Antisense Transcription across Nucleotide Repeat Expansions in Neurodegenerative and Neuromuscular Diseases: Progress and Mysteries

Castro AF, Loureiro JR, Bessa J, Silveira I. Genes. 2020 Nov;11(12). DOI: 10.3390/genes11121418.

Efficacy and Tolerability of Interferon Gamma in Treatment of Friedreich's Ataxia: Retrospective Study

Mehmet Fatih YETKİN and Murat GÜLTEKİN; Noro Psikiyatr Ars. 2020 Sep 21;57(4):270-273. doi: 10.29399/npa.25047. eCollection 2020 Dec. 

 Interferon-gamma (IFN-γ) has been shown to induce frataxin production in many cell types. In this study, the clinical features, tolerability, and the prognosis of individuals with FRDA to whom IFN-γ was administered in a university hospital were evaluated retrospectively and the results were discussed. To the best of our knowledge, this is the first study conducted in our country to evaluate the effect of IFN gamma on this patient group.

FDA requests new trial for Reata's Friedreich's ataxia program; J&J's Tremfya picks up expanded label in Europe

Endpoints News, November 25, 2020. Three months after Reata Pharmaceuticals suggested its Friedreich’s ataxia program omaveloxolone could be delayed, the company revealed that is indeed going to be the case. 

The FDA did not rule out reconsidering omaveloxolone’s application once the new study has been completed, Reata noted.

PTC Therapeutics announced the initiation of its third study of 2020 investigating vatiquinone.

NeurologyLive, December 24, 2020

PTC Therapeutics has announced the initiation of the global phase 3 MOVE-FA study (NCT04577352) of vatiquinone (PTC743) for Friedreich’s ataxia (FA). The study is currently recruiting children and young adults.Initiation of the trial was delayed by COVID-19

The double-blind MOVE-FA trial will evaluate vatiquinone versus placebo in approximately 110 children and young adults with FA in parallel arms over 18 months. Patients will be enrolled from the US, EU, Australia, and Latin America.

A Study to Assess the Efficacy and Safety of Vatiquinone for the Treatment of Participants With Friedreich Ataxia (MOVE-FA)

ClinicalTrials.gov Identifier: NCT04577352; December 19, 2020 

Sponsors and Collaborators PTC Therapeutics 

Double-blind, placebo-controlled phase, participants will be stratified by baseline mFARS score (<40 age="" and="" at="" disease="" of="" onset="" or="" screening="" versus="" years="">21 years) and randomized to receive either vatiquinone or placebo using interactive web response system (IWRS). Following completion of the randomized, double-blind, placebo-controlled phase (72 weeks), participants will enter into an open-label extension phase (24 weeks) during which they will receive open-label treatment with vatiquinone at the dose they received in the randomized phase of the study (for participants entering the extension phase who initially received placebo, the dose of vatiquinone will be determined based on age and weight) and then a safety follow-up (10-30 days after last dose).

Insights Into the Roles of the Sideroflexins / SLC56 Family in Iron Homeostasis and Iron-Sulfur Biogenesis

Tifoun, N.; De las Heras, J.M.; Guillaume, A.; Bouleau, S.; Mignotte, B.; Le Floch, N.; Preprints 2020, 2020120583 doi: 10.20944/preprints202012.0583.v1. 

Frataxin (FXN) is a mitochondrial chaperone that interacts with aconitase in a citrate389 dependent manner to convert (3Fe-4S)1+ inactive enzyme into [4Fe-4S]2+ active one within the Krebs cycle. It also interacts with the ISCU-NFS1 (Iron-Sulfur Cluster Scaffold-Cysteine desulfurase) in the final steps of Fe-S formation [81,82]. The reduction of mitochondrial aconitase (ACO2) in SFXN4 KO cells suggests that SFXN4 could participate in the Fe-S biosynthesis maybe through an interaction with Frataxin (FXN). IIt has been previously reported that FECH, an important enzyme for heme biosynthesis, Mfrn1, an iron transporter into the mitochondria, and ABCB10, a protoporphyrin IX transporter, could form a complex in mouse erythroleukemia (MEL) cells to direct iron incorporation into protoporphyrin to form heme . Taken together, those results open the possibility that SFXN4 and FXN interact with other proteins such as aconitase or the ISCU-NFS1 multimeric complex to maturate the Fe-S clusters. We have recently performed a screen with the aim to identify the direct partners of SFXN1 protein in MCF7 cells (Tifoun et al., in preparation) and, even though Sfxn1 does not interact directly with FXN, it is still possible that Sfxn4 could do so. In Sfxn4 mutants Fe-S synthesis is reduced, pointing out that Sfxn4 may play a role in the first steps of Fe-S cluster formation, maybe through FXN interaction. A recent study shows that the ISC (Iron Sulfur Cluster, composed by NFS1, ISCU and FXN) function requires L-Cysteine to generate de disulfide groups necessary to form the Fe-S clusters.

