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.

Left atrial appendage thrombosis in a patient with Friedreich Ataxia–related cardiomyopathy, left ventricular systolic dysfunction, and atrial fibrillation

. Michele Russo, Annachiara Nuzzo, Matteo Foschi, Simona Boarin, Stefano Lorenzetti, Corrado Tomasi, Pietro Querzani, Andrea Rubboli. SAGE Open Medical Case Reports. January 2021. doi:10.1177/2050313X211056419 

We present the case of a 45-year-old man with a history of paroxysmal atrial fibrillation and a congestive heart failure, hypertension, age ⩾ 75 years, diabetes mellitus, stroke, vascular disease, age 65–74 years, and female sex (CHA2DS2-VASc) score of only 1 (because of reduced left ventricular ejection fraction) who presented with pneumonia and was also found to have atrial fibrillation with a rapid ventricular response. Despite already being on long-term therapy with a non-vitamin K-antagonist oral anticoagulant, a transesophageal echocardiogram showed a mobile floating thrombus in the left atrial appendage. In accordance with previous necropsy evidence of thrombosis and thromboembolism in Friedreich ataxia subjects who likely have had only non-sex-related CHA2DS2-VASc score ⩽1, this case suggests that the risk of thromboembolism in Friedreich ataxia subjects with atrial fibrillation may not be adequately predicted by the sole CHA2DS2-VASc score.

Tract-Specific Spinal Cord Diffusion Tensor Imaging in Friedreich's Ataxia

Ana Luisa C.C. Hernandez MD,Thiago J.R. Rezende PhD,Alberto R.M. Martinez MD, PhD,Mariana R. de Brito MD,Marcondes C. França Jr MD, PhD; Mov Disord. doi:10.1002/mds.28841 

DTI uncovered abnormalities in SC WM tracts, which correlated with clinical features in FRDA. CSA and CST FA in C2 correlated best with disease severity, whereas DC FA showed the largest effect size to differentiate patients and healthy controls. SC WM microstructure is a potential neuroimaging biomarker to be explored in the disease.