Friedreich's Ataxia Frequency in a Large Cohort of Genetically Undetermined Ataxia Patients

Brown AF, Parkinson MH, Garcia-Moreno H, Mudanohwo E, Labrum R, Sweeney M, Giunti P.; Front Neurol. 2021 Dec 9;12:736253. doi: 10.3389/fneur.2021.736253. PMID: 34956042; PMCID: PMC8697107. 

This study demonstrates that FRDA is very rare among patients who were referred purely for SCA testing without the clinical suspicion of FRDA. Such cases should be referred to specialist ataxia centres for more extensive testing to improve patient management and outcomes.

The power and the promise of CRISPR/Cas9 genome editing for clinical application with gene therapy

Ning Guo, Ji-Bin Liu, Wen Li, Yu-Shui Ma, Da Fu; Journal of Advanced Research, 2021, doi:10.1016/j.jare.2021.11.018.

CRISPR/Cas9, derived from the microbial innate immune system, is developed as a robust gene-editing tool and has been applied widely. Due to its high accuracy and efficiency, CRISPR/Cas9 techniques may provide a great chance to treat some gene-related diseases by disrupting, inserting, correcting, replacing, or blocking genes for clinical application with gene therapy.

The power and the promise of CRISPR/Cas9 genome editing for clinical application with gene therapy

The classification of neurodegenerative disease from acoustic speech data

Schultz B, Joukhadar Z, Quiroga MdM, Nattala U, Noffs G, Rojas S, Reece H, Walt Avd, Adam Vogel; Research Square; 2021. DOI: 10.21203/rs.3.rs-1029846/v1.

Neurodegenerative diseases often affect speech. Speech acoustics can be used as objective clinical markers of pathology. Previous investigations of pathological speech have primarily compared controls with one specific condition and excluded comorbidities. We broaden the utility of speech markers by examining how multiple acoustic features can delineate diseases. We used supervised machine learning with gradient boosting (CatBoost) to differentiate healthy speech and speech from people with multiple sclerosis or Friedreich ataxia.

Objective Assessment of Progression and Disease Characterization of Friedreich Ataxia via an Instrumented Drinking Cup: Preliminary Results

Krishna R, Pathirana PN, Horne MK, Szmulewicz DJ, Corben LA.; IEEE Transactions on Neural Systems and Rehabilitation Engineering : a Publication of the IEEE Engineering in Medicine and Biology Society. 2021 ;29:2365-2377. DOI: 10.1109/tnsre.2021.3124869. PMID: 34727035. 

The monitoring of disease progression in certain neurodegenerative conditions can significantly be quantified with the help of objective assessments. The severity assessment of diseases like Friedreich ataxia (FRDA) are usually based on different subjective measures. The ability of a participant with FRDA to perform standard neurological tests is the most common way of assessing disease progression. In this feasibility study, an Ataxia Instrumented Measurement-Cup (AIM-C) is proposed to quantify the disease progression of 10 participants (mean age 39 years, onset of disease 16.3 years) in longitudinal timepoints. The device consists of a sensing system with the provision of extracting both kinetic and kinematic information while engaging in an activity closely associated with activities of daily living (ADL). A common functional task of simulated drinking was used to capture features that possesses disease progression information as well as certain other features which intrinsically correlate with commonly used clinical scales such as the modified Friedreich Ataxia Rating Scale (mFARS), the Functional Staging of Ataxia score and the ADL scale. Frequency and time-frequency domain features allowed the longitudinal assessment of participants with FRDA. Furthermore, both kinetic and kinematic measures captured clinically relevant features and correlated 85% with clinical assessments.

Conformational stability, dynamics and function of human frataxin: Tryptophan side chain interplay

Espeche LD, Sewell KE, Castro IH, Capece L, Pignataro MF, Dain L, Javier Santos; Archives of Biochemistry and Biophysics. 2021 Nov;715:109086. DOI: 10.1016/j.abb.2021.109086. PMID: 34801473. 

In humans, the loss of frataxin results in Friedreich's Ataxia, a neurodegenerative disease, in which a deficit in the iron–sulfur cluster assembly is observed. In this work, we analyzed three frataxin variants in which one tryptophan was replaced by a glycine: W155G, W168G and W173G. As expected, given its localization in the assembly site, W155G was not able to activate the desulfurase activity of the supercomplex for iron–sulfur cluster assembly. In turn, W168G, which was significantly more unstable than W155G, was fully active. W173G, which was highly unstable as W168G, showed a significantly decreased activity, only slightly higher than W155G. As W168G and W173G were highly sensitive to proteolysis, we investigated the protein motions by molecular dynamic simulations. We observed that W173G may display altered motions at the Trp155 site. Furthermore, we revealed a H-bond network in which Trp155 takes part, involving residues Gln148, Asn151, Gln153 and Arg165. We suggest that this motion modulation that specifically alters the population of different Trp155 rotamers can be directly transferred to the assembly site, altering the dynamics of the ISCU His137 key residue. This hypothesis was also contrasted by means of molecular dynamic simulations of frataxin in the context of the complete supercomplex. We propose that the supercomplex requires very definite motions of Trp155 to consolidate the assembly site.

Characterizing cardiac phenotype in Friedreich's ataxia: The CARFA study

Lise Legrand, Jonathan W. Weinsaft, Francoise Pousset, Claire Ewenczyk, Perrine Charles, Stéphane Hatem, Anna Heinzmann, Marie Biet, Alexandra Durr, Alban Redheuil, Volume 1267, Issue 1, 11/2021, Pages 1-73, ISSN 1875-2136, doi:10.1016/j.acvd.2021.10.010 

The multivariable characterization of the cardiac phenotype of patients with Friedreich's ataxia was significantly different from controls at baseline. Over 1 year there were no clinically significant changes in patients with Friedreich's ataxia compared with healthy controls, whereas the neurological severity score increased modestly.

Myocardial and Arrhythmic Spectrum of Neuromuscular Disorders in Children

Anwar Baban, Valentina Lodato, Giovanni Parlapiano, Corrado di Mambro, Rachele Adorisio, Enrico Silvio Bertini, Carlo Dionisi-Vici, Fabrizio Drago, and Diego Martinelli; Biomolecules. 2021 Oct;11(11). DOI: 10.3390/biom11111578. PMID: 34827576; PMCID: PMC8615674. 

Neuromuscular disorders (NMDs) are highly heterogenous from both an etiological and clinical point of view. Their signs and symptoms are often multisystemic, with frequent cardiac involvement. In fact, childhood onset forms can predispose a person to various progressive cardiac abnormalities including cardiomyopathies (CMPs), valvulopathies, atrioventricular conduction defects (AVCD), supraventricular tachycardia (SVT) and ventricular arrhythmias (VA). In this review, we selected and described five specific NMDs: Friedreich’s Ataxia (FRDA), congenital and childhood forms of Myotonic Dystrophy type 1 (DM1), Kearns Sayre Syndrome (KSS), Ryanodine receptor type 1-related myopathies (RYR1-RM) and Laminopathies.

Friedreich cardiomyopathy is a secondary desminopathy

Koeppen, A., Rafique, R., Mazurkiewicz, J., Pelech, S., Sutter, C., Lin, Q., & Qian, J. (2021). Free Neuropathology, 2, 34. doi:10.17879/freeneuropathology-2021-3679 

A proteomic analysis of heart proteins in FA cardiomyopathy by antibody microarray, Western blots, immunohistochemistry, and double-label laser scanning confocal immunofluorescence microscopy revealed upregulation of desmin and its chaperone protein, αB-crystallin. In normal hearts, these two proteins are co-localized at intercalated discs and Z discs. In FA, desmin and αB-crystallin aggregate, causing chaotic modification of intercalated discs, clustering of mitochondria, and destruction of the contractile apparatus of cardiomyocytes. Western blots of tissue lysates in FA cardiomyopathy reveal a truncated desmin isoprotein that migrates at a lower molecular weight range than wild type desmin. While desmin and αB-crystallin are not mutated in FA, the accumulation of these proteins in FA hearts allows the conclusion that FA cardiomyopathy is a desminopathy akin to desmin myopathy of skeletal muscle.

Epigenetic Heterogeneity in Friedreich Ataxia Underlies Variable FXN Reactivation

Rodden LN, Gilliam KM, Lam C, Lynch DR and Bidichandani SI (2021); Front. Neurosci. 15:752921. doi: 10.3389/fnins.2021.752921 

Treatment of the same PBMCs from this cohort with HDACi-109 significantly increased FXN transcript to levels seen in asymptomatic heterozygous carriers, albeit with the expected inter-individual variability. Response to HDACi-109 correlated significantly with the prevalence of unmethylated and partially methylated FXN molecules, supporting the model that FXN reactivation involves a proportion of genes that are amenable to correction in non-dividing somatic cells, and that heavily methylated FXN molecules are relatively resistant to reactivation. FXN reactivation is a promising therapeutic strategy in FRDA, and inter-individual variability is explained, at least in part, by somatic epigenetic heterogeneity.

Indefinite suspension of further development of the Company’s XCUR-FXN program for the treatment of Friedreich’s ataxia

CHICAGO & CAMBRIDGE, Mass., December 10, 2021--(BUSINESS WIRE)--Exicure, Inc.® (NASDAQ: XCUR) announced the results of its previously disclosed independent internal investigation and a number of strategic actions aimed to reduce cash spend and prioritize the Company’s therapeutic pipeline

The results of the investigation are summarized below.

• Beginning in the autumn of 2020, Dr. Corbett misreported raw data from certain research and development experiments related to XCUR-FXN;

• Dr. Corbett misreported the results of at least three different experiments that were conducted through at least February 2021;

• The misreported data related solely to efficacy rather than safety of XCUR-FXN;

• The misreported data was included in various public presentations and SEC filings from as early as January 7, 2021 through as late as August 12, 2021;

Directors has implemented the following approved plan:

• Indefinite suspension of further development of the Company’s XCUR-FXN program for the treatment of Friedreich’s ataxia

• Douglas Feltner, M.D., the Company’s Chief Medical Officer, has agreed to assist in the wind down of the cavrotolimod and XCUR-FXN programs and will depart the Company on January 31, 2022.