Seelos Therapeutics Announces Issuance of a Patent for Trehalose (SLS-005) in Israel

NEW YORK, Dec. 21, 2020 /PRNewswire/ -- Seelos Therapeutics, Inc. (Nasdaq: SEEL), a clinical-stage biopharmaceutical company focused on the development of therapies for central nervous system disorders and rare diseases, announced today that it has been issued Israeli patent number 241757 by the State of Israel Patent Office titled: "TREATMENT OF PROTEIN AGGREGATION MYOPATHIC AND NEURODEGENERATIVE DISEASES BY PARENTERAL ADMINISTRATION OF TREHALOSE".

 The issued patent covers a method of using trehalose (SLS-005) to treat several neurodegenerative conditions including amyotrophic lateral sclerosis (ALS), Sanfilippo syndrome, oculopharyngeal muscular dystrophy (OPMD), Huntington's disease, spinocerebellar ataxia (SCA), spinal and bulbar muscular atrophy (SBMA), dentatomral-pailidoluyssan atrophy (DRPLA), Pick's disease, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), frontotemporal dementia, Parkinson's disease, parkinsonism linked to chromosome 17 (FTDP-17), Alzheimer's disease, and Friedreich ataxia (FA).

Rehabilitation for ataxia study: protocol for a randomised controlled trial of an outpatient and supported home-based physiotherapy programme for people with hereditary cerebellar ataxia

Sarah C Milne1, Louise A Corben, Melissa Roberts, David Szmulewicz, J Burns, Anneke C Grobler, Shannon Williams, Jillian Chua, Christina Liang, Phillipa J Lamont, Alison C Grootendorst, Libby Massey, Carolyn Sue, Kim Dalziel, Desiree LaGrappe, Liz Willis, Aleka Freijah, Paul Gerken, Martin B Delatycki. BMJ Open 2020;10:e040230. doi: 10.1136/bmjopen-2020-040230

Emerging evidence indicates that rehabilitation can improve ataxia, mobility and independence in everyday activities in individuals with hereditary cerebellar ataxia. However, with the rarity of the genetic ataxias and known recruitment challenges in rehabilitation trials, most studies have been underpowered, non-randomised or non-controlled. This study will be the first, appropriately powered randomised controlled trial to examine the efficacy of an outpatient and home-based rehabilitation programme on improving motor function for individuals with hereditary cerebellar ataxia.

Effects of Fe2+/Fe3+ Binding to Human Frataxin and Its D122Y Variant, as Revealed by Site-Directed Spin Labeling (SDSL) EPR Complemented by Fluorescence and Circular Dichroism Spectroscopies

Doni, D.; Passerini, L.; Audran, G.; Marque, S.R.A.; Schulz, M.; Santos, J.; Costantini, P.; Bortolus, M.; Carbonera, Int. J. Mol. Sci. 2020, 21, 9619. doi:10.3390/ijms21249619 

 The data reported in this study reveal that the currently reported binding stoichiometries should be taken with caution. The use of a spin label resistant to reduction, as well as the comparison of the binding effect of Fe2+ in wild type and in the pathological D122Y variant of frataxin, allowed us to characterize the Fe2+ binding properties of different protein sites and highlight the effect of the D122Y substitution on the surrounding residues. We suggest that both Fe2+ and Fe3+ might play a relevant role in the context of the proposed FXN physiological functions.

Minoryx’s clinical candidate leriglitazone shows clinical benefit in a proof of concept Phase 2 study in Friedreich´s ataxia

Mataró, Barcelona, Spain, December 15, 2020 - Minoryx Therapeutics, a Phase 3 clinical stage biotech company focused on the development of differentiating treatment options in orphan central nervous system (CNS) disorders, today announces topline results from the Phase 2 FRAMES clinical trial. “Clinical results from the Minoryx Phase 2 FRAMES clinical trial are promising. Specifically, the reduction in decline in upper limb ataxia in Friedreich's ataxia patients demonstrate the potential of meaningful benefit in tackling this neurodegenerative condition,” said Professor Alexandra Durr, the principal investigator and coordinator of the FRAMES study, from the Brain and Spine Institute of La Pitié-Salpêtrière University Hospital (ICM), Paris.

