Methylated and unmethylated epialleles support variegated epigenetic silencing in Friedreich ataxia

Layne N Rodden, Yogesh K Chutake, Kaitlyn Gilliam, Christina Lam, Elisabetta Soragni, Lauren Hauser, Matthew Gilliam, Graham Wiley, Michael P Anderson, Joel M Gottesfeld, David R Lynch, Sanjay I Bidichandani, Human Molecular Genetics, ddaa267, doi:10.1093/hmg/ddaa267

The higher prevalence in mild FRDA of somatic FXN epialleles devoid of DNA methylation is consistent with variegated epigenetic silencing mediated by expanded triplet-repeats. The proportion of unsilenced somatic FXN genes is an unrecognized phenotypic determinant in FRDA, and has implications for the deployment of effective therapies.

Omaveloxolone: potential new agent for Friedreich ataxia

David R Lynch and Joseph Johnson; Future Medicine, Neurodegenerative Disease Management 0 0:0 Published Online:12 Jan 2021 doi:10.2217/nmt-2020-0057

In this work, we review the evidence for use of omaveloxolone in FRDA from recent clinical trials. Though not at present approved for any indication, the present data suggest that this agent acting though increases in Nrf2 activity may provide a novel therapy for FRDA.

Dimethyl fumarate dose-dependently increases mitochondrial gene expression and function in muscle and brain of Friedreich’s ataxia model mice

Chun Kiu Hui, Elena N Dedkova, Claire Montgomery, Gino Cortopassi, Human Molecular Genetics, , ddaa282, doi:10.1093/hmg/ddaa282 

We observed significant decreases of multiple mitochondrial parameters, including deficits in brain mitochondrial Complex 2, Complex 4, and aconitase activity, supporting the idea that frataxin deficiency reduces mitochondrial gene expression, mitochondrial functions and biogenesis. 110 mg/kg oral DMF rescued these enzyme activities in brain and rescued frataxin and cytochrome oxidase expression in brain, cerebellum and quadriceps muscle of the FXNKD mouse model. Taken together, these results support the idea of using fumarate-based molecules to treat Friedreich’s ataxia or other mitochondrial diseases.

NAF Supports FARA’s Call to Action

January 15, 2021; Friedreich’s Ataxia Research Alliance (FARA) is encouraging Reata Pharmaceuticals to submit a New Drug Application (NDA) for Omaveloxolone, which recently completed a Phase III clinical trial as a treatment for Friedreich’s Ataxia (FA). FARA is also urging the Food and Drug Administration (FDA) to consider approving the NDA. FARA has prepared a letter that will be submitted to Reata Pharmaceuticals and the FDA; they are looking for supporters to sign the letter. NAF submitted a letter of support. To date, FARA has received more than 40,000 signatures from patients, their family and friends, and rare disease advocates. We want you to sign on too!

Jupiter Orphan Therapeutics Announces First Patient Dosed in Phase I Dose Escalation Study of JOTROL™

JUPITER, Fla., Jan. 11, 2021 /PRNewswire/ -- Jupiter Orphan Therapeutics, Inc. ("JOT") a biotechnology company pioneering a novel and disease modifying product named JOTROL™, today announced that the first patient has been dosed in a Phase I dose escalation study of JOTROL™. The Phase I is conducted with healthy volunteers in various ages and include a food effect arm. Per protocol, the first patient cohort has been dosed and the study is continuing in January and February of 2021. Top line data is expected to be available in March 2021. The initial dose appear well-tolerated as the escalation continues toward clinically relevant doses. JOTROL™ is, through its unique bioavailability, the first and only resveratrol product that can deliver a therapeutically effective dose without causing any severe gastro-intestinal side effects. JOTROL™ is a platform product that is expected to be an effective treatment in many rare diseases such as ataxias, lysosomal storage disorders and mitochondrial diseases. 

 We are assuming positive Phase I results, which will be a Proof Of Concept of our product and have started preparations for Phase II trials in MPS-1, Friedreich's ataxia and MELAS in addition to MCI study preparation. We have presently cash covering us through 2021 and are targeting additional financing through an equity raise, possible partnering as well as utilizing non-dilutive funding sources to be able to start several Phase II trials later in 2021," stated Christer Rosén, Chairman and CEO.

Cytoprotective activities of kinetin purine isosteres

Barbara Maková, Václav Mik, Barbora Lišková, Gabriel González, Dominik Vítek, Martina Medvedíková, Beata Monfort, Veronika Ručilová, Alena Kadlecová, Prashant Khirsariya, Zoila Gándara Barreiro, Libor Havlíček, Marek Zatloukal, Miroslav Soural, Kamil Paruch, Benoit D'Autréaux, Marián Hajdúch, Miroslav Strnad, Jiří Voller, Bioorganic & Medicinal Chemistry, 2021, 115993, doi:10.1016/j.bmc.2021.115993. 

