Double blind trial of a deuterated form of linoleic acid (RT001) in Friedreich ataxia

David R. Lynch, Katherine D. Mathews, Susan Perlman, Theresa Zesiewicz, Sub Subramony, Omid Omidvar, Adam P. Vogel, Ana Krtolica, Nadia Litterman, Lex van der Ploeg, Frederic Heerinckx, Peter Milner & Mark Midei; J Neurol (2022). doi:10.1007/s00415-022-11501-4

The results of this study provide no evidence for a significant benefit of RT001 at the dosages tested in this Friedreich ataxia patient population.

Clinical evidence of interventions assessed in Friedreich ataxia: a systematic review

Jain P, Badgujar L, Spoorendonk J, Buesch K.; Therapeutic Advances in Rare Disease. 2022;3. doi:10.1177/26330040221139872

 Identified literature showed a considerable unmet need for therapeutic interventions that halt or slow the deteriorating nature of FA. Novel efficacious drugs should be investigated that aim to improve symptoms or slow disease progression.

Friedreich’s ataxia: major trial readouts and regulatory events to watch in 2023

www.clinicaltrialsarena.com; Analysis. November 30, 2022 

The FDA could approve the first treatment for Friedreich’s ataxia, and at least three other major trials have readouts expected by year end. All signs indicate 2023 will prove a pivotal year in Friedreich’s ataxia drug development. Reata’s omaveloxolone, which met its primary endpoint in a Phase II trial, is up for FDA approval on February 28. Meanwhile, a Phase II/III trial of PTC’s vatiquinone, a Phase I/II trial of Stealth Bio’s elamipretide, and a Phase II study of Larimar’s CI-1601 all have key results expected in 2023.

Acceso a medicamentos huérfanos para el tratamiento de la atrofia muscular espinal en España

B. García-Parra, J.M. Guiu, P. Modamio, A. Martínez-Yélamos, E.L. Mariño-Hernández, M. Povedano[REV NEUROL 2022;75:261-267]PMID: 36285446DOI: doi:10.33588/rn.7509.2022298 

La atrofia muscular espinal (AME) es una enfermedad rara cuyo diagnóstico y tratamiento es complejo. En España hay dos medicamentos huérfanos financiados por el Sistema Nacional de Salud, nusinersén y onasemnogén abeparvovec, y un tercero, risdiplam, pendiente. El objetivo fue analizar el acceso a los fármacos modificadores de la AME y detectar posibles causas de inequidad. Materiales y método. Estudio descriptivo realizado en dos fases: revisión bibliográfica y entrevistas semiestructuradas a expertos clínicos en AME de las comunidades autónomas (CC. AA.) de Andalucía, Castilla-La Mancha, Cataluña y Murcia. El número de centros, servicios o unidades de referencia, la disponibilidad de planes autonómicos para enfermedades raras y los programas piloto de cribado neonatal pueden modular el acceso a los nuevos tratamientos farmacológicos. El número de nuevos pacientes diagnosticados al año se estimó entre uno y seis en cada una de las CC. AA. estudiadas. Dos de las cuatro CC. AA. estaban participando en ensayos clínicos. El tiempo desde la prescripción a la administración de nusinersén estaba entre siete y 60 días. Sólo Cataluña comunicó experiencia con onasemnogén abeparvovec a 30 de junio de 2022. Dos CC. AA. de las cuatro estudiadas disponen de plan autonómico para enfermedades raras; no obstante, se identificó como relevante para el tratamiento de la AME sólo en una de ellas.

Repositioning Drugs for Rare Diseases Based on Biological Features and Computational Approaches

Otero-Carrasco, B.; Prieto Santamaría, L.; Ugarte Carro, E.; Caraça-Valente Hernández, J.P.; Rodríguez-González, Healthcare 2022, 10, 1784. doi:10.3390/healthcare10091784 

Rare diseases are a group of uncommon diseases in the world population. To date, about 7000 rare diseases have been documented. However, most of them do not have a known treatment. As a result of the relatively low demand for their treatments caused by their scarce prevalence, the pharmaceutical industry has not sufficiently encouraged the research to develop drugs to treat them. This work aims to analyse potential drug-repositioning strategies for this kind of disease. Drug repositioning seeks to find new uses for existing drugs. In this context, it seeks to discover if rare diseases could be treated with medicines previously indicated to heal other diseases. Our approaches tackle the problem by employing computational methods that calculate similarities between rare and non-rare diseases, considering biological features such as genes, proteins, and symptoms. Drug candidates for repositioning will be checked against clinical trials found in the scientific literature. In this study, 13 different rare diseases have been selected for which potential drugs could be repositioned. By verifying these drugs in the scientific literature, successful cases were found for 75% of the rare diseases studied. The genetic associations and phenotypical features of the rare diseases were examined. In addition, the verified drugs were classified according to the anatomical therapeutic chemical (ATC) code to highlight the types with a higher predisposition to be repositioned. These promising results open the door for further research in this field of study.

