 18 years of age in the second half of 2021.

Molecular Defects in Friedreich’s Ataxia: Convergence of Oxidative Stress and Cytoskeletal Abnormalities

Frances M. Smith and Daniel J. Kosman; Front. Mol. Biosci., doi:10.3389/fmolb.2020.569293 This review serves to outline a brief history of this research and hones in on pathway dysregulation downstream of iron-related pathology in FRDA related to actin dynamics. The review presented here was not written with the intent of being exhaustive, but to instead urge the reader to consider the essentiality of the cytoskeleton and appreciate the limited knowledge on FRDA-related cytoskeletal dysfunction as a result of oxidative stress. The review examines previous hypotheses of neurodegeneration with brain iron accumulation (NBIA) in FRDA with a specific biochemical focus.

Targeting Expanded Repeats by Small Molecules in Repeat Expansion Disorders

Nakamori, M. and Mochizuki, H. (2020), Mov Disord. doi:10.1002/mds.28397 

 Recent technological advancements in genetic analysis have allowed for the consecutive discovery and elucidation of repeat expansion disorders: diseases caused by the abnormal expansion of repeat sequences in the genome. Many of these repeat expansion disorders are neurodegenerative movement disorders. Radical cures for these disorders have yet to be established. Although conventional treatments for repeat expansion disorders have mainly targeted the abnormal mRNA and proteins encoded by the affected genes, therapeutic approaches targeting repeat DNA, the root cause of repeat disorders, is also being explored in current research. In particular, a small molecule has been found that binds to abnormally expanded CAG repeats, the cause of Huntington's disease, and shortens them. Such small molecules targeting nucleic acids are expected to be developed into groundbreaking therapeutic drugs capable of ameliorating the symptoms of repeat expansion disorders and preventing their onset.

Coronary Artery Disease in Patients With Friedreich's Ataxia

ClinicalTrials.gov Identifier: NCT04649866. Vasculopathy and Remodeling of Coronary Arteries in FRDA Patients.

Patients with HCM can then develop pulmonary hypertension (PH), a deadly condition of the blood vessels of the lung. While most of the research in FRDA has focused on nerves and heart muscle, alterations in blood vessels of the heart and lung may worsen disease in FRDA. But, the role of FXN in these blood vessels has never been defined.Our pilot data suggest that Frataxin (FXN ) deficiency can control senescence and downstream function in various types of Endothelial cells (ECs), we hypothesize that Friedreich's Ataxia (FRDA) patients may demonstrate endothelial cells EC abnormalities throughout the vasculature potentially before overt cardiomyopathy develops.

Afrontamiento familiar ante el diagnóstico y evolución de la enfermedad ataxia de Friedreich, «Family dealing with the diagnosis and evolution of Friedreich’s ataxia disease»

Erika E. López Rios, Yeisy C., Guarate Coronado; Ocronos. Vol. III. Nº 8– Diciembre 2020. Pág. Inicial: Vol. III; nº8:12; ORCID iD: http://orcid.org/ 0000-0003-1526-4693

A partir del diagnóstico y evolución de la Ataxia de Friedreich los familiares experimentaron sentimientos negativos, surgieron cambios a nivel económico, familiar, social y calidad de vida, además el cuidado resulta difícil, por lo que el cuidador principal presentó sobrecarga. Sin embargo, la familia ha logrado afrontar positivamente utilizando estrategias enfocadas al problema y emociones. Conclusiones: La familia utilizó estrategias de afrontamiento enfocadas en las emociones y centradas en el problema, pues emplearon el autocontrol emocional, aceptación de responsabilidades, reevaluación positiva, apoyo familiar y espiritual, búsqueda de información sobre la enfermedad y alternativas de tratamiento.