EU/3/21/2456: Orphan designation for the treatment of Friedreich's ataxia. Withdrawn

Sponsor: Novartis Gene Therapies EU Limited The designation was withdrawn from the Union Register of orphan medicinal products in March 2022 upon request of the sponsor.

Neurological Recovery with Interferon-gamma Treatment in Friedreich's Ataxia

Tekin HG, Levent E.; J Coll Physicians Surg Pak. 2022 May;32(5):671-673. doi: 10.29271/jcpsp.2022.05.671. PMID: 35546709. 

The treatment was evaluated by physical examination and side effects assessment. Friedreich Ataxia Rating Scale (FARS), 9-hole peg test (9HPT), and time of 25-foot walk (T25FW) were measured. Ataxia and cerebellar findings improved within 9 months. Although clinical neurological improvement was achieved, there was no improvement in cardiomyopathy. Key Words: Interferon-gamma, Friedreich ataxia, FARS, Children, Cardiomyopathy.

Frataxin deficiency lowers lean mass and triggers the integrated stress response in skeletal muscle

César Vásquez-Trincado, Julia Dunn, Ji In Han, Briyanna Hymms, Jaclyn Tamaroff, Monika Patel, Sara Nguyen, Anna Dedio, Kristin Wade, Chinazo Enigwe, Zuzana Nichtova, David R. Lynch, Gyorgy Csordas, Shana E. McCormack, Erin L. Seifert. Published May 9, 2022 JCI Insight. 2022;7(9):e155201. doi:10.1172/jci.insight.155201. 

Friedreich’s ataxia (FRDA) is an inherited disorder caused by reduced levels of frataxin (FXN), which is required for iron-sulfur cluster biogenesis. Neurological and cardiac comorbidities are prominent and have been a major focus of study. Skeletal muscle has received less attention despite indications that FXN loss affects it. Here, we show that lean mass is lower, whereas body mass index is unaltered, in separate cohorts of adults and children with FRDA. In adults, lower lean mass correlated with disease severity. To further investigate FXN loss in skeletal muscle, we used a transgenic mouse model of whole-body inducible and progressive FXN depletion. There was little impact of FXN loss when FXN was approximately 20% of control levels. When residual FXN was approximately 5% of control levels, muscle mass was lower along with absolute grip strength. When we examined mechanisms that can affect muscle mass, only global protein translation was lower, accompanied by integrated stress response (ISR) activation. Also in mice, aerobic exercise training, initiated prior to the muscle mass difference, improved running capacity, yet, muscle mass and the ISR remained as in untrained mice. Thus, FXN loss can lead to lower lean mass, with ISR activation, both of which are insensitive to exercise training.

Identification of the Minimum Therapeutic Intravenous Dose of AAVrh.10hFXN to Treat the Cardiac Manifestations of Friedreich’s Ataxia

Presenter: Carlos Munoz Zuluaga, M.D., Weill Cornell Medicine Date/Time: Wednesday, May 18, 2022 at 5:30 PM ET Session Title: AAV Vectors – Preclinical and Proof-of-concept Studies III Abstract Number: 936

 Abstract highlights: This preclinical study identified a therapeutically effective dose of AAVrh10 expressing human FXN (AAVrh.10hFXN) that has the potential to be clinically relevant for the treatment of the cardiac manifestations of FA. Assessment by echocardiography demonstrated that a dose of 1.8x1012 gc/kg (qPCR determined) led to a beneficial outcome with significant improvement in ejection fraction and fractional shortening compared to untreated mice. This dose mediated a 21.5 % improvement in mortality. In nonhuman primates, the levels in the heart were comparable to levels in the range estimated necessary to convert the FA homozygote to an FA heterozygote, which based on prior research, present no clinical manifestations of FA.

 Friedreich’s ataxia (FA) cardiomyopathy program will be presented at the 25th Annual Meeting of the American Society of Gene & Cell Therapy (ASGCT), which is being held live in Washington, D.C. and virtually from May 16-19, 2022.

Towards a metabolomic approach to investigate iron-sulfur cluster biogenesis

Marengo M, Fissore A, Oliaro-Bosso S, Adinolfi S, Pastore A.; IUBMB Life. 2022 Apr 27. doi: 10.1002/iub.2618. Epub ahead of print. PMID: 35474632. 

Our data prove that this ex vivo approach closely reproduces the in vitro results while retaining the full complexity of the system. We demonstrate that co-presence of bacterial frataxin and iron is necessary to observe an inhibitory effect of the enzymatic activity of bacterial frataxin. Our approach provides a new powerful tool for the study of iron-sulfur cluster biogenesis.

Simultaneous Quantification of Mitochondrial Mature Frataxin and Extra-Mitochondrial Frataxin Isoform E in Friedreich’s Ataxia Blood

Wang, Q., L. Laboureur, L. Weng, N. M. Eskenazi, L. A. Hauser, C. Mesaros, D. R. Lynch, and I. A. Blair, 2022, Frontiers, doi:10.3389/fnins.2022.874768. 