Rad9-mediated checkpoint activation is responsible for elevated expansions of GAA repeats in CST-deficient yeast

Spivakovsky-Gonzalez E, Polleys EJ, Masnovo C, Cebrian J, Molina-Vargas AM, Freudenreich CH, Mirkin SM.; Genetics. 2021 Oct 2;219(2):iyab125. doi: 10.1093/genetics/iyab125. 

 Large-scale expansion of (GAA)n repeats in the first intron of the FXN gene is responsible for the severe neurodegenerative disease, Friedreich's ataxia in humans. We have previously conducted an unbiased genetic screen for GAA repeat instability in a yeast experimental system. The majority of genes that came from this screen encoded the components of DNA replication machinery, strongly implying that replication irregularities are at the heart of GAA repeat expansions. This screen, however, also produced two unexpected hits: members of the CST complex, CDC13 and TEN1 genes, which are required for telomere maintenance. To understand how the CST complex could affect intra-chromosomal GAA repeats, we studied the well-characterized temperature-sensitive cdc13-1 mutation and its effects on GAA repeat instability in yeast. We found that in-line with the screen results, this mutation leads to ∼10-fold increase in the rate of large-scale expansions of the (GAA)100 repeat at semi-permissive temperature. Unexpectedly, the hyper-expansion phenotype of the cdc13-1 mutant largely depends on activation of the G2/M checkpoint, as deletions of individual genes RAD9, MEC1, RAD53, and EXO1 belonging to this pathway rescued the increased GAA expansions. Furthermore, the hyper-expansion phenotype of the cdc13-1 mutant depended on the subunit of DNA polymerase δ, Pol32. We hypothesize, therefore, that increased repeat expansions in the cdc13-1 mutant happen during post-replicative repair of nicks or small gaps within repetitive tracts during the G2 phase of the cell cycle upon activation of the G2/M checkpoint.

Longitudinal Assessment Using Optical Coherence Tomography in Patients with Friedreich’s Ataxia

Bogdanova-Mihaylova, P.; Plapp, H.M.; Chen, H.; Early, A.; Cassidy, L.; Walsh, R.A.; Murphy, S.M.; Tomography 2021, 7, 915-931. doi:10.3390/tomography7040076 

Ocular abnormalities occur frequently in Friedreich’s ataxia (FRDA), although visual symptoms are not always reported. We evaluated a cohort of patients with FRDA to characterise the clinical phenotype and optic nerve findings as detected with optical coherence tomography (OCT). A total of 48 patients from 42 unrelated families were recruited. Mean age at onset was 13.8 years (range 4–40), mean disease duration 19.5 years (range 5–43), mean disease severity as quantified with the Scale for the Assessment and Rating of Ataxia 22/40 (range 4.5–38). All patients displayed variable ataxia and two-thirds had ocular abnormalities. Statistically significant thinning of average retinal nerve fibre layer (RNFL) and thinning in all but the temporal quadrant compared to controls was demonstrated on OCT. Significant RNFL and macular thinning was documented over time in 20 individuals. Disease severity and visual acuity were correlated with RNFL and macular thickness, but no association was found with disease duration. Our results highlight that FDRA is associated with subclinical optic neuropathy. This is the largest longitudinal study of OCT findings in FRDA to date, demonstrating progressive RNFL thickness decline, suggesting that RNFL thickness as measured by OCT has the potential to become a quantifiable biomarker for the evaluation of disease progression in FRDA.

The Responsiveness of Gait and Balance Outcomes to Disease Progression in Friedreich Ataxia

Sarah C. Milne, Seok Hun Kim, Anna Murphy, Jane Larkindale, Jennifer Farmer, Ritchie Malapira, Mary Danoudis, Jessica Shaw, Tyagi Ramakrishnan, Fatemeh Rasouli, Eppie M. Yiu, Nellie Georgiou-Karistianis, Geneieve Tai, Theresa Zesiewicz, Martin B. Delatycki & Louise A. Corben. Cerebellum (2021). doi:10.1007/s12311-021-01348-2 

In conclusion, the FARS USS and BBS are highly responsive and can detect change in a wide range of ambulant individuals with FRDA. However, therapeutic effects in children may be best measured by the DGI.

Nuclear Factor Erythroid-Related Factor 2 Signaling in the Neuropathophysiology of Inherited Metabolic Disorders

Bianca Seminotti1, Mateus Grings, Paolo Tucci, Guilhian Leipnitz1, Luciano Saso; Front. Cell. Neurosci., 26 November 2021 doi:10.3389/fncel.2021.785057 

We review here Nrf2 signaling alterations observed in X-linked adrenoleukodystrophy, glutaric acidemia type I, hyperhomocysteinemia, and Friedreich’s ataxia. Additionally, beneficial effects of different Nrf2 activators are shown, identifying a promising target for treatment of patients with these disorders. We expect that this article stimulates research into the investigation of Nrf2 pathway involvement in IMDs and the use of potential pharmacological modulators of this transcription factor to counteract oxidative stress and exert neuroprotection.

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.

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.

Targeting 3′ and 5′ untranslated regions with antisense oligonucleotides to stabilize frataxin mRNA and increase protein expression

Yanjie Li, Jixue Li, Jun Wang, David R Lynch, Xiulong Shen, David R. Corey, Darshan Parekh, Balkrishen Bhat, Caroline Woo, Jonathan J Cherry, Jill S Napierala, Marek Napierala, Nucleic Acids Research, 2021;, gkab954, doi:10.1093/nar/gkab954 

Friedreich’s ataxia (FRDA) is a severe multisystem disease caused by transcriptional repression induced by expanded GAA repeats located in intron 1 of the Frataxin (FXN) gene encoding frataxin. FRDA results from decreased levels of frataxin; thus, stabilization of the FXN mRNA already present in patient cells represents an attractive and unexplored therapeutic avenue. In this work, we pursued a novel approach based on oligonucleotide-mediated targeting of FXN mRNA ends to extend its half-life and availability as a template for translation. We demonstrated that oligonucleotides designed to bind to FXN 5′ or 3′ noncoding regions can increase FXN mRNA and protein levels. Simultaneous delivery of oligonucleotides targeting both ends increases efficacy of the treatment. The approach was confirmed in several FRDA fibroblast and induced pluripotent stem cell-derived neuronal progenitor lines. RNA sequencing and single-cell expression analyses confirmed oligonucleotide-mediated FXN mRNA upregulation. Mechanistically, a significant elongation of the FXN mRNA half-life without any changes in chromatin status at the FXN gene was observed upon treatment with end-targeting oligonucleotides, indicating that transcript stabilization is responsible for frataxin upregulation. These results identify a novel approach toward upregulation of steady-state mRNA levels via oligonucleotide-mediated end targeting that may be of significance to any condition resulting from transcription downregulation.

Iron Metabolism in Pancreatic Beta-Cell Function and Dysfunction

Marku, A.; Galli, A.; Marciani, P.; Dule, N.; Perego, C.; Castagna, M.; Cells 2021, 10, 2841. doi:10.3390/cells10112841 

Iron is an essential element involved in a variety of physiological functions. In the pancreatic beta-cells, being part of Fe-S cluster proteins, it is necessary for the correct insulin synthesis and processing. In the mitochondria, as a component of the respiratory chain, it allows the production of ATP and reactive oxygen species (ROS) that trigger beta-cell depolarization and potentiate the calcium-dependent insulin release. Iron cellular content must be finely tuned to ensure the normal supply but also to prevent overloading. Indeed, due to the high reactivity with oxygen and the formation of free radicals, iron excess may cause oxidative damage of cells that are extremely vulnerable to this condition because the normal elevated ROS production and the paucity in antioxidant enzyme activities. The aim of the present review is to provide insights into the mechanisms responsible for iron homeostasis in beta-cells, describing how alteration of these processes has been related to beta-cell damage and failure. Defects in iron-storing or -chaperoning proteins have been detected in diabetic conditions; therefore, the control of iron metabolism in these cells deserves further investigation as a promising target for the development of new disease treatments.

FDA refusal of Stealth Bio drug shows challenges of ultra-rare disease studies

https://medcitynews.com

The FDA refused to review Stealth BioTherapeutics’ Barth syndrome drug, telling the company results in a study of just eight patients are insufficient to support its submission. The impasse highlights the challenges of testing drugs for ultra-rare diseases. Barth is so rare that Stealth is unsure it can recruit patients to run a new study. Stealth said it is evaluating its next steps and expects to provide an update in early November. But Barth is not the only disease at stake. Elamipretide was developed as a way to treat mitochondrial problems in a range of disorders. Cardiomyopathy, the heart muscle weakness that develops in Barth, also develops in two other rare disorders, Duchenne muscular dystrophy and Friedreich’s ataxia. When Stealth reported its second quarter financial results in August, executives said they hope to begin testing elamipretide in Duchenne patients with cardiomyopathy in the first half of next year. An open label Phase 2a study is also expected in Friedreich’s ataxia. Stealth is also evaluating its drug in other diseases.

Mitochondrial Iron-Sulfur Cluster Biogenesis and Neurological Disorders

Arthavan Selvanathan, Bindu Parayil Sankaran; Mitochondrion, 2021, doi:10.1016/j.mito.2021.10.004.

This review focuses on the disorders of ISC biogenesis that have been described in the literature to-date. Key clinical, biochemical and neuroradiological features will be discussed, providing a reference point for clinicians diagnosing and managing these patients. Therapies are mostly supportive at this stage. However, the improved understanding of the pathophysiology of these conditions could pave the way for disease-modifying therapies in the near future.

Variables affecting pricing of orphan drugs: the Italian case

Claudio Jommi, Elisabetta Listorti, Federico Villa, Simone Ghislandi, Armando Genazzani, Agnese Cangini & Francesco Trotta; Orphanet J Rare Dis 16, 439 (2021). doi:10.1186/s13023-021-02022-w

Our results suggest that value arguments and sustainability (dimension of the target population and its impact on budget impact) issues are considered for orphan drugs pricing: the role played by sustainability is systematically supported by our results. A more transparent and reproducible price negotiation process for orphan drugs is needed in Italy.

In vivo assessment of OXPHOS capacity using 3 T CrCEST MRI in Friedreich's ataxia

Schur GM, Dunn J, Nguyen S, Dedio A, Wade K, Tamaroff J, Mitta N, Wilson N, Reddy R, Lynch DR, McCormack SE.; J Neurol. 2021 Oct 15. doi: 10.1007/s00415-021-10821-1. Epub ahead of print. PMID: 34652504. 