Calcitriol increases frataxin levels and restores mitochondrial function in cell models of Friedreich Ataxia

Elena Britti; Fabien Delaspre; Arabela Sanz; Marta Medina-Carbonero; Marta Llovera; Rosa Purroy; Stefka Mincheva-Tasheva; Jordi Tamarit; Joaquim Ros; Biochem J BCJ20200331. doi: 10.1042/BCJ20200331

We provide data that calcitriol supplementation, used at nanomolar concentrations, is able to reverse the molecular and cellular markers altered in DRG neurons. Calcitriol is able to recover both ferredoxin 1 and NCLX levels and restores mitochondrial membrane potential indicating an overall mitochondrial function improvement. Accordingly, reduction of apoptotic markers and neurite degeneration was observed and, as a result, cell survival was also recovered. All these beneficial effects would be explained by the finding that calcitriol is able to increase the mature frataxin levels in both, frataxin-deficient DRG neurons and cardiomyocytes; remarkably, this increase also occurs in lymphoblastoid cell lines derived from FA patients. In conclusion, these results provide molecular bases to consider calcitriol for an easy and affordable therapeutic approach for FA patients.

Thioredoxin and Glutaredoxin Systems as Potential Targets for the Development of New Treatments in Friedreich’s Ataxia

Seco-Cervera, M.; González-Cabo, P.; Pallardó, F.V.; Romá-Mateo, C.; García-Giménez, J.L. ; Antioxidants 2020, 9, 1257. doi:10.3390/antiox9121257 The thioredoxin family consists of a small group of redox proteins present in all organisms and composed of thioredoxins (TRXs), glutaredoxins (GLRXs) and peroxiredoxins (PRDXs) which are found in the extracellular fluid, the cytoplasm, the mitochondria and in the nucleus with functions that include antioxidation, signaling and transcriptional control, among others. The importance of thioredoxin family proteins in neurodegenerative diseases is gaining relevance because some of these proteins have demonstrated an important role in the central nervous system by mediating neuroprotection against oxidative stress, contributing to mitochondrial function and regulating gene expression. Specifically, in the context of Friedreich’s ataxia (FRDA), thioredoxin family proteins may have a special role in the regulation of Nrf2 expression and function, in Fe-S cluster metabolism, controlling the expression of genes located at the iron-response element (IRE) and probably regulating ferroptosis. Therefore, comprehension of the mechanisms that closely link thioredoxin family proteins with cellular processes affected in FRDA will serve as a cornerstone to design improved therapeutic strategies.

Friedreich’s Ataxia Center of Excellence at CHOP Awarded $1.275 Million to Advance Medical Research

Published on Dec 10, 2020 in CHOP News. The Friedreich’s Ataxia Center of Excellence (COE) at Children’s Hospital of Philadelphia (CHOP) was awarded $1.275 million by the Friedreich’s Ataxia Research Alliance (FARA), along with the Hamilton and Finneran families and the CureFA Foundation, to support the development of breakthrough therapies to improve the quality of life for individuals with Friedreich’s ataxia. The Friedreich’s Ataxia COE at CHOP was established in March 2014 by CHOP, Penn Medicine and FARA, and was a result of a $3.25 million gift from FARA in partnership with the Hamilton and Finneran families. Since 2014, more than $8 million in research funding has been committed to the COE to create a multi-disciplinary, translational research and clinical care center devoted to FA. Its mission is to expedite basic science and drug discovery to treatments and dedicate resources to clinical research and care to improve outcomes for individuals living with FA.

Safety and feasibility of upper limb cardiopulmonary exercise test in Friedreich ataxia

Chiara Pane, Andrea Salzano, Assunta Trinchillo, Claudia Del Prete, Carlo Casali, Christian Marcotulli, Giovanni Defazio, Vincenzo Guardasole, Rossella Vastarella, Francesco Giallauria, Giorgia Puorro, Angela Marsili, Giovanna De Michele, Alessandro Filla, Antonio Cittadini, Francesco Saccà; European Journal of Preventive Cardiology, zwaa134, doi:10.1093/eurjpc/zwaa134 

 Upper limb CPET is useful in the assessment of exercise tolerance and a possible tool to determine the functional severity of the mitochondrial oxidative defect in patients with FRDA. The cardiopulmonary exercise test is an ideal functional endpoint for Phases II and III trials through a simple, non-invasive, and safe exercise test.

Larimar Therapeutics Announces Completion of Dosing of the Single Ascending Dose Clinical Trial in Friedreich’s Ataxia Patients and Provides Program Update

BALA CYNWYD, Pa., Dec. 08, 2020 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (“Larimar”) (Nasdaq: LRMR), a clinical-stage biotechnology company focused on developing treatments for complex rare diseases, today announced the completion of dosing from the Company’s Phase 1 single ascending dose (SAD) clinical trial (n=28) evaluating CTI-1601 as a treatment for Friedreich’s ataxia (FA) and provided additional updates regarding the status of an ongoing multiple ascending dose (MAD) clinical trial, the timing of Phase 1 topline results, and future activities planned for 2021.