The assay is based on stable isotope dilution coupled with immunoprecipitation (IP) and two-dimensional-nano-ultrahigh performance liquid chromatography/parallel reaction monitoring/high resolution mass spectrometry (2D-nano-UHPLC-PRM/HRMS). The assay will make it possible to rigorously monitor the natural history of the disease and explore the potential role of isoform E in etiology of the disease. It will also facilitate the assessment of therapeutic interventions (including gene therapy approaches) that attempt to increase frataxin protein expression as a treatment for this devastating disease.

Increased brain tissue sodium concentration in Friedreich ataxia: a multimodal MR Imaging study

Janna Krahe, Imis Dogan, Claire Didszun, Shahram Mirzazade, Alexa Haeger, Nadim Joni Shah, Ilaria A. Giordano, Thomas Klockgether, Guillaume Madelin, Jörg B. Schulz, Sandro Romanzetti, Kathrin Reetz; NeuroImage: Clinical, 2022, 103025, ISSN 2213-1582, doi:10.1016/j.nicl.2022.103025. 

Our findings support the potential of in vivo sodium MRI to detect metabolic changes of increased total sodium concentration in the cerebellum and brainstem, the key regions in Friedreich ataxia. In addition to structural changes, sodium changes were present in cerebellar hemispheres and vermis without concomitant significant atrophy.

Posttranslational Regulation of Mitochondrial Frataxin and Identification of Compounds that Increase Frataxin Levels in Friedreich’s Ataxia

Peter T. Hackett, Xuan Jia, Liangtao Li, Diane M. Ward; Journal of Biological Chemistry, 2022, 101982, ISSN 0021-9258, doi:10.1016/j.jbc.2022.101982. 

We screened a library of FDA-approved compounds and identified 38 compounds that increased yeast frataxin levels, including the azole Bifonazole, antiparasitic Fipronil, anti-tumor compound Dibenzoylmethane (DBM), antihypertensive 4-hydroxychalcone (4’-OHC), and a non-specific anion channel inhibitor 4,4-diisothiocyanostilbene-2,2-sulfonic acid (DIDS). We show that top hits 4’-OHC and DBM increased mRNA levels of transcription factor Nrf2 in FRDA patient-derived fibroblasts, as well as downstream antioxidant targets thioredoxin (TXN), glutathione reductase (GSR), and superoxide dismutase 2 (SOD2). Taken together, these findings reveal that FRDA progression may be in part due to oxidant-mediated decreases in frataxin, and that some approved compounds may be effective in increasing mitochondrial frataxin in FRDA, delaying disease progression

Spinal cord damage in Friedreich's ataxia: Results from ENIGMA-Ataxia

Thiago JR Rezende, Isaac M Adanyeguh, Filippo Arrigoni, Benjamin Bender, Fernando Cendes, Louise A Corben, Andreas Deistung, Martin Delatycki, Imis Dogan, Gary Egan, Sophia L Goricke, Nellie Georgiou-Karistianis, Pierre-Gilles Henry, Diane Hutter, Neda Jahanshad, James M Joers, Christophe Lenglet, Tobias Lindig, Alberto RM Martinez, Andrea Martinuzzi, Gabriella Paparella, Denis Peruzzo, Kathrin Reetz, Sandro Romanzetti, Ludger Schols, Jorg B Schulz, Matthis Synofzik, Sophia I Thomopoulos, Paul M Thompson, Dagmar Timmann, Ian H Harding, Marcondes C Franca Jr.; medRxiv 2022.04.20.22273878; doi: 10.1101/2022.04.20.22273878

Interpretation: Previous research has shown that increased eccentricity reflects dorsal column (DC) damage, while decreased CSA reflects either DC or corticospinal tract (CST) damage or both. Hence, our data support the hypothesis that damage to DC and CST follow distinct courses in FRDA: developmental abnormalities likely define the DC, whereas CST alterations may be both developmental and degenerative. These results provide new insights about FRDA pathogenesis and indicate that CSA of the cervical spinal cord should be investigated further as a potential biomarker of disease progression.

Targeting NLRP3 Inflammasome With Nrf2 Inducers in Central Nervous System Disorders

Tastan B, Arioz BI, Genc S.;Frontiers in Immunology. 2022 ;13:865772. DOI: 10.3389/fimmu.2022.865772. PMID: 35418995; PMCID: PMC8995746. 

 In this review, current knowledge on NLRP3 inflammasome activation and Nrf2 pathways is presented; the relationship between NLRP3 inflammasome signaling and Nrf2 pathway, as well as the pre/clinical use of Nrf2 activators against NLRP3 inflammasome activation in disorders of the central nervous system, are thoroughly described. Cumulative evidence points out therapeutic use of Nrf2 activators against NLRP3 inflammasome activation or diseases that NLRP3 inflammasome contributes to would be advantageous to prevent inflammatory conditions; however, the side effects of these molecules should be kept in mind before applying them to clinical practice.