In FRDA, CrCEST MRI may be a useful biomarker of muscle-group-specific decline in OXPHOS capacity that can be leveraged to track within-participant changes over time. Appropriate participant selection and further optimization of the exercise stimulus will enhance the utility of this technique.

Neuroinflammation in the Cerebellum and Brainstem in Friedreich Ataxia: An [18F]-FEMPA PET Study

Khan, W., Corben, L.A., Bilal, H., Vivash, L., Delatycki, M.B., Egan, G.F. and Harding, I.H. (2021), Mov Disord. doi:10.1002/mds.28825 

Neuroinflammation is evident in brain regions implicated in FRDA neuropathology. Increased neuroimmune activity may be related to earlier disease onset and attenuate over the course of the illness.

Friedreich's ataxia-associated childhood hypertrophic cardiomyopathy: a national cohort study

Norrish G, Rance T, Montanes E, Field E, Brown E, Bhole V, Stuart G, Uzun O, McLeod KA, Ilina M, Adwani S, Daubeney P, Delle Donne G, Linter K, Jones CB, Bharucha T, Cervi E, Kaski JP.; Arch Dis Child. 2021 Oct 5:archdischild-2021-322455. doi: 10.1136/archdischild-2021-322455. Epub ahead of print. PMID: 34610949. 

This is the largest cohort of childhood FA-HCM reported to date and describes a high prevalence of atrial arrhythmias and impaired systolic function in childhood, suggesting early progression to end-stage disease. Overall mortality is similar to that reported in non-syndromic childhood HCM, but no patients died suddenly.

Highlighting the Significant Strides Made in Friedreich Ataxia Care

NeurologyLive. October 1, 2021. David R. Lynch, MD, PhD, professor of neurology, University of Pennsylvania Perelman School of Medicine, discussed why omaveloxolone’s recent success speaks to the progress made within the FA treatment space.

Reata Pharmaceuticals Plans NDA Submission for Omaveloxolone in First Quarter of 2022 Following Completion of Pre-NDA Meeting with FDA

September 30, 2021. PLANO, Texas--(BUSINESS WIRE)--Reata Pharmaceuticals, Inc. (Nasdaq: RETA) (“Reata,” the “Company,” or “we”), a clinical-stage biopharmaceutical company, today announced that it has completed its pre-New Drug Application (“NDA”) meeting with the United States Food and Drug Administration (“FDA”) for omaveloxolone for the treatment of patients with Friedreich’s ataxia and reaffirmed its plan to submit an NDA in the first quarter of 2022.

A mitochondrial membrane-bridging machinery mediates signal transduction of intramitochondrial oxidation

Li Li, Devon M. Conradson, Vinita Bharat, Min Joo Kim, Chung-Han Hsieh, Paras S. Minhas, Amanda M. Papakyrikos, Aarooran Sivakumaran Durairaj, Anthony Ludlam, Katrin I. Andreasson, Linda Partridge, Michael A. Cianfrocco & Xinnan Wang; Nature Metabolism. 2021 Sep;3(9):1242-1258. DOI: 10.1038/s42255-021-00443-2. PMID: 34504353. 

 Cysteine oxidation of MIC60, an inner mitochondrial membrane protein, triggers the formation of disulfide bonds and the physical association of MIC60 with Miro, an outer mitochondrial membrane protein. The oxidative structural change of this membrane-crossing complex ultimately elicits cellular responses that delay mitophagy, impair cellular respiration and cause oxidative stress. Blocking the MIC60–Miro interaction or reducing either protein, genetically or pharmacologically, extends lifespan and health-span of healthy fruit flies, and benefits multiple models of Parkinson’s disease and Friedreich’s ataxia. Our discovery provides a molecular basis for common treatment strategies against oxidative stress.

Adaptation of the heart to Frataxin depletion: Evidence that integrated stress response can predominate over mTORC1 activation

César Vásquez-Trincado, Monika Patel, Aishwarya Sivaramakrishnan, Carmen Bekeová, Lauren Anderson-Pullinger, Nadan Wang, Hsin-Yao Tang, Erin L Seifert, Human Molecular Genetics, 2021;, ddab216, doi:10.1093/hmg/ddab216

Altogether, these findings suggest that the FXN depleted heart can suppress a major ATP demanding process such as protein translation, which, together with some preservation of β-oxidation, could be adaptive, at least in the short term.

Microvascular Breakdown Due to Retinal Neurodegeneration in Ataxias

Christopher A. Turski MD, Gabrielle N. Turski MD, Jennifer Faber MD, Stefan J. Teipel MD, Frank G. Holz MD, Thomas Klockgether MD, Robert P. Finger MD; Mov Disord. (2021), doi:10.1002/mds.28791

These findings demonstrate a distinct pattern of concurrent changes in vessel density of the retinal superficial vascular complex, encompassing the superficial vascular plexus, RPC network and cdONH, and retinal GCL volume, providing new insights into the ongoing degeneration in ataxias. Our findings may have relevance for design of novel therapeutic approaches for ataxias and possibly other neurodegenerative diseases.

The temporal dynamics of the DMN state also correlated with minute-long DMN rsFC

Naeije G, Coquelet N, Wens V, et al. . Human Brain Mapping. 2021 Sep. DOI: 10.1002/hbm.25621. PMID: 34523778. ; This study demonstrates that ASO is the main determinant of alterations in the sub-second dynamics of posterior associative neocortices in FRDA patients and substantiates a direct link between sub-second network activity and functional brain integration over long timescales.

Blood Neurofilament Light Chain in Genetic Ataxia: A Meta-Analysis

Peng L, Wang S, Chen Z, Peng Y, Wang C, Long Z, Peng H, Shi Y, Hou X, Lei L, Wan L, Liu M, Zou G, Shen L, Xia K, Qiu R, Tang B, Ashizawa T, Klockgether T, Jiang H.; Mov Disord. 2021 Sep 14. doi: 10.1002/mds.28783. Epub ahead of print. PMID: 34519102. 

 bNfL can be used as a potential biomarker to predict disease onset, severity, and progression of genetic ataxia. Reference-value setting of bNfL should be divided according to age

Plasma idebenone monitoring in Friedreich's ataxia patients during a long-term follow-up

Paredes-Fuentes AJ, Cesar S, Montero R, Latre C, Genovès J, Martorell L, Cuadras D, Colom H, Pineda M, Del Mar O'Callaghan M, Sarquella-Brugada G, Darling A, Artuch R.; Biomed Pharmacother. 2021 Sep 7;143:112143. doi: 10.1016/j.biopha.2021.112143. Epub ahead of print. PMID: 34507114. 

The large variations observed among the different individuals involved in this study should be considered for optimization of individual dosage regimens.

A translational approach to determine target concentrations of MIN-102 (leriglitazone) to support a Phase II study in Friedreich’s ataxia

S. Poli, L. Rodríguez-Pascau, J. Ros, P. González-Cabo, E. Britti, D. Lynch, G. Pina, S. Pascual, M. Cerrada-Gimenez, D. Eckland, E. Traver, J. Wetering-de-Rooij, M. Martinell, U. Meya, P. Pizcueta.; Mov Disord. 2020; 35 (suppl 1). https://www.mdsabstracts.org/abstract/a-translational-approach-to-determine-target-concentrations-of-min-102-leriglitazone-to-support-a-phase-ii-study-in-friedreichs-ataxia/. Accessed September 7, 2021. 

Target plasma concentrations determined in preclinical studies could be safely achieved in a Phase I study. At these plasma concentrations, CNS target engagement was confirmed in healthy volunteers. This approach has supported the design of the current Phase 2 clinical trial in Friedreich´s Ataxia, and also in other indications.

Mechanisms of impaired mitochondrial homeostasis and NAD+ metabolism in a model of mitochondrial heart disease exhibiting redox active iron accumulation

Chiang S, Braidy N, Maleki S, Lal S, Richardson DR, Huang ML.; Redox Biol. 2021 Jun 10;46:102038. doi: 10.1016/j.redox.2021.102038. Epub ahead of print. PMID: 34416478; PMCID: PMC8379503. 

This investigation examined the muscle creatine kinase conditional frataxin knockout mouse, which closely mimics FA cardiomyopathy, to dissect the mechanisms of dysfunctional mitochondrial homeostasis. Dysfunction of key mitochondrial homeostatic mechanisms were elucidated in the knockout hearts relative to wild-type littermates, namely: (1) mitochondrial proliferation with condensed cristae; (2) impaired NAD+ metabolism due to perturbations in Sirt1 activity and NAD+ salvage; (3) increased mitochondrial biogenesis, fusion and fission; and (4) mitochondrial accumulation of Pink1/Parkin with increased autophagic/mitophagic flux. Immunohistochemistry of FA patients' heart confirmed significantly enhanced expression of markers of mitochondrial biogenesis, fusion/fission and autophagy. These novel findings demonstrate cardiac frataxin-deficiency results in significant changes to metabolic mechanisms critical for mitochondrial homeostasis. This mechanistic dissection provides critical insight, offering the potential for maintaining mitochondrial homeostasis in FA and potentially other cardio-degenerative diseases by implementing innovative treatments targeting mitochondrial homeostasis and NAD+ metabolism.

Retrotope eyes $100m raise for neurodegenerative disease platform

https://www.clinicaltrialsarena.com   27 Aug 2021 California-based Retrotope aims to expand its investor pool as it prepares to potentially go public in the coming years. 

Currently, Retrotope has ongoing trials for RT001 in three of the four most common orphan neurodegenerative diseases— amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP) and Friedreich’s ataxia (FA). The ALS and PSP trials are Phase II, while the FA trial is a Phase II/III potentially IND-enabling study, company president Anil Kumar said.

Determine Range of Tissue Frataxin Concentrations and Other Potential Biomarkers

ClinicalTrials.gov Identifier: NCT05028764, First Posted : August 31, 2021; Sponsor: Larimar Therapeutics, Inc. 

Brief Summary: To examine range of tissue frataxin (FXN) concentrations, specific ribonucleic acids, other proteins and specialized lipids in the buccal cells, blood, and skin cells of normal healthy volunteers without Friedreich's ataxia (FRDA).