A Safety Review Committee reviewed preliminary blinded data after each cohort of the placebo-controlled SAD clinical trial and recommended continuation of the trial. Dosing has been completed and based on preliminary data, single subcutaneous injections of CTI-1601 at doses up to 100 mg are thought to have been well tolerated. Injection site adverse events were mild and transient, and no serious adverse events were reported. Analysis of clinical trial results remains ongoing.

Patients completing the SAD and/or MAD clinical trials are eligible to screen for an open-label extension clinical trial, which is expected to initiate in the second half of 2021. Larimar also expects to initiate a MAD clinical trial in patients under 18 years of age in the second half of 2021.

Molecular Defects in Friedreich’s Ataxia: Convergence of Oxidative Stress and Cytoskeletal Abnormalities

Frances M. Smith and Daniel J. Kosman; Front. Mol. Biosci., doi:10.3389/fmolb.2020.569293 This review serves to outline a brief history of this research and hones in on pathway dysregulation downstream of iron-related pathology in FRDA related to actin dynamics. The review presented here was not written with the intent of being exhaustive, but to instead urge the reader to consider the essentiality of the cytoskeleton and appreciate the limited knowledge on FRDA-related cytoskeletal dysfunction as a result of oxidative stress. The review examines previous hypotheses of neurodegeneration with brain iron accumulation (NBIA) in FRDA with a specific biochemical focus.

Targeting Expanded Repeats by Small Molecules in Repeat Expansion Disorders

Nakamori, M. and Mochizuki, H. (2020), Mov Disord. doi:10.1002/mds.28397 

 Recent technological advancements in genetic analysis have allowed for the consecutive discovery and elucidation of repeat expansion disorders: diseases caused by the abnormal expansion of repeat sequences in the genome. Many of these repeat expansion disorders are neurodegenerative movement disorders. Radical cures for these disorders have yet to be established. Although conventional treatments for repeat expansion disorders have mainly targeted the abnormal mRNA and proteins encoded by the affected genes, therapeutic approaches targeting repeat DNA, the root cause of repeat disorders, is also being explored in current research. In particular, a small molecule has been found that binds to abnormally expanded CAG repeats, the cause of Huntington's disease, and shortens them. Such small molecules targeting nucleic acids are expected to be developed into groundbreaking therapeutic drugs capable of ameliorating the symptoms of repeat expansion disorders and preventing their onset.

Coronary Artery Disease in Patients With Friedreich's Ataxia

ClinicalTrials.gov Identifier: NCT04649866. Vasculopathy and Remodeling of Coronary Arteries in FRDA Patients.

Patients with HCM can then develop pulmonary hypertension (PH), a deadly condition of the blood vessels of the lung. While most of the research in FRDA has focused on nerves and heart muscle, alterations in blood vessels of the heart and lung may worsen disease in FRDA. But, the role of FXN in these blood vessels has never been defined.Our pilot data suggest that Frataxin (FXN ) deficiency can control senescence and downstream function in various types of Endothelial cells (ECs), we hypothesize that Friedreich's Ataxia (FRDA) patients may demonstrate endothelial cells EC abnormalities throughout the vasculature potentially before overt cardiomyopathy develops.

Afrontamiento familiar ante el diagnóstico y evolución de la enfermedad ataxia de Friedreich, «Family dealing with the diagnosis and evolution of Friedreich’s ataxia disease»

Erika E. López Rios, Yeisy C., Guarate Coronado; Ocronos. Vol. III. Nº 8– Diciembre 2020. Pág. Inicial: Vol. III; nº8:12; ORCID iD: http://orcid.org/ 0000-0003-1526-4693

A partir del diagnóstico y evolución de la Ataxia de Friedreich los familiares experimentaron sentimientos negativos, surgieron cambios a nivel económico, familiar, social y calidad de vida, además el cuidado resulta difícil, por lo que el cuidador principal presentó sobrecarga. Sin embargo, la familia ha logrado afrontar positivamente utilizando estrategias enfocadas al problema y emociones. Conclusiones: La familia utilizó estrategias de afrontamiento enfocadas en las emociones y centradas en el problema, pues emplearon el autocontrol emocional, aceptación de responsabilidades, reevaluación positiva, apoyo familiar y espiritual, búsqueda de información sobre la enfermedad y alternativas de tratamiento.

Ferroptosis: molecular mechanisms and health implications

Daolin Tang, Xin Chen, Rui Kang, Guido Kroemer; Cell Res (2020). doi:10.1038/s41422-020-00441-1

The ferroptosis inhibitor SRS11-92 is highly effective in protecting human primary fibroblasts from cell death induced by frataxin depletion, indicating that targeting ferroptosis might be useful for the treatment of Friedreich ataxia, pending confirmation in animal models.

