Therapeutic roles of natural remedies in combating hereditary ataxia: A systematic review

Michael Weng Lok Phang, Sze Yuen Lew, Ivy Chung, William Kiong-Seng Lim, Lee Wei Lim & Kah Hui Wong; Chin Med 16, 15 (2021). https://doi.org/10.1186/s13020-020-00414-x

Ten pre-clinical and two clinical studies were eligible for inclusion in this systematic review. We identified the therapeutic roles of medicinal plants Brassica napus, Gardenia jasminoides, Gastrodia elata, Ginkgo biloba, Glycyrrhiza inflata, Paeonia lactiflora, Pueraria lobata and Rehmannia glutinosa; herbal formulations Shaoyao Gancao Tang and Zhengan Xifeng Tang; and medicinal mushroom Hericium erinaceus in the treatment of HA. In this review, we evaluated the mode of actions contributing to their therapeutic effects, including activation of the ubiquitin–proteasome system, activation of antioxidant pathways, maintenance of intracellular calcium homeostasis and regulation of chaperones. We also briefly highlighted the integral cellular signalling pathways responsible for orchestrating the mode of actions.

Replication-independent instability of Friedreich's ataxia GAA repeats during chronological aging

Neil AJ, Hisey JA, Quasem I, McGinty RJ, Hitczenko M, Khristich AN, Mirkin SM.; Proc Natl Acad Sci U S A. 2021 Feb 2;118(5):e2013080118. doi: 10.1073/pnas.2013080118.

Somatic instability is commonly observed in terminally differentiated, postmitotic cells, such as neurons. To unravel the mechanisms of repeat instability in nondividing cells, we created an experimental system to analyze the mutability of Friedreich's ataxia (GAA)n repeats during chronological aging of quiescent Saccharomyces cerevisiae Unexpectedly, we found that the predominant repeat-mediated mutation in nondividing cells is large-scale deletions encompassing parts, or the entirety, of the repeat and adjacent regions. These deletions are caused by breakage at the repeat mediated by mismatch repair (MMR) complexes MutSβ and MutLα and DNA endonuclease Rad1, followed by end-resection by Exo1 and repair of the resulting double-strand breaks (DSBs) via nonhomologous end joining. We also observed repeat-mediated gene conversions as a result of DSB repair via ectopic homologous recombination during chronological aging. Repeat expansions accrue during chronological aging as well-particularly in the absence of MMR-induced DSBs. These expansions depend on the processivity of DNA polymerase δ while being counteracted by Exo1 and MutSβ, implicating nick repair. Altogether, these findings show that the mechanisms and types of (GAA)n repeat instability differ dramatically between dividing and nondividing cells, suggesting that distinct repeat-mediated mutations in terminally differentiated somatic cells might influence Friedreich's ataxia pathogenesis.

Ectopic Burden Via Holter Monitors in Friedreich’s Ataxia,

Erika Mejia, Abigail Lynch, Patrick Hearle, Oluwatimilehin Okunowo, Heather Griffis, Maully Shah, David Lynch, Kimberly Y. Lin; Pediatric Neurology, 2021, doi:10.1016/j.pediatrneurol.2021.01.004. 

Patients with longer disease duration had higher rates of SVE. Heart rhythm monitoring may be considered for risk stratification, however longitudinal analysis is needed.

AVXS-401, by Novartis Gene Therapies

25/01/2021. AVXS-401 is a gene therapy developed by Novartis Gene Therapies (AveXis, now is part of Novartis). It uses the AAV9 adeno-associated virus (AAV) vector to deliver a functional copy of the FXN gene to restore the production of frataxin in tissues that are severely affected by FA. Early toxicity studies conducted in healthy mice showed that AVXS-401 has good safety and tolerability. Efficacy studies have shown that in a FA mouse model lacking frataxin in the central nervous system, a single intracerebroventricular (ICV) injection of low-dose AVXS-401 can improve behavior and promote glial cell proliferation. In a mouse model lacking frataxin in the heart, AVXS-401 can restore heart function, prolong the median survival by more than 3 times, and prevent the onset of cardiovascular disease. When the therapeutic dose is increased proportionally and administered in non-human primates, AVXS-401 can achieve sustained expression of frataxin in the central nervous system and heart, and the effect is still obvious after 6 months of treatment.