Brain Structure and Degeneration Staging in Friedreich Ataxia: MRI Volumetrics from the ENIGMA-Ataxia Working Group

Harding IH, Chopra S, Arrigoni F, Boesch S, Brunetti A, Cocozza S, Corben LA, Deistung A, Delatycki M, Diciotti S, Dogan I, Evangelisti S, França MC Jr, Göricke SL, Georgiou-Karistianis N, Gramegna LL, Henry PG, Hernandez-Castillo CR, Hutter D, Jahanshad N, Joers JM, Lenglet C, Lodi R, Manners DN, Martinez AR, Martinuzzi A, Marzi C, Mascalchi M, Nachbauer W, Pane C, Peruzzo D, Pisharady PK, Pontillo G, Reetz K, Rezende TJ, Romanzetti S, Saccà F, Scherfler C, Schulz JB, Stefani A, Testa C, Thomopoulos SI, Timmann D, Tirelli S, Tonon C, Vavla M, Egan GF, Thompson PM.; Ann Neurol. 2021 Aug 26. doi: 10.1002/ana.26200. Epub ahead of print. PMID: 34435700. 

The brainstem, dentate nucleus region, and superior and inferior cerebellar peduncles showed greatest reductions in volume relative to controls (Cohen's d = 1.5-2.6). Cerebellar grey matter alterations were most pronounced in lobules I-VI (d = 0.8), while cerebral differences occurred most prominently in precentral gyri (d = 0.6) and corticospinal tracts (d = 1.4). Earlier onset age predicted less volume in the motor cerebellum (rmax = 0.35) and peduncles (rmax = 0.36). Disease duration and severity correlated with volume deficits in the dentate nucleus region, brainstem, and superior/inferior cerebellar peduncles (rmax = -0.49); subgrouping showed these to be robust and early features of FRDA, and strong candidates for further biomarker validation. Cerebral white matter abnormalities, particularly in corticospinal pathways, emerge as intermediate disease features. Cerebellar and cerebral grey matter loss, principally targeting motor and sensory systems, preferentially manifests later in the disease course.

Treatment with ROS detoxifying gold quantum clusters alleviates the functional decline in a mouse model of Friedreich ataxia

CHIARA VILLA, MARIELLA LEGATO, ALESSANDRO UMBACH, CHIARA RIGANTI, REBECCA JONES, BEATRICE MARTINI, MARINA BOIDO, CLAUDIO MEDANA, IRENE FACCHINETTI, DARIO BARNI, MILENA PINTO, TANIA ARGUELLO, MARZIA BELICCHI, GIGLIOLA FAGIOLARI, CARLA LIACI, MAURIZIO MOGGIO, RICCARDO RUFFO, CARLOS T. MORAES, ANGELO MONGUZZI, GIORGIO R. MERLO, YVAN TORRENTE; Science Translational Medicine 18 Aug 2021: Vol. 13, Issue 607, eabe1633 DOI: 10.1126/scitranslmed.abe1633 

Patients with Friedreich ataxia (FRDA) present neurological deficits and impaired muscle coordination. Mitochondrial energy conversion and oxidative phosphorylation have been shown to contribute to disease pathophysiology. Now, Villa et al. tested whether gold cluster superstructures (Au8-pXs), previously shown to have antioxidant properties, could be effective in reducing the hallmarks of FRDA in vitro and in vivo. Au8-pXs improved mitochondrial function, rescued autophagy flux, and increased FXN protein expression in mesenchymal stem cells from patients. In vivo, the treatment had therapeutic effects in a mouse mode, suggesting that Au8-pXs might be effective in reducing FRDA symptoms.

Data-derived wearable digital biomarkers predict Frataxin gene expression levels and longitudinal disease progression in Friedreich’s Ataxia

Aldo Faisal, Balasundaram Kadirvelu, Constantinos Gavriel, Sathiji Nageshwaran, Ping Kei Jackson Chan, Stavros Athanasopoulos, Paola Giunti, Valeria Ricotti, Thomas Voit, Richard Festenstein; Research Square; 2021. DOI: 10.21203/rs.3.rs-737100/v1. 

Our wearable digital biomarker can accurately predict for each patient their personal FXN gene expression levels, demonstrating the sensitivity of our approach and the importance of FXN levels in FA. Therefore, our data-derived biomarker approach can not only cross-sectionally predict disease and their gene expression levels but also their longitudinal disease trajectory: it is sensitive and accurate enough to detect disease progression with much fewer subjects or shorter time scales than existing primary endpoints. Our work demonstrates that data-derived wearable biomarkers have the potential to substantially reduce clinical trial durations and a first in-human demonstration of reconstructing FXN gene expression levels from behavioral data alone.

SS-31 efficacy in a mouse model of Friedreich ataxia by upregulation of frataxin expression

Liu Y, Cai J, Shen J, Dong W, Xu L, Fang M, Lin Y, Liu J, Ding Y, Qiao T, Li K.; Hum Mol Genet. 2021 Aug 13:ddab232. doi: 10.1093/hmg/ddab232. Epub ahead of print. PMID: 34387346. 

We found that SS-31 treatment upregulated FXN expression not only at translational levels as observed in cell culture, but also at mRNA levels in vivo. Consequently, mitochondrial morphology and function were greatly improved in all tested tissues. Importantly, our data provided additional evidence that the maintenance of the therapeutic benefits needed continuous drug administration. Taken together, our findings have demonstrated the effectiveness of SS-31 treatment through the upregulation of FXN in vivo and offer guidance of the potential usage in clinical application for FRDA.

CRISPR/Cas9 gene-edited HSPCs for Friedreich’s ataxia

Stephanie Cherqui, PhD, University of California, San Diego, La Jolla, CA, describes a CRISPR/Cas9 gene-edited hematopoietic stem and progenitor cell (HSPC)-based therapy for Friedreich’s ataxia (FRDA)

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

CHICAGO & CAMBRIDGE, Mass.--(BUSINESS WIRE)​; XCUR-FXN 

– Friedreich’s Ataxia 

 The Company hosted a virtual R&D Day on July 15, 2021 to present new and previously unreleased preclinical data and discuss progress with XCUR-FXN: Observed 2-3x fold change in measurable Frataxin protein in the cerebellum and dorsal root ganglia (amongst other important brain and spinal regions) in Pook800J mouse model indicating potential for disease resolution; Showed no adverse, test-related histopathological findings in repeat dose range finding rat study. The Company continues to expect to file for an IND for XCUR-FXN in FA by the end of 2021 and to dose the first human patient in the first half of 2022.

Larimar Therapeutics Reports Second Quarter 2021 Operating and Financial Results

BALA CYNWYD, Pa., Aug. 12, 2021 (GLOBE NEWSWIRE), “We finished the second quarter in a strong financial position and with a compelling clinical data set that demonstrates proof-of-concept for CTI-1601, which to our knowledge is the only clinical-stage candidate designed to address the root cause of Friedreich’s ataxia,” said Carole Ben-Maimon, MD, President and Chief Executive Officer of Larimar. “These positive Phase 1 data along with non-clinical pharmacology data demonstrate proof-of-concept, and CTI-1601’s differentiated mechanism of action helped us to earn a PRIME designation from the European Medicines Agency, providing us with valuable regulatory benefits and important external validation. Looking forward, we continue to collect and analyze data from our 180-day non-human primate toxicology study and remain confident that there is a path forward through the resolution of the CTI-1601 clinical hold and towards the initiation of our Jive open-label extension and pediatric multiple ascending dose trials.”

Reata Pharmaceuticals, Inc. Announces Second Quarter 2021 Financial Results and Provides an Update on Clinical Development Programs

August 09, 2021, PLANO, Texas--(BUSINESS WIRE)--Reata Pharmaceuticals, Inc. (Nasdaq: RETA) (“Reata,” the “Company,” “our,” “us,” or “we”), a clinical-stage biopharmaceutical company, today announced financial results for the quarter ended June 30, 2021, and provided an update on the Company’s business operations and clinical development programs. 

Omaveloxolone in Patients with Friedreich’s Ataxia (“FA”). Based on a communication received from the U.S. Food and Drug Administration (“FDA”) regarding omaveloxolone for the treatment of FA, we withdrew our request for a Type C meeting and requested a pre-NDA meeting with the FDA. The pre-NDA meeting request has been granted, a pre-NDA meeting has been scheduled during the third quarter of this year, and we have submitted briefing materials for the meeting. We recently received a communication from the FDA requesting the estimated date of our New Drug Application (“NDA”) for its planning purposes. We plan to submit the NDA during the first quarter of 2022.

Design Therapeutics Reports GeneTAC™ Portfolio Progress and Second Quarter 2021 Results

CARLSBAD, Calif., Aug. 09, 2021 (GLOBE NEWSWIRE) -- Design Therapeutics, Inc. (Nasdaq: DSGN), a biotechnology company developing treatments for degenerative genetic disorders, today reported recent progress with its portfolio of novel small molecule gene targeted chimeras (GeneTACsTM), as well as business highlights and second quarter 2021 financial results. New Data from IND-enabling Studies with GeneTAC Product Candidate for Friedreich Ataxia (FA) Support Initiation of Clinical Trial in First Half of 2022: Data from IND-enabling studies in rodents and non-human primates showed that multidose systemic administration of the company’s FA GeneTAC was well tolerated and achieved higher concentrations in the CNS (cerebrum, cerebellum, brainstem and spinal cord), heart, and skeletal muscle than needed to restore frataxin (FXN) gene expression. In addition, the company observed that exposure to low nanomolar (nM) concentrations of its FA GeneTAC in neurons and cardiomyocytes derived from FA patient stem cells in in vitro experiments led to robust and durable increases in FXN mRNA, as well as an increase in endogenous protein reaching levels comparable to unaffected individuals.

Diagnostic and Prognostic Value of Cardiovascular Magnetic Resonance in Neuromuscular Cardiomyopathies

Almogheer B, Antonopoulos AS, Azzu A, Al Mohdar S, Vlachopoulos C, Pantazis A, Mohiaddin RH.; Pediatr Cardiol. 2021 Aug 3. doi: 10.1007/s00246-021-02686-y. Epub ahead of print. PMID: 34342696. 

