Source of medical information and behavioral seeking patterns in patients affected with Friedreich's ataxia and their caregivers: a survey study

Miele G, Lavorgna L, De Mercanti SF, Iudicello M, Abbadessa G, Matta M, Bonavita S, Clerico M.; Neurol Sci. 2021 Nov 28. doi: 10.1007/s10072-021-05738-6. Epub ahead of print. PMID: 34839412. 

For patients and caregivers, the main source of information was the FRDA specialist and the media. The most searched items were "general information"; patients and particularly caregivers desired to get more information on existing and experimental therapies. Adequate information supply is part of good medical care; therefore, a deeper insight of clinicians in information-seeking behavior of FRDA patients and caregivers would provide tailored information and improve therapeutic alliance.

Diagnosis and Management of Cardiovascular Involvement in Friedreich Ataxia

Emanuele Monda, Michele Lioncino, Marta Rubino, Silvia Passantino, Federica Verrillo, Martina Caiazza, Annapaola Cirillo, Adelaide Fusco, Francesco Di Fraia, Fabio Fimiani, Federica Amodio, Nunzia Borrelli, Alfredo Mauriello, Francesco Natale, Gioacchino Scarano, Francesca Girolami, Silvia Favilli, Giuseppe Limongelli; Heart Failure Clinics, Volume 18, Issue 1, 2022, Pages 31-37, doi:10.1016/j.hfc.2021.07.001. 

Cardiac involvement represents a common disorder in Friedreich ataxia and is responsible for premature death, particularly in early-onset cases. No specific treatments are available for Friedreich ataxia cardiomyopathy. However, gene therapy and stem cells–based therapy might be available as future therapeutic options.

Cellular pathophysiology of Friedreich's ataxia cardiomyopathy

Jarmon G. Lees, Marek Napierala, Alice Pébay, Mirella Dottori, Shiang Y. Lim; International Journal of Cardiology, 2021, doi:10.1016/j.ijcard.2021.11.033. 

At the cellular level, cardiomyocyte hypertrophy, apoptosis and fibrosis contribute to the cardiac pathology. However, the heart is composed of multiple cell types and several clinical studies have reported the involvement of cardiac non-myocytes such as vascular cells, autonomic neurons, and inflammatory cells in the pathogenesis of FRDA cardiomyopathy. In fact, several of the cardiac pathologies associated with FRDA including cardiomyocyte necrosis, fibrosis, and arrhythmia, could be contributed to by a diseased vasculature and autonomic dysfunction. Here, we review available evidence regarding the current understanding of cellular mechanisms for and the involvement of cardiac non-myocytes in the pathogenesis of FRDA cardiomyopathy.

Exicure, Inc. Reports Third Quarter 2021 Financial Results and Corporate Progress

Published : Friday, November 19, 2021, ACROFAN=Businesswire. 

XCUR-FXN–Friedreich’s Ataxia Exicure remains committed to maintaining its development plans and to pursuing its business strategy in the best interests of its stockholders as well as the patients it looks to serve; however, it acknowledges that, at this point in time, it is unable to determine the potential impact of the asserted claim on its research and development activities or the timing of completion of its current research and development of its XCUR-FXN preclinical program for the treatment of FA, as the investigation of the asserted claim remains ongoing.

Reata Pharmaceuticals Receives Fast Track Designation From the FDA for Omaveloxolone for the Treatment of Friedreich’s Ataxia

November 18, 2021, PLANO, Texas--(BUSINESS WIRE)--Reata Pharmaceuticals, today announced the U.S. Food and Drug Administration (“FDA”) has granted Fast Track Designation for omaveloxolone for the treatment of Friedreich’s ataxia.

“We are pleased to receive Fast Track Designation as it highlights the potential of omaveloxolone to address a significant unmet medical need for the treatment of patients with Friedreich’s ataxia, a severe and devastating disease,” said Warren Huff, Reata’s President and Chief Executive Officer. “We remain committed to submitting our New Drug Application during the first quarter of 2022 and continue working with the FDA to secure regulatory approval as quickly as possible.” 

The Fast Track program is designed to accelerate the development and review of products such as omaveloxolone, which are intended to treat serious diseases and for which there is an unmet medical need. Fast Track Designation enables more frequent communication with the FDA and eligibility for FDA programs such as priority review and rolling review, if relevant criteria are met.

Body Mass Index and Height in Friedreich Ataxia What Do We Know?

Sylvia M. Boesch, Elisabetta Indelicato; Neurol Genet Dec 2021, 7 (6) e637; DOI: 10.1212/NXG.0000000000000637 

In this issue of Neurology® Genetics, members of the Friedreich Ataxia Clinical Outcome Measure Study (FACOMS) present a first large study that aimed to investigate cross-sectional and longitudinal associations between demographic, genetic, and clinical factors and anthropometric outcomes such as height and body mass index (BMI) in FRDA.4 The authors reported on 961 FRDA participants from 12 centers in the United States and Australia with a median age at baseline of 20 years, and 49% (n = 475) patients were female.