Altered Expression of Mitoferrin and Frataxin, Larger Labile Iron Pool and Greater Mitochondrial DNA Damage in the Skeletal Muscle of Older Adults

Picca, A.; Saini, S.K.; Mankowski, R.T.; Kamenov, G.; Anton, S.D.; Manini, T.M.; Buford, T.W.; Wohlgemuth, S.E.; Xiao, R.; Calvani, R.; Coelho-Júnior, H.J.; Landi, F.; Bernabei, R.; Hood, D.A.; Marzetti, E.; Leeuwenburgh, C; Cells 2020, 9, 2579. doi:10.3390/cells9122579

An inverse association was found between total Fe and the heavier Fe isotope (56Fe), indicating an increase in labile Fe abundance in cells with greater Fe content. The highest levels of labile Fe were detected in old participants with a Short Physical Performance Battery (SPPB) score ≤ 7 (low-functioning, LF). Protein levels of mitoferrin and frataxin were, respectively, higher and lower in the LF group relative to young participants and older adults with SPPB scores ≥ 11 (high-functioning, HF). The mtDNA4977 relative abundance was greater in old than in young participants, regardless of SPPB category. Higher protein levels of Pink1 were detected in LF participants compared with young and HF groups. Finally, the ratio between lipidated and non-lipidated microtubule-associated protein 1A/1B-light chain 3 (i.e., LC3B II/I), as well as p62 protein expression was lower in old participants regardless of SPPB scores. Our findings indicate that cellular and mitochondrial Fe homeostasis is perturbed in the aged muscle (especially in LF older adults), as reflected by altered levels of mitoferrin and frataxin, which, together with MQC derangements, might contribute to loss of mtDNA stability.

PTC Therapeutics Announces Initiation of Global Phase 3 Clinical Trial to Evaluate Vatiquinone in Friedreich Ataxia

SOUTH PLAINFIELD, N.J., Nov. 30, 2020 /PRNewswire/ -- PTC Therapeutics, Inc. (NASDAQ: PTCT), today announced the initiation of the registration-directed Phase 3 MOVE-FA study evaluating vatiquinone (PTC743) in children and young adults with Friedreich ataxia (FA) The Phase 3 MOVE-FA trial is an 18-month parallel arm, placebo-controlled study evaluating vatiquinone versus placebo in approximately 110 children and young adults with FA. The primary endpoint is the change from baseline in the modified Friedreich ataxia rating scale (mFARS), with key secondary endpoints assessing ambulation and activities of daily living. This endpoint strategy was developed in consultation with both the FDA and European Medicines Agency. The study will include sites in the U.S., E.U., Australia and Latin America.

FDA sends Reata back to the drawing board

Evaluate Vantage, Madeleine Armstrong, November 25, 2020

The need for another pivotal trial of omaveloxolone in Friedreich's ataxia looks increasingly likely. This result for omaveloxolone was not entirely unexpected; Reata said during its second-quarter results that the FDA had asked for a second pivotal trial to support the Moxie study. Part two of Moxie was declared a success, but only after Reata switched endpoints to increase its chances after the first part failed (Reata looks to outsmart Abbvie again, October 15, 2019).

Overview of Friedreich's ataxia models: Comparison of frataxin protein levels and phenotype

27 November 2020. The Jackson Laboratory .

Watch this presentation from Dr. Cat Lutz, Senior Director of Mouse Repository & In Vivo Pharmacology at The Jackson Laboratory, titled: Overview of Friedreich's ataxia models: Comparison of frataxin protein levels and phenotype. This talk was presented at the SelectScience® Virtual Neuroscience Summit.

https://www.selectscience.net/SelectScience-TV/Videos/overview-of-friedreichs-ataxia-models-comparison-of-frataxin-protein-levels-and-phenotype/?videoID=5178

Central Nervous System Therapeutic Targets in Friedreich Ataxia

Dr. Ian Harding, Dr. David R Lynch, Dr. Arnulf Koeppen, and Dr. Massimo Pandolfo; Human Gene Therapy 0 0:ja; doi:10.1089/hum.2020.264

In general, the proprioceptive system appears to be affected early, while later in the disease the dentate nucleus of the cerebellum and, to some degree, the corticospinal tracts degenerate. In the current era of expanding therapeutic discovery in FRDA, including progress towards novel gene therapies, a deeper and more specific consideration of potential treatment targets in the nervous system is necessary. In the present work, we have re-examined the neuropathology of FRDA, recognizing new issues superimposed on classical findings and dissected the peripheral nervous system (PNS) and central nervous system (CNS) aspects of the disease and the affected cell types. Understanding the temporal course of neuropathological changes is needed to identify areas of modifiable disease progression and the CNS and PNS locations that can be targeted at different timepoints. As most major targets of long-term therapy are in the CNS, the present review uses multiple tools for evaluation of the importance of specific CNS locations as targets. In addition to clinical observations, the conceptualizations here include physiological, pathological and imaging approaches, and animal models. We believe that this review, through analysis of a more complete set of data derived from multiple techniques, provides a comprehensive summary of therapeutic targets in FRDA.