We present data from a unique cohort of NMD patients and provide evidence on the incidence, patterns, and the prognostic value of LGE in NMD-related cardiomyopathy. LGE is variably present in NMD subtypes and correlates with LV remodelling, dysfunction, and clinical outcomes in patients with NMD. The study included retrospective analysis of a cohort of 111 patients with various forms of NMD; mitochondrial: n = 14, Friedreich's ataxia (FA): n = 27, myotonic dystrophy: n = 27, Becker/Duchenne's muscular dystrophy (BMD/DMD): n = 15, Duchenne's carriers: n = 6, other: n = 22.

Un bri d’esperança

Dissabte, 7 agost 2021, El Punt Avui.

L’atàxia de Friedreich provoca problemes de coordinació, força muscular i cor i escurça l’esperança de vida fins als 40 anys. L’objectiu del fàrmac, que ja està en fase clínica, és aturar la progressió d’aquestes malalties o, almenys, alentir-la. “No és el mateix treballar desenvolupant medicaments per a malalties on hi ha moltes opcions terapèutiques que aquí, on si no te’n surts els malalts no tenen res més. La pressió és molt alta però també la motivació”, reflexiona el CEO de Minoryx.

Digital endpoints for self-administered home-based functional assessment in pediatric Friedreich’s ataxia

Arne Mueller, Elaine Paterson, Avery McIntosh, Jens Praestgaard, Mary Bylo, Holger Hoefling, McKenzie Wells, David R. Lynch, Christian Rummey, Michelle L. Krishnan, Meredith Schultz, C. J. Malanga; Ann Clin Transl Neurol. doi:10.1002/acn3.51438

Deploying digital endpoints in home settings is feasible in this population, results in meaningful and robust data collection, and may allow for frequent sampling over longer periods of time to track disease progression. Care must be taken when training participants, and investigators should consider the complexity of the tasks and equipment used.

The Role of Voltage-Dependent Anion Channel in Mitochondrial Dysfunction and Human Disease

Varughese J, Buchanan S, Pitt A., Cells. 2021 Jul;10(7). PMCID: PMC8305817 doi:10.3390/cells10071737

The voltage-dependent anion channel (VDAC) is a β-barrel membrane protein located in the outer mitochondrial membrane (OMM). VDAC has two conductance states: an open anion selective state, and a closed and slightly cation-selective state. VDAC conductance states play major roles in regulating permeability of ATP/ADP, regulation of calcium homeostasis, calcium flux within ER-mitochondria contact sites, and apoptotic signaling events. Three reported structures of VDAC provide information on the VDAC open state via X-ray crystallography and nuclear magnetic resonance (NMR). Together, these structures provide insight on how VDAC aids metabolite transport. The interaction partners of VDAC, together with the permeability of the pore, affect the molecular pathology of diseases including Parkinson’s disease (PD), Friedreich’s ataxia (FA), lupus, and cancer.

Determining the Validity of Conducting Rating Scales in Friedreich Ataxia through Video

Tai, G., Corben, L.A., Woodcock, I.R., Yiu, E.M. and Delatycki, M.B. (2021); Mov Disord Clin Pract, 8: 688-693. doi:10.1002/mdc3.13204 

Excellent test–retest reliability was demonstrated in the majority of the mFARS sections, and in the total mFARS and SARA scores, suggesting that video is a valid method of conducting these scales. This method enables inclusion of participants who are unable to travel to study sites. A larger cohort will be required to further validate the use of video mFARS and SARA for future studies.

Polyuria and Acute Hyperglycemia Secondary to New-Onset Diabetes in a Young Woman With Friedreich’s Ataxia

Santos J, Woloski J R, Wu N (June 29, 2021); Cureus 13(6): e16032. doi:10.7759/cureus.16032 

Diabetes is a common complication in patients with FRDA and should be routinely screened for by healthcare providers, preferably via an OGTT. Treatment of diabetes can be challenging due to neurodegenerative symptoms that may interfere with the ability to self-administer insulin. Additionally, close follow-up with cardiology is important to monitor for any signs or symptoms of cardiomyopathy, especially after the initiation of diabetes medications. Once diabetes is diagnosed, an individualized treatment plan along with efficient coordination of care is essential for successful diabetes management in patients with FRDA.

Cardiac Involvement in Movement Disorders

Rossi M, Wainsztein N, Merello M.; Mov Disord Clin Pract. 2021 Apr 7;8(5):651-668. doi: 10.1002/mdc3.13188. PMID: 34307738; PMCID: PMC8287161.

As cardiac disease is part of the phenotypic spectrum of several movement disorders, heart involvement should be carefully investigated and increased awareness of this association encouraged as it may represent a leading cause of morbidity and mortality.

Neuro-Ophthalmological Findings in Friedreich’s Ataxia

Rojas, P.; de Hoz, R.; Cadena, M.; Salobrar-García, E.; Fernández-Albarral, J.A.; López-Cuenca, I.; Elvira-Hurtado, L.; Urcelay-Segura, J.L.; Salazar, J.J.; Ramírez, J.M.; Ramírez, A.I.; J. Pers. Med. 2021, 11, 708. doi:10.3390/jpm11080708 

Although most patients with FRDA do not present with symptomatic visual impairment, 73% present with clinical neuro-ophthalmological alterations such as optic atrophy and altered eye movement, among others. This review provides a brief overview of the main aspects of FRDA and then focuses on the ocular involvement of this pathology and the possible use of retinal biomarkers.

Very late-onset Friedreich’s ataxia with rapid course mimicking as possible multiple system atrophy cerebellar type

Tushar Ashok Vidhale, Hemant R Gupta, Rohan PJ and Charmi Gandhi; BMJ Case Reports CP 2021;14:e242073, doi:10.1136/bcr-2021-242073 

This 55-year-old man was admitted to the hospital with an insidious onset, progressive backward fall (due to severe truncal ataxia), dysarthria, stiffness in extremities, distal dominant muscle wasting along with behavioural changes and urinary incontinence. Clinical assessment indicated mild cognitive decline (Mini-Mental State Examination 22/27) with cerebellar, pyramidal and peripheral nerves involvement. On investigations, nerve conduction studies revealed symmetrical, sensorimotor peripheral neuropathy affecting both lower limbs. Brain and whole spine MRI revealed widespread cerebral and mild cerebellar atrophy, pons and medulla volume loss, and a normal spinal cord. Transthoracic echocardiography revealed concentric left ventricular hypertrophy. His gene analysis revealed eight GAA repeats on allele 1, and 37 GAA repeats on allele 2 in the first intron of the frataxin gene. Considering his clinical profile and genetic analysis, he was diagnosed as a case of very late-onset Friedreich’s ataxia with likely compound heterozygous genotype.

A Study to Assess Efficacy, Long Term Safety and Tolerability of RT001 in Subjects With Friedreich's Ataxia

UCLA Health, NCT No. NCT04102501; Phase 3 

 The purpose of this study is to assess the Efficacy, Long Term Safety and Tolerability of RT001 in subjects with Friedreich's Ataxia 

 Open Actively Recruiting

Rare occurrence of severe blindness and deafness in Friedreich ataxia: a case report

Joana Damásio, Ana Sardoeira, Maria Araújo, Isabel Carvalho, Jorge Sequeiros & José Barros; Cerebellum & Ataxias volume 8, Article number: 17 (2021) doi:10.1186/s40673-021-00140-6 

With this report we wish to further contribute to the characterization of optic and auditory involvement in FRDA, stress the need to better understand the underlying mechanisms, as well as their genetic and epigenetic modifying factors (including somatic heterogeneity); and increase awareness for this rare extreme phenotype. Improved healthcare services and longer survival of early-onset patients will probably increase the frequency of these devastating manifestations.

Gene therapies and COVID-19 vaccines: a necessary discussion in relation with viral vector-based approaches

Angel Aledo-Serrano, Antonio Gil-Nagel, Julian Isla, Ana Mingorance, Fernando Mendez-Hermida & Ruben Hernandez-Alcoceba; Orphanet J Rare Dis 16, 316 (2021). doi:10.1186/s13023-021-01958-3 

 In conclusion, the potential interference between gene therapy and virus-based vaccines deserves a careful consideration and discussion involving the patient community. This is a adequate moment to do so, since current vaccine candidates are not expected to cause such interference. Should people with monogenic diseases preferentially receive, or be given the option to be immunized COVID-19 vaccines based on non-viral platforms, such as the mRNA vaccines? A careful consideration of the impact on the use of vectors for vaccine production and the plausible negative impact in the development of suitable gene therapy medicinal products, should be on top of the scientific and regulatory table discussion in order to facilitate access to patients suffering monogenic diseases and also prevent unnecessary delays in future vector vaccines development.

Myocardial Perfusion Reserve in Children with Friedreich Ataxia

Hutchens JA, Johnson TR, Payne RM.; Pediatric Cardiology. 2021 Jul. DOI: 10.1007/s00246-021-02675-1. 

This retrospective study shows that children with FA develop MPR defects early in the disease process. It also suggests MPR may be a sensitive tool to evaluate underlying cardiac compromise and could be of use in directing surgical management decisions in children with FA.

Interruptions of the FXN GAA Repeat Tract Delay the Age at Onset of Friedreich’s Ataxia in a Location Dependent Manner

Nethisinghe, S.; Kesavan, M.; Ging, H.; Labrum, R.; Polke, J.M.; Islam, S.; Garcia-Moreno, H.; Callaghan, M.F.; Cavalcanti, F.; Pook, M.A.; Giunti, P. Int. J. Mol. Sci. 2021, 22, 7507. doi:10.3390/ijms22147507 

The GAA repeat tract in some cases may be impure with sequence variations called interruptions. It has previously been observed that large interruptions of the GAA repeat tract, determined by abnormal MboII digestion, are very rare. Here we have used triplet repeat primed PCR (TP PCR) assays to identify small interruptions at the 5′ and 3′ ends of the GAA repeat tract through alterations in the electropherogram trace signal. We found that contrary to large interruptions, small interruptions are more common, with 3′ interruptions being most frequent. Based on detection of interruptions by TP PCR assay, the patient cohort (n = 101) was stratified into four groups: 5′ interruption, 3′ interruption, both 5′ and 3′ interruptions or lacking interruption. Those patients with 3′ interruptions were associated with shorter GAA1 repeat tracts and later ages at disease onset. The age at disease onset was modelled by a group-specific exponential decay model. Based on this modelling, a 3′ interruption is predicted to delay disease onset by approximately 9 years relative to those lacking 5′ and 3′ interruptions. This highlights the key role of interruptions at the 3′ end of the GAA repeat tract in modulating the disease phenotype and its impact on prognosis for the patient.

