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.

Ferroptosis: molecular mechanisms and health implications

Daolin Tang, Xin Chen, Rui Kang, Guido Kroemer; Cell Res (2020). doi:10.1038/s41422-020-00441-1

The ferroptosis inhibitor SRS11-92 is highly effective in protecting human primary fibroblasts from cell death induced by frataxin depletion, indicating that targeting ferroptosis might be useful for the treatment of Friedreich ataxia, pending confirmation in animal models.

Altered Expression of Mitoferrin and Frataxin, Larger Labile Iron Pool and Greater Mitochondrial DNA Damage in the Skeletal Muscle of Older Adults

Picca, A.; Saini, S.K.; Mankowski, R.T.; Kamenov, G.; Anton, S.D.; Manini, T.M.; Buford, T.W.; Wohlgemuth, S.E.; Xiao, R.; Calvani, R.; Coelho-Júnior, H.J.; Landi, F.; Bernabei, R.; Hood, D.A.; Marzetti, E.; Leeuwenburgh, C; Cells 2020, 9, 2579. doi:10.3390/cells9122579

An inverse association was found between total Fe and the heavier Fe isotope (56Fe), indicating an increase in labile Fe abundance in cells with greater Fe content. The highest levels of labile Fe were detected in old participants with a Short Physical Performance Battery (SPPB) score ≤ 7 (low-functioning, LF). Protein levels of mitoferrin and frataxin were, respectively, higher and lower in the LF group relative to young participants and older adults with SPPB scores ≥ 11 (high-functioning, HF). The mtDNA4977 relative abundance was greater in old than in young participants, regardless of SPPB category. Higher protein levels of Pink1 were detected in LF participants compared with young and HF groups. Finally, the ratio between lipidated and non-lipidated microtubule-associated protein 1A/1B-light chain 3 (i.e., LC3B II/I), as well as p62 protein expression was lower in old participants regardless of SPPB scores. Our findings indicate that cellular and mitochondrial Fe homeostasis is perturbed in the aged muscle (especially in LF older adults), as reflected by altered levels of mitoferrin and frataxin, which, together with MQC derangements, might contribute to loss of mtDNA stability.

PTC Therapeutics Announces Initiation of Global Phase 3 Clinical Trial to Evaluate Vatiquinone in Friedreich Ataxia

SOUTH PLAINFIELD, N.J., Nov. 30, 2020 /PRNewswire/ -- PTC Therapeutics, Inc. (NASDAQ: PTCT), today announced the initiation of the registration-directed Phase 3 MOVE-FA study evaluating vatiquinone (PTC743) in children and young adults with Friedreich ataxia (FA) The Phase 3 MOVE-FA trial is an 18-month parallel arm, placebo-controlled study evaluating vatiquinone versus placebo in approximately 110 children and young adults with FA. The primary endpoint is the change from baseline in the modified Friedreich ataxia rating scale (mFARS), with key secondary endpoints assessing ambulation and activities of daily living. This endpoint strategy was developed in consultation with both the FDA and European Medicines Agency. The study will include sites in the U.S., E.U., Australia and Latin America.

FDA sends Reata back to the drawing board

Evaluate Vantage, Madeleine Armstrong, November 25, 2020

The need for another pivotal trial of omaveloxolone in Friedreich's ataxia looks increasingly likely. This result for omaveloxolone was not entirely unexpected; Reata said during its second-quarter results that the FDA had asked for a second pivotal trial to support the Moxie study. Part two of Moxie was declared a success, but only after Reata switched endpoints to increase its chances after the first part failed (Reata looks to outsmart Abbvie again, October 15, 2019).