New drug confirmed as a potential therapeutic agent for a rare disease, Friedreich's Ataxia

http://biotech-spain.com , 25/11/2020, Fuente: IRB Lleida. Institut de Recerca Biomèdica.

It is the leriglitazone that improves the loss of frataxin, the cause of the disease .

A recent study has confirmed the benefits of the drug leriglitazone in treating Friedrich's Ataxia, a rare disease that affects 2-4 people in 100,000 and for which there is currently no effective cure. Research has confirmed that this drug improves the deficiencies of frataxin loss in cellular and animal models of Friedreich's Ataxia. This disease is caused by a deficiency in frataxin levels, which leads to mitochondrial dysfunction with neurological and cardiac involvement. The research has been published in the journal Neurobiology of Disease.

The research has been carried out in collaboration between the company Minoryx Therapeutics, the Oxidative stress biochemistry Stress Group of the University of Lleida (UdL) and the Institute of Biomedical Research of Lleida (IRBLleida), the Department of Physiology of the Faculty of Medicine and Dentistry of the University of Valencia - INCLIVA, the Centre for Biomedical Research Network on Rare Diseases (CIBERER) and the Department of Paediatrics and Neurology of The Children's Hospital of Philadelphia.

Confirman un nuevo fármaco como potencial agente terapéutico para tratar la ataxia de Friedreich

Universitat de València, GABINETE DE PRENSA, 25 noviembre de 2020.

La investigación ha confirmado los beneficios del fármaco leriglitazona para tratar la ataxia de Friedrich, una enfermedad rara que afecta a 2-4 personas de cada 100.000 y para la cual, actualmente, no hay una cura efectiva. La investigación es una colaboración entre el grupo de investigación que lidera Federico Pallardó, la empresa Minoryx Therapeutics, y el INCLIVA, perteneciente al Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), el Grupo de Investigación Bioquímica del Estrés Oxidativo, de la Universidad de Lleida (UdL) y el Instituto de Investigación Biomédica de Lleida (IRBLleida), y el Departamento de Pediatría y Neurología del The Children's Hospital of Philadelphia.

Reata Provides Update on Omaveloxolone Program for Patients with Friedreich’s Ataxia

November 24, 2020 17:00 ET | Source: Reata Pharmaceuticals, Inc. PLANO, Texas, Nov. 24, 2020 (GLOBE NEWSWIRE) -- Reata Pharmaceuticals, Inc. (Nasdaq: RETA) (“Reata,” the “Company,” or “we”), a clinical-stage biopharmaceutical company, today announced that the U.S. Food and Drug Administration (“FDA”) completed its internal review of the Baseline-Controlled Study results of omaveloxolone for the treatment of patients with Friedreich’s ataxia (“FA”) and concluded that the results do not strengthen the results of Part 2 of the MOXIe study. The FDA proposed some additional exploratory analyses using patients randomized to placebo during the MOXIe Part 2 study, but stated that the potential for these analyses to strengthen the study results was questionable due to the small number of patients available for analysis. The FDA stated that they remain interested in reviewing the results of the additional exploratory analyses as those may inform the future development program. The Company plans to submit to the FDA the analyses that they proposed and to request a meeting with the FDA to discuss the development program. In addition, based on the FDA’s conclusion, the Company is considering the next steps for the development program, including whether to conduct a second pivotal study in patients with FA. “Omaveloxolone improved motor function as measured by the modified Friedreich’s Ataxia Rating Scale in both Part 2 of the MOXIe study and the Baseline-Controlled study. We are grateful to the families, physicians, investigators, and advocates who have supported this program to date,” said Warren Huff, Reata’s Chairman and Chief Executive Officer. “Though we are disappointed in the FDA’s feedback on this program, we will carefully consider the potential paths forward for making omaveloxolone available to patients with FA.”

Hand dexterity and pyramidal dysfunction in Friedreich Ataxia, a finger tapping study

Gilles Naeije MD, PhD Antonin Rovai PhD Massimo Pandolfo MD Xavier De Tiège MD, PhD.; Mov Disord Clin Pract. Accepted Author Manuscript. doi:10.1002/mdc3.13126

This study provides evidence for a prominent involvement of pyramidal dysfunction in upper limb dexterity loss as well as a potential outcome measure for clinical studies in FRDA. FRDA patients had slower and more regular FT rate than controls. Eleven FRDA patients showed FT rate slowing. Those patients had longer disease duration and higher SARA scores. Seven patients with FT rate slowing had MEP and all displayed prolonged CMCT, while the four other patients with constant FT rate had normal CMCT.