Would Francisco Soca have been the first to relate toe phenomenon as pyramidal disorders?

élio A.G. Teive, Carlos Henrique F. Camargo, Nicolás Sommaruga, Héctor Ignacio Amorin-Costábile, Olivier Walusinski; Journal of Clinical Neuroscience, Volume 91, 2021, Pages 172-175, doi:10.1016/j.jocn.2021.07.013. 

 The Uruguayan physician Francisco Soca, who specialized in neurology in Jean-Martin Charcot’s clinic, defended a thesis at the Paris Faculty of Medicine in 1888 on Friedreich's ataxia in eleven patients. In this work he described the presence of toe phenomenon. In the late 1800s Soca completed a specialization in neurology at the service run by Charcot in Paris. He defended an important thesis in 1888 assessing data from 11 Friedreich’s ataxia. In his thesis, Soca also described the toe phenomenon and the presence of structural changes in the feet of these patients that were not described in the Friedreich study published in 1863. The Soca’s thesis contained the description of toe extension associated with pyramidal tract lesions, eight years later described and further immortalized as Babiński's sign. Therefore, Soca had already publicized this sign as being representative of a pyramidal dysfunction before Babiński or any other neurologist.

A systematic review of moral reasons on orphan drug reimbursement

Zimmermann, B.M., Eichinger, J. & Baumgartner, M.R.; Orphanet J Rare Dis 16, 292 (2021). doi:10.1186/s13023-021-01925-y This study aims to provide a systematic analysis of moral reasons for and against such a special status for the reimbursement of OMPs in publicly funded healthcare systems from a multidisciplinary perspective. 

Results suggest that OMP reimbursement issues should be assessed and analysed from a multidisciplinary perspective. Despite the higher occurrence of reasons and articles in favour of a special status, there is no clear-cut solution for this ethical challenge. The binary perspective of whether or not OMPs should be granted special status oversimplifies the issue: both OMPs and rare diseases are too heterogeneous in their characteristics for such a binary perspective. Thus, the scientific debate should focus less on the question of disease prevalence but rather on how the important variability of different OMPs concerning e.g. target population, cost-effectiveness, level of evidence or mechanism of action could be meaningfully addressed and implemented in Health Technology Assessments.

Stealth BioTherapeutics Joins the Rare Disease Company Coalition

BOSTON, July 7, 2021 /PRNewswire/ -- Stealth BioTherapeutics Corp (Nasdaq: MITO). 

The Coalition will engage with policy stakeholders to advocate for impactful drug and healthcare policies and regulations currently under discussion, including prescription drug pricing, to highlight the consequences that blanket legislation can have on continued innovation for rare disease treatments.

The Cost of Living with Inherited Ataxia in Ireland

Mark J. Kelly, Petya Bogdanova-Mihaylova, Joshua Skeens, Sharon Moran, Sorcha Farrelly, Richard A. Walsh & Sinéad M. Murphy. Cerebellum (2021). doi:10.1007/s12311-021-01271-6 

Inherited ataxias carry high financial costs to the health system, patients, caregivers and society as a whole. Costs are similar between FRDA and other forms of inherited ataxia and grow as disability increases over the course of the illness. Indirect costs or ‘productivity losses’ make up half the COI and place a significant financial burden on patients. Despite this, there is evidence to suggest that certain clinical standards of care such as frequency of clinician review, OHP input and monitoring investigations are not being met, possibly reflecting the limited availability of resources. The results of this study advocate the need for greater funding in inherited ataxia care in Ireland to ease the financial burden on patients and improve resource availability.

Clinical trials: regulators’ inaction has left EU registry “riddled with inaccurate and missing data”

BMJ 2021; 374 doi: doi:10.1136/bmj.n1707 (Published 05 July 2021), Cite this as: BMJ 2021;374:n1707 

 Nearly 6000 clinical trial results are currently missing from the European trial registry, despite transparency rules requiring countries to upload results within 12 months of trial completion, a report has found. 

 Researchers from the University of Oxford said the findings show that medicines regulators in the 14 European countries included in the report have failed to ensure that important data on new drugs and vaccines are rapidly and consistently made public. 

 The report, published 5 July, found that the largest gaps were in Italy (1221 results missing), Spain (884), the Netherlands (839), France (698), and Germany (554).

Identifying the most potent and effective treatment of Friedreich ataxia

Brunel University London, Dr Mark Pook. 

This project aims to identify the most potent and effective known drugs to investigate treatment of the inherited disease, Friedreich ataxia, motivating pharma to fund more clinical trials. 

This international collaborative project between the Cortopassi, Giunti and Pook laboratories aims to test a number of differently-acting drug compounds to identify the most potent and effective known drugs to address Friedreich ataxia.

Molecular Details of the Frataxin-Scaffold Interaction during Mitochondrial Fe-S Cluster Assembly

Campbell CJ, Pall AE, Naik AR, Thompson LN, Stemmler TL.; Int J Mol Sci. 2021 Jun 2;22(11):6006. doi: 10.3390/ijms22116006. 

These details support a complex dynamic interaction between the FXN and ISCU proteins when both are part of the NIAUF complex and this provides additional insight into the coordinated mechanism of Fe-S cluster assembly.

Clinical Ethics Consultation in Neurology – a case series

Benjamin Ilse, Bernd Alt-Epping, Albrecht Günther, Jan Liman & Alfred Simon; BMC Neurol 21, 216 (2021). doi:10.1186/s12883-021-02244-2 

The concept of clinical ethics consultation (CECs) was implemented to provide support in ethical controversies in clinical settings and are offered in at least every second hospital in Germany. Neurological disorders often require complex decision-making. The aims of this study were to determine which situations lead to CEC in neurology and to investigate the influence of the individual patient’s wishes on the recommendation.

Friedreich's ataxia researcher Associate Professor Mirella Dottori has received a funding boost

JULY 2 2021, Associate Professor Mirella Dottori, a researcher at the University of Wollongong will receive $982,861 over three years from the Medical Research Future Fund (MRFF) and National Health and Medical Research Council (NHMRC) for her ground-breaking research into Friedreich's ataxia.

 

LEXEO Therapeutics Receives Rare Pediatric Disease Designation and Orphan Drug Designation for LX2006 for the Treatment of Friedreich’s Ataxia

NEW YORK, June 30, 2021 (GLOBE NEWSWIRE) -- LEXEO Therapeutics, a clinical-stage gene therapy company, today announced that the U.S. Food and Drug Administration (FDA) has granted Rare Pediatric Disease designation and Orphan Drug designation to LX2006 for the treatment of Friedreich’s ataxia (FA). LX2006 is an IV-administered, adeno-associated virus (AAV)-mediated gene therapy encoding the human frataxin gene. The designations granted to LX2006 cover cardiac disease and broader symptoms associated with FA.

LEXEO plans to initiate a Phase I/II clinical trial of LX2006 in patients with cardiomyopathy associated with FA in 2021.

Generation of transgene-free iPSC lines from three patients with Friedreich’s ataxia (FRDA) carrying GAA triplet expansions in the first intron of FXN gene

Simge Kelekçi, Deniz Uğurlu-Çimen, Deniz Ata, Burcu Özçimen, Abdullah Burak Yıldız, Mehmet Batuhan Karakuş, Esra Börklü Yücel, Tamer T. Önder, Stem Cell Research, 2021, 102438, doi:10.1016/j.scr.2021.102438. 

In this present study, we generated induced pluripotent stem cells (iPSC) lines from fibroblasts of three unrelated FRDA patients using integration-free episomal vectors. All iPSC lines express the pluripotency markers such as OCT4 and SSEA4, display normal karyotypes and can differentiate into all three germ layers via in vivo teratoma formation assay.

Friedreich Ataxia: Multidisciplinary Clinical Care

Lynch DR, Schadt K, Kichula E, McCormack S, Lin KY., J Multidiscip Healthc 2021;14:1645-1658 doi:10.2147/JMDH.S292945 

This review provides a summary of the diverse manifestation of FRDA, existing symptomatic therapies, and approaches for integrative care for future therapy in FRDA.

The cardiomyopathy of Friedreich's ataxia common in a family: A case report

Amini O, Lakziyan R, Abavisani M, Sarchahi Z. Ann Med Surg (Lond). 2021 May 24;66:102408. doi: 10.1016/j.amsu.2021.102408. 

Because early diagnosis of the disease is difficult, clinical signs and the patient's current profile at the time of referral will be very helpful.

New biotech kid on the block making news

June 17, 2021. Capsida Biotherapeutics, a Newbury Park-based startup that recently raised $140 million in Series A funding, is partnering with a high-profile biotech company to develop treatment for Lou Gehrig’s disease (amyotrophic lateral sclerosis) and Friedreich’s ataxia, another neurodegenerative disease. CRISPR, a publicly traded company valued at around $9 billion, will lead the Friedreich’s ataxia program, and Capsida will lead the ALS program. Should their efforts be successful, the companies would equally share all research, development and commercialization costs and profits worldwide related to the collaboration product, according to the release.

Inicio Ronda de Inversión Biointaxis con Capital Cell

06.17.2021. Biointaxis es una spin-off biotecnológica surgida del Instituto de Investigación Germans Trias i Pujol (IGTP) y del grupo farmacéutico multinacional Gentec S.A. en 2018 establecida en el campus de Can Ruti de Badalona.

Nuestro objetivo en Biointaxis es llevar el fármaco de terapia génica BTX-101 que ha demostrado unos perfiles de seguridad y eficacia excelentes en 2 modelos de ratón de la enfermedad, uno crónico y otro agudo, al tratamiento curativo del paciente con Ataxia de Friedreich. La ataxia de Friedreich es una enfermedad hereditaria actualmente incurable que está causada por los déficits de la proteína frataxina. Con esta ronda de inversión Biointaxis con Capital Cell demostrará la seguridad y biodistribución adecuadas en primates no humanos para solicitar a la Agencia Europea del Medicamento su autorización para la fase clínica en pacientes con la enfermedad.