STEALTH BIOTHERAPEUTICS REPORTS THIRD QUARTER 2021 FINANCIAL RESULTS AND RECENT BUSINESS HIGHLIGHTS

11/12/2021. MarketScreener. Friedreich's ataxia. The investigator is awaiting Institutional Review Board approval of the planned Phase 2a clinical trial in patients with Friedreich's ataxia and expects to begin enrollment in early 2022.

Larimar expects to initiate its Jive open-label extension and pediatric multiple ascending dose trials in the first half of next year.

BALA CYNWYD, Pa., Nov. 12, 2021 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (“Larimar”), a clinical-stage biotechnology company focused on developing treatments for complex rare diseases. 

Prior to the third quarter, the United States Food and Drug Administration (FDA) placed a clinical hold on the CTI-1601 clinical program after Larimar notified the agency of mortalities that occurred at the highest dose levels of a 180-day non-human primate (NHP) toxicology study designed to support extended dosing of patients with CTI-1601. In the clinical hold letter, the FDA stated that it needs a full study report from the NHP study and that Larimar may not initiate additional clinical trials until the Company has submitted the report and received notification from the agency that additional clinical trials may commence. At the time of the notice, the Company had no interventional clinical trials with patients enrolled or enrolling. 

In July 2021, Larimar completed dosing in the 180-day NHP toxicology study, and it continues to collect and analyze data. While there is no way to predict the FDA’s response (which the Company anticipates will not be received prior to the first quarter of 2022) or whether they will require additional data or testing before lifting the clinical hold on CTI-1601 in full or in part, the Company expects to initiate its Jive open-label extension and pediatric multiple ascending dose trials in the first half of next year. 

In August 2021, Larimar initiated a non-interventional healthy volunteer study designed to generate data for comparison to patients with FA.

Body Mass Index and Height in the Friedreich Ataxia Clinical Outcome Measures Study

Maya Patel, Ashley McCormick, Jaclyn Tamaroff, Julia Dunn, Jonathan A. Mitchell, Kimberly Y. Lin, Jennifer Farmer, Christian Rummey, Susan L. Perlman, Martin B. Delatycki, George R. Wilmot, Katherine D. Mathews, Grace Yoon, Joseph Hoyle, Manuela Corti, S.H. Subramony, Theresa Zesiewicz, David Lynch, Shana E. McCormack; Neurol Genet Dec 2021, 7 (6) e638; DOI: 10.1212/NXG.0000000000000638 

FRDA affects both weight gain and linear growth. These insights will inform assessments of affected individuals in both research and clinical settings.

Friedreich's ataxia. The investigator is awaiting Institutional Review Board approval of the planned Phase 2a clinical trial in patients with Friedreich's ataxia and expects to begin enrollment in early 2022.

BOSTON, Nov. 11, 2021 /PRNewswire/ -- Stealth Biotherapeutics (Nasdaq:MITO), a clinical-stage biotechnology company focused on the discovery, development, and commercialization of novel therapies for diseases involving mitochondrial dysfunction, today reported financial results for the three months ended September 30, 2021 and announced recent business highlights.

Friedreich's ataxia. The investigator is awaiting Institutional Review Board approval of the planned Phase 2a clinical trial in patients with Friedreich's ataxia and expects to begin enrollment in early 2022.

Clinical Initiation of Lead GeneTACTM Program for Friedreich Ataxia On-track for the First Half of 2022

CARLSBAD, Calif., Nov. 09, 2021 (GLOBE NEWSWIRE); Design Therapeutics Reports Pipeline Progress and Third Quarter 2021 Results 

Friedreich Ataxia (FA) GeneTACTM Program On-track for Clinical Initiation in First Half of 2022: In ongoing IND-enabling studies, Design’s FA GeneTACTM clinical candidate has been shown to be well tolerated in repeat dose GLP toxicity studies in rats and non-human primates at doses that exceed what we estimate to be biologically active in the clinic. Design remains on track to initiate a Phase 1 clinical trial in patients with FA in the first half of 2022, with initial topline clinical data expected in 2022.

Molecular approaches for the treatment and prevention of Friedreich's ataxia

Wenyao Yang, Bruce Thompson, Faith A.A. Kwa, Drug Discovery Today, 2021, doi:10.1016/j.drudis.2021.11.003

Current management strategies aim for symptomatic relief and no treatments can prevent disease onset or progression. Thus, research efforts have focused on targeting the molecular pathways that silence FXN and downstream pathological processes. However, progression of potential therapies into clinical use has been hindered by inconclusive clinical trials because of the small patient sample size associated with the low prevalence of this condition. Here, we discuss various molecular approaches and explore their therapeutic potential to alter the course of this progressive condition.