Patient-Reported Impact of Symptoms in Friedreich Ataxia

Jamison Seabury, Danae Alexandrou, Nuran Dilek, Brittany Cohen, John Heatwole, Jane Larkindale, David R Lynch, Courtney Park, Spencer Rosero, Sub H Subramony, Anika Varma, Ellen Wagner, Susan Walther, Jennifer Weinstein, McKenzie Wells, Christine Zizzi, Chad Heatwole Neurology Nov 2022, 10.1212/WNL.0000000000201598; DOI: 10.1212/WNL.0000000000201598 

There are a wide variety of symptoms that affect the lives of individuals with FA. These symptoms, many underrecognized, have different levels of importance and occur at different rates in the FA population. The most common and life altering of these symptoms represent potential targets for future therapeutic interventions.

Efficacy of Omaveloxolone in Friedreich's Ataxia: Delayed-Start Analysis of the MOXIe Extension

Lynch, D.R., Chin, M.P., Boesch, S., Delatycki, M.B., Giunti, P., Goldsberry, A., Hoyle, J.C., Mariotti, C., Mathews, K.D., Nachbauer, W., O'Grady, M., Perlman, S., Subramony, S., Wilmot, G., Zesiewicz, T. and Meyer, C.J. (2022), . Mov Disord. doi:10.1002/mds.29286 

 The noninferiority testing demonstrated that the difference in mFARS between omaveloxolone and placebo observed at the end of placebo-controlled MOXIe part 2 (−2.17 ± 1.09 points) was preserved after 72 weeks in the extension (−2.91 ± 1.44 points). In addition, patients previously randomized to omaveloxolone in MOXIe part 2 continued to show no worsening in mFARS relative to their extension baseline through 144 weeks.

METTL17 is an Fe-S cluster checkpoint for mitochondrial translation

Ast T, Itoh Y, Sadre S, McCoy JG, Namkoong G, Chicherin I, Joshi PR, Kamenski P, Suess DLM, Amunts A, Mootha VK.; bioRxiv; 2022. DOI: 10.1101/2022.11.24.517765. 

Friedreich’s ataxia (FA) is the most common monogenic mitochondrial disease. FA is caused by a depletion of the mitochondrial protein frataxin (FXN), an iron-sulfur (Fe-S) cluster biogenesis factor. To better understand the cellular consequences of FA, we performed quantitative proteome profiling of human cells depleted for FXN. Nearly every known Fe-S cluster-containing protein was depleted in the absence of FXN, indicating that as a rule, cluster binding confers stability to Fe-S proteins. Proteomic and genetic interaction mapping identified impaired mitochondrial translation downstream of FXN loss, and specifically highlighted the methyltransferase-like protein METTL17 as a candidate effector. Using comparative sequence analysis, mutagenesis, biochemistry and cryogenic electron microscopy we show that METTL17 binds to the mitoribosomal small subunit during late assembly and harbors a previously unrecognized [Fe 4 S 4 ] 2+ cluster required for its stability on the mitoribosome. Notably, METTL17 overexpression rescued the mitochondrial translation and bioenergetic defects, but not the cellular growth, of FXN null cells. Our data suggest that METTL17 serves as an Fe-S cluster checkpoint: promoting the translation and assembly of Fe-S cluster rich OXPHOS proteins only when Fe-S cluster levels are replete.

Personal factors understood through the Ecological-Enactive Model of Disability and implications for rehabilitation research

Schwab SM, Spencer C, Carver NS, Andrade V, Dugan S, Greve K, Silva PL.; Front Rehabil Sci. 2022 Aug 12;3:954061. doi:10.3389/fresc.2022.954061. 

The International Classification of Functioning, Disability and Health (ICF) recognizes that disability arises from the interaction between an individual with a medical condition and the context in which they are embedded. Context in the ICF is comprised of environmental and personal factors. Personal factors, the background life and lifestyle of an individual, are poorly understood in rehabilitation. There is limited knowledge about how personal and environmental factors interact to shape the contextual conditions critical for explaining functioning and disability. In this paper, we explore how a newly proposed model of disability, the Ecological-Enactive Model of Disability, can enhance understanding of personal factors across multiple rehabilitation disciplines. We draw from a review of evidence and phenomenological interviews of individuals with Friedreich's Ataxia. We consider the practical impact of this understanding on disability and rehabilitation research and pathways for the future focusing on representative design.

Multimodal Analysis of the Visual Pathways in Friedreich's Ataxia Reveals Novel Biomarkers

Thomas-Black, G., Altmann, D.R., Crook, H., Solanky, N., Carrasco, F.P., Battiston, M., Grussu, F., Yiannakas, M.C., Kanber, B., Jolly, J.K., Brett, J., Downes, S.M., Moran, M., Chan, P.K., Adewunmi, E., Gandini Wheeler-Kingshott, C.A., Németh, A.H., Festenstien, R., Bremner, F. and Giunti, P. (2022), Mov Disord. doi:10.1002/mds.29277 

We demonstrate that frataxin level correlates with peripapillary retinal nerve fibre layer thickness and that retinal sectors differ in their degree of degeneration. We also shown that retinal nerve fibre layer is thinner in FRDA patients than controls and that this thinning is influenced by the AAO and GAA1. Furthermore we show that the ganglion cell and inner plexiform layers are affected in FRDA. Our MRI data indicate that there are borderline correlations between retinal layers and areas of the cortex involved in visual processing. 

Our study demonstrates the uneven distribution of the axonopathy in the retinal nerve fibre layer and highlight the relative sparing of the papillomacular bundle and temporal sectors. We show that thinning of the retinal nerve fibre layer is associated with frataxin levels, supporting the use the two biomarkers in future clinical trials design.