Novartis Gene Therapies gets FDA Orphan Drug Designation in Friedreich's Ataxia

01/21/2021. Novartis Gene Therapies gets FDA Orphan Drug Designation in Friedreich's Ataxia, Novartis Gene Therapies announced that the U.S. Food and Drug Administration has granted Orphan Drug Designation for its "Adeno-associated virus isoform 9 gene vector construct expressing the human Frataxin gene" for the treatment of Friedreich's Ataxia.

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Generic Name:	Adeno-associated virus isoform 9 gene vector construct expressing the human Frataxin gene
Date Designated:	01/21/2021
Orphan Designation:	Treatment of Friedreich`s Ataxia.
Orphan Designation Status:	Designated
FDA Orphan Approval Status:	Not FDA Approved for Orphan Indication
Sponsor:	Novartis Gene Therapies 2275 Half Day Road, Suite 300 Bannockburn, Illinois 60015 United States The sponsor address listed is the last reported by the sponsor to OOPD.

*Exclusivity Protected Indications are shown for approvals from Jan. 1, 2013, to the present.

Supportive care needs of patients with rare chronic diseases: multi-method, cross-sectional study

Miram K. Depping, Natalie Uhlenbusch, Yskert von Kodolitsch, Hans F. E. Klose, Victor-Felix Mautner & Bernd Löwe; Orphanet J Rare Dis 16, 44 (2021). doi:10.1186/s13023-020-01660-w 

Patients affected by rare diseases have high unmet support needs in all areas studied. Multidisciplinary care, including psychological support and the provision of information regarding the healthcare system, treatment options, disease course and sexuality, might help address these needs.

PGC‐1α protects from myocardial ischaemia‐reperfusion injury by regulating mitonuclear communication

Li, Y‐Q, Jiao, Y, Liu, Y‐N, Fu, J‐Y, Sun, L‐K, Su, J.; J Cell Mol Med. 2021; 00: 1‐ 8. doi:10.1111/jcmm.16236 In this review, we speculate the role of PGC‐1α as a key regulator of mitonuclear communication, which may interacts with nuclear factor, erythroid 2 like ‐1 and ‐2 (NRF‐1/2) to inhibit mitochondrial oxidative stress, promote the clearance of damaged mitochondria, enhance mitochondrial biogenesis, and reduce the burden of IRI.

Efficacy of echocardiography for differential diagnosis of left ventricular hypertrophy: special focus on speckle-tracking longitudinal strain

Tanaka, H.; J Echocardiogr (2021). doi:10.1007/s12574-020-00508-3 

The underlying mechanisms of myocardial dysfunction in patients with Friedreich’s ataxia might be associated with myocyte cellular hypertrophy, iron deposits, focal necrosis, and diffuse fibrosis.

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).

Developing an Instrumented Measure of Upper Limb Function in Friedreich Ataxia

Louise A. Corben, Khoa D. Nguyen, Pubudu N. Pathirana, Malcolm K. Horne, David J. Szmulewicz, Melissa Roberts & Martin B. Delatycki; Cerebellum (2021). doi:10.1007/s12311-020-01228-1

We have developed an objective measure, the Ataxia Instrumented Measure–Spoon (AIM-S), which consists of a spoon equipped with a BioKin wireless motion capture device, and algorithms that analyse these signals, to measure ataxia of the upper limb during the pre-oral phase of eating. The aim of this study was to evaluate the AIM-S as a sensitive and functionally relevant clinical outcome for use in clinical trials.

Two ways to control CjCas9 expression in the deletion of pathogenic GAA repeat in frataxin gene

Pouiré Yaméogo; Genetic Engineering Research, Vol.9 Iss.3:sc165

Our results showed that despite the self-destruction of the CjCas9 gene, an effective genome editing of the FXN gene was obtained in vitro. CRISPR-SCReT (Stop Codon Read Through), we inserted a stop codon (TGA) at the beginning of the CjCas9 gene to repress its expression. Subsequently, we induced the expression of Cas9 by molecules capable to allow translation despite the presence of the premature stop codon.