 Our findings indicate that kinetin isosteres protect Friedreich́s ataxia patient-derived fibroblasts against glutathione depletion, protect neuron-like SH-SY5Y cells from glutamate-induced oxidative damage, and correct aberrant splicing of the ELP1 gene in fibroblasts derived from a familial dysautonomia patient. Although the mechanism of action of kinetin derivatives remains unclear, our data suggest that the cytoprotective activity of some purine isosteres is mediated by their ability to reduce oxidative stress. Further, the studies of permeation across artificial membrane and model gut and blood-brain barriers indicate that the compounds are orally available and can reach central nervous system. Overall, our data demonstrate that isosteric replacement of the kinetin purine scaffold is a fruitful strategy for improving known biological activities of kinetin and discovering novel therapeutic opportunities.

DNA REPAIR PATHWAYS ARE ALTERED IN NEURAL CELL MODELS OF FRATAXIN DEFICIENCY

Jara Moreno-Lorite, Sara Pérez-Luz, Yurika Katsu-Jiménez, Daniel Oberdoerfer, Javier Díaz-Nido, Molecular and Cellular Neuroscience, 2021, 103587, doi:10.1016/j.mcn.2020.103587. 

 These results suggest that the deficiency of FXN leads to a down-regulation of DNA repair pathways that synergizes with oxidative stress to provoke DNA damage, which may be involved in the pathogenesis of FRDA. Thus, a failure in DNA repair may be considered a shared common molecular mechanism contributing to neurodegeneration in a number of hereditary ataxias including FRDA.

Friedreich ataxia in COVID-19 time: current impact and future possibilities

Tommaso Schirinzi, Andrea Sancesario, Enrico Castelli, Enrico Bertini & Gessica Vasco; Cerebellum & Ataxias volume 8, Article number: 4 (2021). doi:10.1186/s40673-020-00127-9

COVID-19 outbreak profoundly impacted on daily-life of patients with neurodegenerative diseases, including those with ataxia. Effects on interventional trials have been recently described. Conversely, changes in physical activity programs, which are crucial in care of ataxic patients, have not been assessed yet. Here we used a structured electronic survey to interview twenty patients with Friedreich ataxia (FA) on changes in physical activity during the lockdown in Italy. Regular physiotherapy was interrupted for most patients and up to 60% of them referred a substantial worsening of self-perceived global health. However, FA patients (especially those mildly affected) adopted voluntarily home-based training strategies and, in 30% of cases, used technology-based tools (TBTs) for exercise. COVID-19 crisis thus disclosed the urgent need to support ataxic patients improving systems for remote physical activity and technology-based assistance.

Current report, slide presentation, Form 8-K Exicure, Inc.

Form 8-K Exicure, Inc. Current report, items 7.01 and 9.01; Published: 2021-01-07 On January 7, 2021, Exicure, Inc. (the “Company”) will host a virtual R&D Day on Thursday, January 7, 2021 from 9:00 am to 10:30 am ET to discuss its neuroscience pipeline, including its lead program for Friedreich’s Ataxia (FA). The R&D Day webcast will include a slide presentation, which is attached as Exhibit 99.1 to this Current Report on Form 8-K and incorporated by reference in this Item 7.01. The R&D Day webcast will be available on the Company’s website for 30 days following the event.

LEXEO Therapeutics Launches with $85 Million Series A Financing to Develop Gene Therapies for Rare and Non-Rare Monogenic Diseases

NEW YORK, Jan. 07, 2021 (GLOBE NEWSWIRE) -- LEXEO Therapeutics, a clinical-stage gene therapy company, debuted today with an oversubscribed $85 million Series A financing, led by Longitude Capital and Omega Funds, and joined by Lundbeckfonden Ventures, PBM Capital, Janus Henderson Investors, Invus, Woodline Partners LP, the Alzheimer’s Drug Discovery Foundationi and Alexandria Venture Investments. Proceeds from the financing will help advance the company’s three lead investigational programs, including: LX2006, an IV-administered therapy for cardiomyopathy associated with Friedreich’s ataxia (Phase 1 start planned for 2021); LX1004, a CNS-administered therapy for CLN2 Batten disease (Phase 1/2 completed); and LX1001, a CNS-administered therapy for APOE4-associated Alzheimer’s disease (Phase 1 ongoing).