Inhibition of the SUV4-20 H1 histone methyltransferase increases frataxin expression in Friedreich's ataxia patient cells

Gabriela Vilema-Enríquez, Robert Quinlan, Peter Kilfeather, Roberta Mazzone, Saba Saqlain, Irene del Molino del Barrio, Annalidia Donato, Gabriele Corda, Fengling Li, Masoud Vedadi, Andrea H Németh, Paul E Brennan, Richard Wade-Martins; bioRxiv 2020.03.26.010439; doi:10.1101/2020.03.26.010439

Finally, based on the structural activity relationship and crystal structure of A-196, novel small molecule A-196 analogues were synthesized and shown to give a 20-fold increase in potency for increasing FXN expression. Overall, our results suggest that histone methylation is important in the regulation of FXN expression, and highlight SUV4-20 H1 as a potential novel therapeutic target for FRDA.

Neurophysiologic intraoperative monitoring (NIOM) in pediatric patients with polyneuropathy

McKinney JL, Islam MP. Child's Nervous System : Chns : Official Journal of the International Society for Pediatric Neurosurgery. 2020 Mar DOI: 10.1007/s00381-020-04571-0.

Neurophysiologic intraoperative monitoring (NIOM) abnormalities during scoliosis surgery led to a diagnosis of Friedreich’s ataxia in this illustrative case. This prompted the retrospective examination of NIOM for pediatric scoliosis surgery in polyneuropathy patients.

Onset features and time to diagnosis in Friedreich's Ataxia

Elisabetta Indelicato, Wolfgang Nachbauer, Andreas Eigentler, Matthias Amprosi, Raffaella Matteucci Gothe, Paola Giunti, Caterina Mariotti, Javier Arpa, Alexandra Durr, Thomas Klopstock, Ludger Schöls, Ilaria Giordano, Katrin Bürk, Massimo Pandolfo, Claire Didszdun, Jörg Schulz, Sylvia Boesch; Research Square; 2020. DOI: 10.21203/rs.3.rs-18562/v1.

Background: In rare disorders diagnosis may be delayed due to limited awareness and unspecific presenting symptoms. Herein, we address the issue of diagnostic delay in Friedreich´s Ataxia (FRDA), a genetic disorder caused by homozygous GAA-repeat expansions.

Inherited Metabolic Diseases and Cardiac Pathology in Adults: Diagnosis and Prevalence in a CardioMetabo Study

Brailova, M.; Clerfond, G.; Trésorier, R.; Minet-Quinard, R.; Durif, J.; Massoullié, G.; Pereira, B.; Sapin, V.; Eschalier, R.; Bouvier, D.; J. Clin. Med. 2020, 9, 694. Doi:10.3390/jcm9030694

Many inherited metabolic diseases (IMD) have cardiac manifestations. The aim of this study was to estimate the prevalence of IMD in adult patients with hypertrophic cardiomyopathy (HCM) and cardiac rhythm abnormalities that require cardiac implantable electronic devices (CIEDs). The study included a review of the medical files of patients aged 18 to 65 years who were followed in our cardiology department during the period 2010–2017. Metabolic explorations for Fabry disease (FD), mitochondrial cytopathies, and fatty-acid metabolism disorders were carried out in patients with unexplained etiology. The prevalence of IMD in patients with HCM was 5.6% (confidence interval (CI): 2.6–11.6). Six cases of IMD were identified: 1 mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome, 1 Hurler syndrome, 2 Friedreich’s ataxia, 1 FD, and 1 short-chain acyl-CoA dehydrogenase deficiency. Three cases of IMD were identified in patients requiring CIEDs: 1 patient with Leber hereditary optic neuropathy, 1 FD, and 1 short chain acyl-CoA dehydrogenase (SCAD) deficiency. IMD prevalence in patients with CIEDs was 3.1% (CI: 1.1–8.8). IMD evaluation should be performed in unexplained HCM and cardiac rhythm abnormalities adult patients, since the prevalence of IMD is relatively important and they could benefit from specific treatment and family diagnosis.

Design Therapeutics Launches with $45 Million to Develop a New Class of Disease-Modifying Therapies for Serious Degenerative Disorders

SAN DIEGO--(BUSINESS WIRE)--Mar 20, 2020
Design Therapeutics announced today that it is launching to create and develop a new class of therapies for patients with serious degenerative disorders caused by nucleotide repeat expansions. The company has closed a $45 million Series A financing led by SR One, with participation from Cormorant Asset Management, Quan Capital and WestRiver Group, to advance its lead therapeutic candidate into clinical development for the treatment of Friedreich’s ataxia, and support advancement of its discovery programs for multiple other degenerative diseases, including fragile X syndrome and myotonic dystrophy.
Design Therapeutics has developed a novel program that unblocks transcription, thereby restoring the natural production and function of frataxin. With the use of proceeds from the Series A fundraising, Design Therapeutic intends to conduct IND-enabling studies and initiate clinical development for its program for Friedreich’s ataxia.