Progression Characteristics in Friedreich's Ataxia: A 4-Year Observational Study

Reetz, Kathrin and Dogan, Imis and Hilgers, Ralf-Dieter and Giunti, Paola and Mariotti, Caterina and Nanetti, Lorenzo and Durr, Alexandra and Ewenczyk, Claire and Boesch, Sylvia and Nachbauer, Wolfgang and Klopstock, Thomas and Stendel, Claudia and Javier Rodríguez de Rivera Garrido, Francisco and Schöls, Ludger and Hayer, Stefanie and Klockgether, Thomas and Giordano, Ilaria and Didszun, Claire and Rai, Myriam and Pandolfo, Massimo and Schulz, Jörg B. and Group, EFACTS Study. "Preprints with The Lancetare are not Lancet publications or necessarily under review with a Lancet journal. These preprints are early stage research papers that have not been peer-reviewed". doi:10.2139/ssrn.3723615

Background: The European Friedreich’s Ataxia Consortium for Translational Studies (EFACTS) investigates the natural history of Friedreich’s ataxia (FRDA) in a prospective multinational registry study. We aimed to assess progression and metric characteristics of clinical rating scales based on longitudinal 4-year data.

Antiferroptotic Activity of Phenothiazine Analogues: A Novel Therapeutic Strategy for Oxidative Stress Related Disease

Jun Liu, Indrajit Bandyopadhyay, Lei Zheng, Omar M. Khdour, and Sidney M. Hecht; ACS Med. Chem. Lett. 2020, 11, 11, 2165–2173,  September 15, 2020, doi:10.1021/acsmedchemlett.0c00293.

Recently, we showed that lipophilic methylene blue (MB) and methylene violet (MV) analogues both promoted increased frataxin levels and mitochondrial biogenesis, in addition to their antioxidant activity in cultured FRDA cells. Presently, we report the synthesis of series of lipophilic phenothiazine analogues that potently inhibit ferroptosis. The most promising compounds (1b–5b) exhibited an improved protection compared to the parent phenothiazine against erastin- and RSL3-induced ferroptotic cell death. These analogues have equivalent or better potency than ferrostatin-1 (Fer-1) and liproxstatin-1 (Lip-1), that are among the most potent inhibitors of this regulated cell death described so far. They represent novel lead compounds with therapeutic potential in relevant ferroptosis-driven disease models such as FRDA.

Analysis of Postural Control in Sitting by Pressure Mapping in Patients with Multiple Sclerosis, Spinal Cord Injury and Friedreich’s Ataxia: A Case Series Study

Reguera-García, M.M.; Leirós-Rodríguez, R.; Álvarez-Barrio, L.; Alonso-Cortés Fradejas, B.; Sensors 2020, 20, 6488.

The tests applied were: pressure mapping, seated Lateral Reach Test, seated Functional Reach Test, Berg Balance Scale, Posture and Postural Ability Scale, Function in Sitting Test, and Trunk Control Test. The participants with Friedreich’s ataxia showed a tendency to present a higher mean pressure on the seat of subject’s wheelchair compared to other groups. In parallel, users with spinal cord injury showed a tendency to present the highest values of maximum pressure and area of contact. People with different neurological pathologies and similar results in functional tests have very different results in the pressure mapping. Although it is not possible to establish a strong statistical correlation, the relationships between the pressure mapping variables and the functional tests seem to be numerous, especially in the multiple sclerosis group.

Left ventricular unloading with transaortic Impella 2.5 implantation in a pediatric patient supported by ECLS.

Sandoval Boburg, R., Mustafi, M., Magunia, H., Kling, S., Schlensak, C. and Popov, A.‐F., Artificial Organs. Accepted Author Manuscript. (2020) doi:10.1111/aor.13862 

We report the case of a 12-year old female patient with Friedreich´s Ataxia and diabetes mellitus. Due to a progressive multi-organ failure a veno-arterial extracorporeal membrane oxygenation (VA-ECMO) was implanted through the axillary vessels. However, due to a lack of ejection and severe dilatation of the left ventricle, an Impella 2.5 was implanted. Due to the small diameter of the femoral arteries, we performed a trans-aortic implantation through a median sternotomy via a dacron tube graft. We report on the procedure and peri-operative outcome.