CRISPR Therapeutics and Capsida Biotherapeutics Announce Strategic Collaboration to Develop Gene-Edited Therapies for Amyotrophic Lateral Sclerosis and Friedreich’s Ataxia

ZUG, Switzerland and CAMBRIDGE, Mass. and THOUSAND OAKS, Calif., June 15, 2021 (GLOBE NEWSWIRE) -- CRISPR Therapeutics (Nasdaq: CRSP), a biopharmaceutical company focused on developing transformative gene-based medicines for serious diseases, and Capsida Biotherapeutics Inc., a biotechnology company dedicated to developing breakthrough gene therapies using fully integrated adeno-associated virus (AAV) engineering, cargo development and manufacturing, today announced a strategic partnership to research, develop, manufacture and commercialize in vivo gene editing therapies delivered with engineered AAV vectors for the treatment of familial amyotrophic lateral sclerosis (ALS) and Friedreich’s ataxia.

A pathogenic role for histone H3 copper reductase activity in a yeast model of Friedreich's Ataxia

Oscar A Campos, Narsis Attar, Nathan V Mallipeddi, Chen Cheng, Maria Vogelauer, Stefan Schmollinger, Sabeeha S Merchant, Siavash K Kurdistani; bioRxiv 2021.06.14.448268; doi:10.1101/2021.06.14.448268 

Campos OA, Attar N, Cheng C, Vogelauer M, Mallipeddi NV, Schmollinger S, Matulionis N, Christofk HR, Merchant SS, Kurdistani SK. A pathogenic role for histone H3 copper reductase activity in a yeast model of Friedreich's ataxia. Sci Adv. 2021 Dec 17;7(51):eabj9889. doi: 10.1126/sciadv.abj9889. Epub 2021 Dec 17.

Disruptions to iron-sulfur (Fe-S) clusters, essential cofactors for a broad range of proteins, cause widespread cellular defects resulting in human disease. An underappreciated source of damage to Fe-S clusters are cuprous (Cu1+) ions. Since histone H3 enzymatically produces Cu1+ to support copper-dependent functions, we asked whether this activity could become detrimental to Fe-S clusters. Here, we report that histone H3-mediated Cu1+ toxicity is a major determinant of cellular Fe-S cluster quotient. Inadequate Fe-S cluster supply, either due to diminished assembly as occurs in Friedreich's Ataxia or defective distribution, causes severe metabolic and growth defects in S. cerevisiae. Decreasing Cu1+ abundance, through attenuation of histone cupric reductase activity or depletion of total cellular copper, restored Fe-S cluster-dependent metabolism and growth. Our findings reveal a novel interplay between chromatin and mitochondria in Fe-S cluster homeostasis, and a potential pathogenic role for histone enzyme activity and Cu1+ in diseases with Fe-S cluster dysfunction.

Evaluation of the Effect of Artesunate in Friedreich Ataxia (FA) (ARTEMIS)

ClinicalTrials.gov Identifier: NCT04921930; Sponsor: Institut National de la Santé Et de la Recherche Médicale, France Collaborator: Imagine Institute 

This dose-escalation study is aimed at investigating a novel application for artesunate in the treatment of Friedreich ataxia. It will evaluate this novel application of oral artesunate using a surrogate biological marker as primary endpoint in a phase I-II open trial.

Automatic speech recognition in neurodegenerative disease

Authors: Benjamin G. Schultz, Venkata S. Aditya Tarigoppula, Gustavo Noffs, Sandra Rojas, Anneke van der Walt, David B. Grayden, Adam P. Vogel; International Journal of Speech Technology, doi:10.1007/s10772-021-09836-w 

Automatic speech recognition (ASR) could potentially improve communication by providing transcriptions of speech in real time. ASR is particularly useful for people with progressive disorders that lead to reduced speech intelligibility or difficulties performing motor tasks. ASR services are usually trained on healthy speech and may not be optimized for impaired speech, creating a barrier for accessing augmented assistance devices. We tested the performance of three state-of-the-art ASR platforms on two groups of people with neurodegenerative disease and healthy controls. We further examined individual differences that may explain errors in ASR services within groups, such as age and sex. Speakers were recorded while reading a standard text. Speech was elicited from individuals with multiple sclerosis, Friedreich’s ataxia, and healthy controls. Recordings were manually transcribed and compared to ASR transcriptions using Amazon Web Services, Google Cloud, and IBM Watson.

Blindness and Deafness – an Extreme Phenotype in Friedreich Ataxia

Joana Damásio, Ana Sardoeira, Maria Araújo, Isabel Carvalho, Jorge Sequeiros, José Barros; Research Square; 2021. DOI: 10.21203/rs.3.rs-573040/v1. 

Severe vision loss and extreme deafness has been described in very few patients with Friedreich ataxia. Long duration, severe disease and large expanded alleles may account for such an extreme phenotype; nonetheless, the role of factors as modifying genes warrants further investigation in this subset of patients.

Luz verde a un ensayo clínico con calcitriol para validar su potencial terapéutico para tratar la Ataxia de Friedreich

Comunicación y Prensa IRBLleida; Lunes, 7 de junio de 2021

Un ensayo clínico podría validar el uso del calcitriol, la forma activa de la vitamina D, para tratar la Ataxia de Friedreich, tal como propone el grupo de investigación Bioquímica del Estrés Oxidativo del Instituto de Investigación Biomédica de Lleida (IRBLleida) y la Universidad de Lleida (UdL). Su investigación es la base de este ensayo que realizarán la Unidad de Ataxias del Hospital Josep Trueta de Girona y del Hospital Santa Caterina del Parc Hospitalari Martí i Julià de Salt conjuntamente con el Instituto de Investigación Biomédica de Girona (IDIBGI).

A clinical trial with calcitriol has begun to validate its therapeutic potential for treating Friedreich's Ataxia

Biotech-spain.com; 07/06/2021 

A clinical trial could validate the use of calcitriol, the active form of vitamin D, to treat Friedreich's Ataxia, as proposed by the Biochemistry of Oxidative Stress Group at the Biomedical Research Institute of Lleida (IRBLleida) and the University of Lleida (UdL). Their research is the basis of this trial to be carried out by the Ataxia Unit of the Josep Trueta Hospital in Girona and the Santa Caterina Hospital of the Parc Hospitalari Martí i Julià de Salt in conjunction with the Institute for Research in Biomedicine of Girona (IDIBGI).

6 Clinical presentation and outcomes of childhood hypertrophic cardiomyopathy associated with friedreich’s ataxia: a national cohort study

Rance T, Norrish G; Heart 2021;107:A5. doi:10.1136/heartjnl-2021-BCS.

This national study of childhood FA-HCM is the largest cohort reported to date and describes a high prevalence of atrial arrhythmias and early progression to end-stage disease. Overall mortality is similar to that reported in non-syndromic childhood HCM but no patients died suddenly.

Quantitative Assessment of Friedreich Ataxia via Self-Drinking Activity

R. Krishna, P. N. Pathirana, M. K. Horne, L. A. Corben and D. J. Szmulewicz; IEEE Journal of Biomedical and Health Informatics, vol. 25, no. 6, pp. 1985-1996, June 2021, doi: 10.1109/JBHI.2021.3069007. 

Effective monitoring of the progression of neurodegenerative conditions can be significantly improved by objective assessments. Clinical assessments of conditions such as Friedreich's Ataxia (FA), currently rely on subjective measures commonly practiced in clinics as well as the ability of the affected individual to perform conventional tests of the neurological examination. In this study, we propose an ataxia measuring device, in the form of a pressure canister capable of sensing certain kinetic and kinematic parameters of interest to quantify the impairment levels of participants particularly when engaged in an activity that is closely associated with daily living. In particular, the functional task of simulated drinking was utilised to capture characteristic features of disability manifestation in terms of diagnosis (separation of individuals with FA and controls) and severity assessment of individuals diagnosed with the debilitating condition of FA. Time and frequency domain analysis of these biomarkers enabled the classification of individuals with FA and control subjects to reach an accuracy of 98% and a correlation level reaching 96% with the clinical scores.

Coexistence of Tyrosinemia and Friedreich Ataxia in a Single Patient: Treatment with Liver Transplantation

Diya Cherian, Kimberly Schadt, Courtney Park, Stephanie Veasey, David Goldberg, David Lynch; Ann Case Report 6: 581. DOI: 10.29011/2574-7754.100581

Here we describe a young woman with coincidental presence of both FRDA and HT1, focusing on possible interactions between HT1 and FRDA, as well as her treatment by liver transplantation.

Rescue of central and peripheral neurological phenotype of friedreich's ataxia by intravenous delivery

Application US16/651,617- Assigned to VOYAGER THERAPEUTICS, INC. 

Described herein are compositions and methods for treating Friedreich's Ataxia (FA) using adeno-associated virus (AAV) to deliver therapeutics agents.

AavantiBio lands manufacturing partner in Friedreich's Ataxia program; NC Research Triangle lands another CDMO

June 3, 2021. ENDPOINTNEWS. AavantiBio and Resilience have announced a collaboration to manufacture a pipeline of therapies, including AavantiBio’s Friedreich’s Ataxia program, the company announced Thursday. 

The new facility will double its existing footprint, and support development, clinical and small-scale commercial manufacturing. The site is just a few miles from its current office, and will meet all FDA, EMA and GMP requirements, the company said.

FARA FA Pipeline Webinar - Jun 2, 2021

Molecular Details of the Frataxin–Scaffold Interaction during Mitochondrial Fe–S Cluster Assembly

Campbell, C.J.; Pall, A.E.; Naik, A.R.; Thompson, L.N.; Stemmler, T.L.; Int. J. Mol. Sci. 2021, 22, 6006. doi:10.3390/ijms22116006

Molecular Details of the Frataxin–Scaffold Interaction during Mitochondrial Fe–S Cluster Assembly

Results of a randomized double-blind study evaluating luvadaxistat in adults with Friedreich ataxia

Hao Wang, Jonathan Norton, Lin Xu, Nicholas DeMartinis, Rohini Sen, Ankit Shah, Jennifer Farmer, David Lynch; Annals of Clinical and Translational Neurology. 2021 May. DOI: 10.1002/acn3.51373.

Luvadaxistat (also known as TAK-831; NBI-1065844) was safe and well tolerated in this cohort of adults with FRDA; however, it did not demonstrate efficacy as a treatment for this condition.