ENDOTHELIAL FRATAXIN DEFICIENCY DRIVES NUCLEAR REPLICATION STRESS-INDUCED SENESCENCE AND MITOCHONDRIAL DYSFUNCTION ACROSS MULTIPLE SUBTYPES OF PULMONARY HYPERTENSION

Miranda K. Culley, Jingsi Zhao, Ying Tang, Yi Yin Tai, Dror Perk, Vinny Negi, Yen-Chun Lai, Qiujun Yu, Adam Handen, Gil Speyer, Seungchan Kim, Taijyu Satoh, Michael Reynolds, Sruti Shiva, Annie Watson, Yassmin Al Aaraj, John Sembrat, Mauricio Rojas, Karen Norris, Aditi Gurkar, Mingxia Gu, Marlene Rabinovitch, Thomas Bertero and Stephen Chan; Journal of the American College of Cardiology, Volume 75, Issue 11 Supplement 1, March 2020 DOI: 10.1016/S0735-1097(20)34284-4

Endothelial DNA damage and metabolic dysfunction are linked to pulmonary hypertension (PH). Their joint regulation, control of cellular senescence, and relevance across PH subtypes are unknown. Mutations in the iron-sulfur (Fe-S) biogenesis gene frataxin (FXN) disrupt DNA integrity and metabolism, causing Friedreich’s ataxia (FRDA) and hypertrophic cardiomyopathy, often complicated by PH. Because Fe-S loss promotes PH, we hypothesized endothelial FXN deficiency induces genotoxic and metabolic dysregulation and predisposes to PH, particularly vascular remodeling due to ventricular stiffening.

FXN deficiency promotes replication stress-induced senescence and metabolic reprogramming across PH subtypes, including a predisposition to PH in FRDA. Our data endorse developing PH diagnostics and therapeutics related to Fe-S biology and genotoxic stress, namely for PH due to left heart disease.

Enhanced production of herpes simplex virus 1 (HSV-1) amplicon vectors by gene modification and optimization of packaging cell growth medium

Iván Fernández-Frías, Sara Pérez-Luz, Javier Díaz-Nido, Molecular Therapy - Methods & Clinical Development, 2020, doi:10.1016/j.omtm.2020.03.005.

This work improved HSV-1 amplicons by genetic modification of the packaging cell line and optimization of the culture medium. A stably-transfected Vero 2-2 cell line overexpressing the anti-apoptotic Bcl-2 protein was generated, exhibiting an increased resistance to apoptosis, prolonged culture duration and a significant improvement in viral vector production. Additionally, supplementation of the growth medium with antioxidants, polyamines, amino acids and reduced glutathione further increased the yield of packaged amplicon vectors. With these modifications, HSV-1 amplicons could be isolated from culture supernatants instead of cell lysates, leading to vector preparations with higher titer and purity and paving the way for generation of stable cell lines that are capable of continuous herpesviral vector production.

Advances in drug therapy for mitochondrial diseases.

Lufei Zhang, Zhaoyong Zhang, Aisha Khan, Hui Zheng, Chao Yuan, Haishan Jiang; Annals of Translational Medicine, 01 Jan 2020, 8(1):17
DOI: 10.21037/atm.2019.10.113

Mitochondrial diseases are a group of clinically and genetically heterogeneous disorders driven by oxidative phosphorylation dysfunction of the mitochondrial respiratory chain which due to pathogenic mutations of mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). Recent progress in molecular genetics and biochemical methodologies has provided a better understanding of the etiology and pathogenesis of mitochondrial diseases, and this has expanded the clinical spectrum of this conditions. But the treatment of mitochondrial diseases is largely symptomatic and thus does not significantly change the course of the disease. Few clinical trials have led to the design of drugs aiming at enhancing mitochondrial function or reversing the consequences of mitochondrial dysfunction which are now used in the clinical treatment of mitochondrial diseases. Several other drugs are currently being evaluated for clinical management of patients with mitochondrial diseases. In this review, the current status of treatments for mitochondrial diseases is described systematically, and newer potential treatment strategies for mitochondrial diseases are also discussed.

Outlining the Complex Pathway of Mammalian Fe-S Cluster Biogenesis

Nunziata Maio, Tracey A. Rouault; Trends in Biochemical Sciences, 2020, doi:10.1016/j.tibs.2020.02.001.

Structural determinations of the architecture of the initial ISC biogenesis complex, comprising NFS1, ISD11, ACP, ISCU, and FXN, have shed light on the interactions that govern de novo ISC assembly.

The Assessment of Upper Limb Functionality in Friedreich Ataxia via Self-Feeding Activity

K. D. Nguyen, L. A. Corben, P. N. Pathirana, M. K. Horne, M. B. Delatycki and D. J. Szmulewicz, IEEE Transactions on Neural Systems and Rehabilitation Engineering. DOI: 10.1109/TNSRE.2020.2977354

The objective assessment of motor impairment resulting from neurological disorders forms the basis for effective rehabilitation and therapeutic programs. Such assessments conducted through the engagement of suitable daily activities can serve as an effective surrogate measure for the assessment of independent living. This study considers an instrumented spoon in the assessment of upper-limb functionality through the self-feeding activity of a group of individuals clinically diagnosed with the debilitating condition, Friedreich ataxia (FRDA). Thirty-five subjects with FRDA (34±14 years old) and 14 age-matched healthy subjects performed three cycles of self-feeding consisting of grasping, scooping, transferring food to mouth and returning the spoon. Parameters relating to the feeding rate, trajectory of the rotation, range of motion and movement variability with specific attention to each segment were considered for the capture of ataxia pertaining to the disability. Movement variability measured by Dynamic Time Warping (DTW) resulted in an average accuracy of 96% in the diagnosis of ataxia (separation of the two cohorts). The severity of ataxia estimated using a combination of features from Random Forest (RF) increased the correlation with the clinical estimates of ataxia by 13% and achieved higher coefficient (0.72 in patient scale) than the currently used tests (Box & Block, Pegboard). While the overall results provided an objective, daily activity based means of capturing intrinsic abnormalities, the different segments of the task demonstrated the presence of ataxia in a spatial context concurring with relevant clinical observations.