Frataxin deficiency alters gene expression in Friedreich ataxia derived IPSC-neurons and cardiomyocytes

Angulo, M. B., Bertalovitz, A., Argenziano, M. A., Yang, J., Patel, A., Zesiewicz, T., & McDonald, T. V. (2022). Molecular Genetics & Genomic Medicine, 00, e2093. doi:10.1002/mgg3.2093 

 RNA-seq and differential gene expression enrichment analyses demonstrated that frataxin deficiency affected the expression of glycolytic pathway genes in neurons and extracellular matrix pathway genes in cardiomyocytes. Genes in these pathways were differentially expressed when compared to a control and restored to control levels when FRDA cells were supplemented with frataxin.

Clinical management guidelines for Friedreich ataxia: best practice in rare diseases

Corben, L.A., Collins, V., Milne, S. et al. Orphanet J Rare Dis 17, 415 (2022). doi:10.1186/s13023-022-02568-3 

Individuals with Friedreich ataxia (FRDA) can find it difficult to access specialized clinical care. To facilitate best practice in delivering healthcare for FRDA, clinical management guidelines (CMGs) were developed in 2014. However, the lack of high-certainty evidence and the inadequacy of accepted metrics to measure health status continues to present challenges in FRDA and other rare diseases. To overcome these challenges, the Grading of Recommendations Assessment and Evaluation (GRADE) framework for rare diseases developed by the RARE-Bestpractices Working Group was adopted to update the clinical guidelines for FRDA. This approach incorporates additional strategies to the GRADE framework to support the strength of recommendations, such as review of literature in similar conditions, the systematic collection of expert opinion and patient perceptions, and use of natural history data.

Clinical Management Guidelines for Friedreich Ataxia (FRDA)

In 2020, an executive guidelines panel comprising seven international clinicians was commissioned to provide oversight of the guidelines development process and endorse the final recommendations. The guidelines panel invited international expert clinicians and researchers (the authors) to write background chapter content and develop recommendations for topics that were assigned according to their particular expertise.

REATA PHARMACEUTICALS INC Management's Discussion and Analysis of Financial Condition and Results of Operations

11/08/2022​.

REATA PHARMACEUTICALS INC Management's Discussion and Analysis of Financial Condition and Results of Operations (form 10-Q)

Evolution of an Iron-Detoxifying Protein: Eukaryotic and Rickettsia Frataxins Contain a Conserved Site Which Is Not Present in Their Bacterial Homologues

Alves, R.; Pazos-Gil, M.; Medina-Carbonero, M.; Sanz-Alcázar, A.; Delaspre, F.; Tamarit, J., Int. J. Mol. Sci. 2022, 23, 13151. doi:10.3390/ijms232113151

 Friedreich’s ataxia is a neurodegenerative disease caused by mutations in the frataxin gene. Frataxin homologues, including bacterial CyaY proteins, can be found in most species and play a fundamental role in mitochondrial iron homeostasis, either promoting iron assembly into metaloproteins or contributing to iron detoxification. While several lines of evidence suggest that eukaryotic frataxins are more effective than bacterial ones in iron detoxification, the residues involved in this gain of function are unknown. In this work, we analyze conservation of amino acid sequence and protein structure among frataxins and CyaY proteins to identify four highly conserved residue clusters and group them into potential functional clusters.

Design Therapeutics Highlights Pipeline Progress and Upcoming Milestones and Reports Third Quarter 2022 Financial Results

CARLSBAD, Calif., Nov. 03, 2022 (GLOBE NEWSWIRE) -- Design Therapeutics, Inc. (Nasdaq: DSGN), a clinical-stage biotechnology company developing treatments for serious degenerative genetic diseases, today highlighted recent progress and anticipated upcoming milestones across its clinical and research-stage pipeline of novel GeneTAC™ small molecules and reported third quarter 2022 financial results.

Design is evaluating DT-216 in a Phase 1 single-ascending dose (SAD) clinical trial in adult patients with FA, and plans to report initial SAD data, including safety, tolerability, pharmacokinetics and FXN levels in December 2022.

Design plans to complete the MAD trial in mid-2023.

Efficacy and Safety of Leriglitazone in Patients With Friedreich Ataxia, A Phase 2 Double-Blind, Randomized Controlled Trial (FRAMES)

Massimo Pandolfo, Kathrin Reetz, Alejandra Darling, Francisco Javier Rodriguez de Rivera, Pierre-Gilles Henry, James Joers, Christophe Lenglet, Isaac Adanyeguh, Dinesh Deelchand, Fanny Mochel, Françoise Pousset, Sílvia Pascual, Delphine Van den Eede, Itziar Martin-Ugarte, Anna Vilà-Brau, Adriana Mantilla, María Pascual, Marc Martinell, Uwe Meya, Alexandra Durr Neurol Genet Dec 2022, 8 (6) e200034; DOI: 10.1212/NXG.0000000000200034 

 The primary endpoint of change in spinal cord area was not met. Secondary endpoints provide evidence supporting proof of concept for leriglitazone mode of action and, with acceptable safety data, support larger studies in patients with FRDA.

Progressive Spinal Cord Degeneration in Friedreich's Ataxia: Results from ENIGMA-Ataxia

Thiago J.R. Rezende PhD, Isaac M. Adanyeguh PhD, Filippo Arrigoni MD, Benjamin Bender MD, Fernando Cendes MD, PhD, Louise A. Corben PhD, Andreas Deistung PhD, Martin Delatycki PhD, Imis Dogan PhD, Gary F. Egan PhD, Sophia L. Göricke MD, Nellie Georgiou-Karistianis PhD, Pierre-Gilles Henry PhD, Diane Hutter RN, Neda Jahanshad PhD, James M. Joers PhD, Christophe Lenglet PhD, Tobias Lindig MD, Alberto R.M. Martinez MD, PhD, Andrea Martinuzzi MD, PhD, Gabriella Paparella MD, Denis Peruzzo PhD, Kathrin Reetz MD, Sandro Romanzetti PhD, Ludger Schöls, Jörg B. Schulz MD, Matthis Synofzik MD, Sophia I. Thomopoulos BA, Paul M. Thompson PhD, Dagmar Timmann MD, Ian H. Harding PhD, Marcondes C. França Jr MD, PhD; (2022), Mov Disord. doi:10.1002/mds.29261 

The objective of this study was to perform a characterization of cervical spinal cord structural damage in a large multisite FRDA cohort. 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 the DC and damage to CST follow distinct courses in FRDA: developmental abnormalities likely define the DC, while 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.

Spinal cord magnetic resonance imaging and spectroscopy detect early-stage alterations and disease progression in Friedreich ataxia

James M Joers, Isaac M Adanyeguh, Dinesh K Deelchand, Diane H Hutter, Lynn E Eberly, Isabelle Iltis, Khalaf O Bushara, Christophe Lenglet, Pierre-Gilles Henry; Brain Communications, Volume 6, Issue 5, October 2022, fcac246, doi:10.1093/braincomms/fcac246

Graphical abstract

Larimar Therapeutics Announces Issuance of U.S. Patent Providing Composition of Matter Protection for CTI-1601

BALA CYNWYD, Pa., Oct. 20, 2022 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (“Larimar”) (Nasdaq: LRMR), a clinical-stage biotechnology company focused on developing treatments for complex rare diseases, today announced the issuance of U.S. Patent No. 11,459,363. The patent, titled, “Materials and Methods for Treating Friedreich's Ataxia,” provides composition of matter protection for CTI-1601 into at least July 2040. Larimar has an exclusive license to the patent per a prior agreement with Indiana University.