Designing phase II clinical trials in Friedreich ataxia

Rodden LN, Lynch DR.; Expert Opin Emerg Drugs. 2021 Oct 25. doi: 10.1080/14728214.2021.1998452. Epub ahead of print. PMID: 34693848. 

A growing number of drug candidates are being tested in phase II clinical trials for FRDA; however, most have not met their primary endpoints, and none have received FDA approval. In this review, we aim to summarize completed phase II clinical trials in FRDA, outlining critical lessons that have been learned and that should be incorporated into future trial design to ultimately optimize drug development in FRDA.

Construction of DNA/RNA Triplex Helices Based on GAA/TTC Trinucleotide Repeats

Zhang J, Fakharzadeh A, Pan F, Roland C, Sagui C.; Bio Protoc. 2021 Sep 20;11(18):e4155. doi: 10.21769/BioProtoc.4155. PMID: 34692905; PMCID: PMC8481028. 

Atypical DNA and RNA secondary structures play a crucial role in simple sequence repeat (SSR) diseases, which are associated with a class of neurological and neuromuscular disorders known as "anticipation diseases," where the age of disease onset decreases and the severity of the disease is increased as the intergenerational expansion of the SSR increases. While the mechanisms underlying these diseases are complex and remain elusive, there is a consensus that stable, non-B-DNA atypical secondary structures play an important - if not causative - role. These structures include single-stranded DNA loops and hairpins, G-quartets, Z-DNA, triplex nucleic acid structures, and others. While all of these structures are of interest, structures based on nucleic acid triplexes have recently garnered increased attention as they have been implicated in gene regulation, gene repair, and gene engineering. Our work here focuses on the construction of DNA triplexes and RNA/DNA hybrids formed from GAA/TTC trinucleotide repeats, which underlie Friedreich's ataxia. While there is some software, such as the Discovery Studio Visualizer, that can aid in the initial construction of DNA triple helices, the only option for the triple helix is constrained to be that of an antiparallel pyrimidine for the third strand. In this protocol, we illustrate how to build up more generalized DNA triplexes and DNA/RNA mixed hybrids. We make use of both the Discovery Studio Visualizer and the AMBER simulation package to construct the initial triplexes. Using the steps outlined here, one can - in principle - build up any triple nucleic acid helix with a desired sequence for large-scale molecular dynamics simulation studies.

Longitudinal investigation of brain activation during motor tasks in Friedreich ataxia: 24-month data from IMAGE-FRDA

Shishegar R, Harding IH, Selvadurai LP, Corben LA, Delatycki MB, Egan GF, Georgiou-Karistianis N.; Brain Struct Funct. 2021 Oct 23. doi: 10.1007/s00429-021-02413-6. Epub ahead of print. PMID: 34687355. 

We investigated the hypothesis that progressive functional changes in both the cerebellum and cerebrum are related to longitudinal changes in performance on complex motor tasks in individuals with FRDA. Twenty-two individuals with FRDA and 28 controls participated over 24 months. The longitudinal investigation included finger tapping tasks with different levels of complexity (i.e., visually cued, multi-finger; self-paced, single finger), performed in conjunction with fMRI acquisitions, to interrogate changes in the neurobiology of motor and attentional brain networks including the cerebellum and cerebrum. We demonstrated evidence for significant longitudinal decreased cerebral fMRI activity over time in individuals with FRDA, relative to controls, during an attentionally-demanding motor task (visually cued tapping of multiple fingers) in six cerebral regions: right and left superior frontal gyri, right superior temporal gyrus, right primary somatosensory area, right anterior cingulate cortex, and right medial frontal gyrus. Importantly, longitudinal decreased activity was associated with more severe disease status at baseline, higher GAA1 repeat length and earlier age of onset. These findings suggest a dynamic pattern of neuronal activity in motor, attention and executive control networks over time in individuals with FRDA, which is associated with increased disease severity at baseline, increased GAA1 repeat length and earlier age at onset.

Clinical and Molecular Features of First Mexican Friedreich's Ataxia Patients with Compound Heterozygous FXN Mutations

Boll MC, Gasca-Saldaña D, Mayén-Lobo YG, Dávila-Ortiz de Montellano DJ, Monroy-Jaramillo N.; Neurol India 2021;69:1363-7. DOI: 10.4103/0028-3886.329555

Eighteen patients had a homozygous FXN genotype; whereas five were CH patients with a slow progression and phenotypic variability, including a late-onset case with spastic paraparesis, and a Charcot-Marie-Tooth-like case.