SAFETY AND EFFICACY OF THE STEM CELL TRANSPLANTATION IN FRIEDREICH’S ATAXIA: A REPORT OF THREE CASES

Riza Azeri, Duygu Koyuncu Irmak, Eda Sun, Erdal Karaöz; Int J Physiother. Vol 8(1), 31-35, February (2021) doi:10.15621/ijphy/2021/v8i1/903 

Case Summary: Here, we report three FRDA cases treated with four consecutive allogeneic transplantations of umbilical cord-derived MSCs with 30 days interval, upon per patient regulatory approvals for advanced cellular therapy. Outcome Measures: The cases were followed up after the treatment in means of the therapeutic effect of the cellular treatment by attenuating the neurological findings and gene expression parameters. Conclusions: Closely followed promising safety and efficacy outcomes demonstrated that the MSC treatment for FRDA might positively affect the clinical results caused by the defect in this genetic-based disease.

An unusual combination of large Eustachian valve in a young patient with Friedreich's ataxia cardiomyopathy

Stylianos A. Karvounaris, Georgios S. Papaetis, Petros P. Mavrommatis; Cardiol J 2021;28(3):498-499. DOI: 10.5603/CJ.2021.0051 According to available research this is the first published description of a large Eustachian valve in a patient with FA-CM.

Gene therapy in PIDs, hemoglobin, ocular, neurodegenerative, and hemophilia B disorders

Odiba AS, Okoro NO, Durojaye OA, Wu Y., Open Life Sciences. 2021 ;16(1):431-441. DOI: 10.1515/biol-2021-0033.

Molecular biology and biotechnology tools remained important elements in gene therapy. Gene editing/modification (replacement, insertion, and deletion) largely characterizes this field of biological sciences. The idea of gene therapy was implemented clinically about three decades ago as an alternative to the limitations of pharmacotherapy. Approximately 3,000 known clinical trials are on record. Some limitations are associated with gene therapy; and hence, the need to improve on the current strategies. This has resulted in sophisticated tools using viral and nonviral vectors. Although most of the gene therapy studies are directed toward cancer worldwide, other areas of notable disease require the gene therapy approach; and these include primary immunodeficiency disorders (PIDs), hemoglobin, hemophilia B, ocular, and neurodegenerative disorders.

Mitochondrial and metabolic dysfunction in Friedreich ataxia: update on pathophysiological relevance and clinical interventions

David R. Lynch, Garrett Farmer; Mitochondrial and metabolic dysfunction in Friedreich ataxia: update on pathophysiological relevance and clinical interventions. Neuronal Signal 25 June 2021; 5 (2): NS20200093. doi: doi:10.1042/NS20200093

Friedreich ataxia (FRDA) is a recessive disorder resulting from relative deficiency of the mitochondrial protein frataxin. Frataxin functions in the process of iron–sulfur (Fe–S) cluster synthesis. In this review, we update some of the processes downstream of frataxin deficiency that may mediate the pathophysiology. Based on cellular models, in vivo models and observations of patients, ferroptosis may play a major role in the pathogenesis of FRDA along with depletion of antioxidant reserves and abnormalities of mitochondrial biogenesis. Ongoing clinical trials with ferroptosis inhibitors and nuclear factor erythroid 2-related factor 2 (Nrf2) activators are now targeting each of the processes. In addition, better understanding of the mitochondrial events in FRDA may allow the development of improved imaging methodology for assessing the disorder. Though not technologically feasible at present, metabolic imaging approaches may provide a direct methodology to understand the mitochondrial changes occurring in FRDA and provide a methodology to monitor upcoming trials of frataxin restoration.

The Oxford-Harrington Rare Disease Centre initiates first disease priority area: Friedreich’s Ataxia

27 May 2021, The Oxford-Harrington Rare Disease Centre is redoubling efforts to develop a therapeutics programme for Friedreich’s Ataxia.

OHC will be building on the long history of important contributions to the FA field by Oxford researchers. As a first step in this new journey, with the support of EndFA, a philanthropic partner focused on FA, the OHC has recruited a new Research Facilitator in Friedreich’s Ataxia. Dr Geoffrey Denwood joined the OHC at the University of Oxford site in April 2021, and will dedicate his time and expertise into coordinating the activities of the OHC in FA. Dr Denwood will evaluate the current status of FA translational research and therapeutics development locally and globally, then work to fund and implement an OHC programme harnessing the best expertise and most promising therapeutic opportunities.

Iron-sulfur cluster deficiency can be sensed by IRP2 and regulates iron homeostasis and sensitivity to ferroptosis independent of IRP1 and FBXL5

ERDEM M. TERZI, VLADISLAV O. SVIDERSKIY, SAMANTHA W. ALVAREZ, GABRIELLE C. WHITEN, RICHARD POSSEMATO; Science Advances 26 May 2021: Vol. 7, no. 22, eabg4302, DOI: 10.1126/sciadv.abg4302 

Intracellular iron levels are strictly regulated to support homeostasis and avoid iron-mediated ROS production. Loss of iron-sulfur cluster (ISC) synthesis can increase iron loading and promote cell death by ferroptosis. Iron-responsive element-binding proteins IRP1 and IRP2 posttranscriptionally regulate iron homeostasis. IRP1 binding to target mRNAs is competitively regulated by ISC occupancy. However, IRP2 is principally thought to be regulated at the protein level via E3 ubiquitin ligase FBXL5–mediated degradation. Here, we show that ISC synthesis suppression can activate IRP2 and promote ferroptosis sensitivity via a previously unidentified mechanism. At tissue-level O2 concentrations, ISC deficiency enhances IRP2 binding to target mRNAs independent of IRP1, FBXL5, and changes in IRP2 protein level. Deletion of both IRP1 and IRP2 abolishes the iron-starvation response, preventing its activation by ISC synthesis inhibition. These findings will inform strategies to manipulate ferroptosis sensitivity and help illuminate the mechanism underlying ISC biosynthesis disorders, such as Friedreich’s ataxia.

Larimar Therapeutics Reports FDA Clinical Hold on CTI-1601 and Termination of Recently Announced Private Placement Financing

BALA CYNWYD, Pa., May 25, 2021 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (“Larimar”) (Nasdaq: LRMR), a clinical-stage biotechnology company focused on developing treatments for Friedreich’s ataxia (FA) and other complex rare diseases, today announced that the United States Food and Drug Administration (FDA) has placed a clinical hold on the CTI-1601 clinical program and that the company will not be closing a previously announced private placement financing. 

The clinical hold follows the previous notification by Larimar to the FDA of mortalities which occurred at the highest dose levels in an ongoing 180-day non-human primate (NHP) toxicology study, which is designed to support extended dosing of patients with CTI-1601. 

In the clinical hold letter, the FDA stated it needs a full study report from the ongoing NHP study and 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.

Generation of a Friedreich’s Ataxia patient-derived iPSC line USFi001-A

Mariana Burgos Angulo, Jiajia Yang, Mariana A. Argenziano, Alexander C. Bertalovitz, Maliheh Najari Beidokhti, Thomas V. McDonald; Stem Cell Research, Volume 54, 2021, 102399, doi:10.1016/j.scr.2021.102399. 

We generated an induced pluripotent stem cell (iPSC) line from an FA patient with a homozygous GAA expansion in intron 1 of the FXN gene. The IPSCs display pluripotent cell morphology, expression of pluripotency markers, normal karyotype, and the capability to differentiate into all three germ layers.

Larimar Therapeutics Announces $95 Million Private Placement Financing

BALA CYNWYD, Pa., May 21, 2021 (GLOBE NEWSWIRE) -- Larimar Therapeutics (“Larimar”) (Nasdaq: LRMR), a clinical-stage biotechnology company focused on developing treatments for Friedreich’s ataxia (FA) and other complex rare diseases, today announced that it has executed a securities purchase agreement to raise gross proceeds of approximately $95 million in a private placement financing of common stock.

Larimar intends to use the net proceeds from the private placement to support the clinical development of CTI-1601, for additional research and development and for working capital and general corporate purposes.

Larimar Therapeutics Receives European Medicines Agency Priority Medicines (PRIME) Designation for CTI-1601 in Friedreich’s Ataxia

BALA CYNWYD, Pa., May 20, 2021 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (“Larimar”) (Nasdaq: LRMR), a clinical-stage biotechnology company focused on developing treatments for Friedreich’s ataxia (FA) and other complex rare diseases, today announced that the European Medicines Agency (EMA) has granted Priority Medicines (PRIME) designation to CTI-1601 for the treatment of FA. CTI-1601 is a recombinant fusion protein intended to deliver human frataxin into the mitochondria of patients with FA who are unable to produce enough of this essential protein.

We look forward to CTI-1601’s continued clinical development and to the planned initiations of our Jive open label extension and pediatric multiple-ascending dose trials, which are expected in the second half of the year. 

In addition to PRIME designation, CTI-1601 has also been granted Rare Pediatric Disease designation, Fast Track designation and Orphan Drug designation by the U.S. Food and Drug Administration and Orphan Drug Designation by the European Commission.

Reata Announces that The FDA Has Asked The Company to Request a Pre-NDA Meeting for Omaveloxolone for the Treatment of Friedreich’s Ataxia

PLANO, Texas, May 19, 2021 (GLOBE NEWSWIRE) -- Reata Pharmaceuticals, Inc. (Nasdaq: RETA) (“Reata,” the “Company,” or “we”), a clinical-stage biopharmaceutical company, today announced that it received a communication from the Division of Neurology Products 1 (“Division”) of the U.S. Food and Drug Administration (“FDA”) stating that, after a preliminary review of briefing materials for an upcoming Type C meeting, a pre-NDA meeting is the most appropriate format for a discussion of the development program for omaveloxolone in Friedreich’s ataxia (“FA”). The Division suggested that the Company withdraw the current meeting request for a Type C meeting and instead request a pre-NDA meeting, which the Division will grant upon receipt. The Division asked the Company to focus the new briefing package on questions, issues, and needs applicable to a pre-NDA meeting. As requested by the FDA, the Company plans to withdraw the current request for a Type C meeting and submit a request for a pre-NDA meeting as soon as practicable. 

“We welcome the opportunity to have a pre-NDA meeting regarding our omaveloxolone development program for the treatment of patients with FA,” said Warren Huff, Reata’s President and Chief Executive Officer. “We look forward to working with the FDA on our goal of securing the regulatory review and approval necessary to make omaveloxolone available to patients with FA.”