Minoryx’s preclinical data for leriglitazone in Friedreich’s Ataxia published in Neurobiology of Disease Journal

Mataró, Barcelona, Spain and Gosselies, Belgium, November 16, 2020 – Minoryx Therapeutics, a Phase 3 clinical stage biotech company focused on the development of differentiating treatment options in orphan central nervous system (CNS) disorders with high unmet need, today announces the publication in ‘Neurobiology of disease’ of preclinical data on its lead compound, leriglitazone, showing potential therapeutic action and protection against neurodegeneration, in particular against Friedreich’s Ataxia (FRDA).

The preclinical data, published on November 7, 2020, supports the on-going clinical development in treating FRDA. The results show that the company’s lead compound, leriglitazone, improves impairments that are derived from frataxin loss – the genetic deficiency that causes FRDA.

Ferroptosis in Friedreich’s Ataxia: A Metal-Induced Neurodegenerative Disease

La Rosa, P.; Petrillo, S.; Fiorenza, M.T.; Bertini, E.S.; Piemonte, F.; Biomolecules 2020, 10, 1551. doi:10.3390/biom10111551 

This review provides an analysis of the most recent advances in ferroptosis, with a special focus on Friedreich’s Ataxia (FA), the most common autosomal recessive neurodegenerative disease, caused by reduced levels of frataxin, a mitochondrial protein involved in iron–sulfur cluster synthesis and antioxidant defenses. The hypothesis is that the iron-induced oxidative damage accumulates over time in FA, lowering the ferroptosis threshold and leading to neuronal cell death and, at last, to cardiac failure. The use of anti-ferroptosis drugs combined with treatments able to activate the antioxidant response will be of paramount importance in FA therapy, such as in many other neurodegenerative diseases triggered by oxidative stress.

Cardiomyopathy as the first manifestation of Friedreich's ataxia

Rafael Tuzino Leite Neves Maffei; Giulio de los Santos Fortuna; Luca Campolino Rosso; Pedro Dragone Pires; Ivan Rondelli Autops Case Rep, vol.10, n3, e2020204, 2020; doi:10.4322/acr.2020.204 

 We present the case of a female patient diagnosed in childhood with Friedreich Ataxia (FA). At the age of 6, she developed left congestive heart failure with cardiomyopathy, as evident on echocardiogram. Neurologic signs only appeared at age 7, including marked loss of muscle mass, gait instability, muscle clonus, and Babinski's signal. At age 27, she had a stroke and was hospitalized; a few days later, she had a cardiorespiratory arrest with asystole, leading to death. The autopsy disclosed severe cardiomyopathy and significant myocardial replacement with fibrosis; therefore, the cause of death was assumed to be heart failure. Compared to the literature, our case has some unique features, such as cardiac disease as the presenting manifestation instead of gait instability, which is the major initial sign in most FA cases. Since our patient was submitted to an autopsy, it was an opportunity to retrieve important data to confirm the diagnosis and to evaluate the pathophysiology of this entity, such as myocardium fibrosis and cerebellar degeneration. In summary, our case demonstrates that cardiac disease can be the first manifestation of FA, with eventual diagnostic and prognostic implications. In addition, the autopsy provided findings of severe cardiomyopathy associated with FA.

Epigenetic Regulation of the Clinical Signs of Friedreich’s Disease

E. P. Nuzhny, N. Yu. Abramycheva, N. S. Nikolaeva, M. V. Ershova, S. A. Klyushnikov, S. N. Illarioshkin & E. Yu. Fedotova; Neurosci Behav Physi (2020). doi:10.1007/s11055-020-00998-9 

Studies of genetic-epigenetic interactions identified correlations between the extent of methylation of a series of CpG sites in the UP-GAA and DOWN-GAA and the number of GAA repeats in both expanded alleles of the FXN gene in patients with FD. We also found a link between methylation and the presence of the extraneural signs of FD: cardiomyopathy was more likely to be present when the CpG site of the promoter region was hypermethylated, while impairments to carbohydrate metabolism were more common in hypomethylation of CpG sites in the DOWN-GAA area. Conclusions. The data obtained here provide evidence that epigenetic modifications of the FXN gene make a significant contribution to forming the clinical picture of FD.

The Nrf2 induction prevents ferroptosis in Friedreich’s Ataxia

Piergiorgio La Rosa, Sara Petrillo, Riccardo Turchi, Francesco Berardinelli, Tommaso Schirinzi, Gessica Vasco, Daniele Lettieri-Barbato, Maria Teresa Fiorenza, Enrico S. Bertini, Katia Aquilano, Fiorella Piemonte, Redox Biology, 2020, 101791, doi:10.1016/j.redox.2020.101791.

Ferroptosis is an iron-dependent cell death caused by impaired glutathione metabolism, lipid peroxidation and mitochondrial failure. Emerging evidences report a role for ferroptosis in Friedreich’s Ataxia (FRDA), a neurodegenerative disease caused by the decreased expression of the mitochondrial protein frataxin. Nrf2 signalling is implicated in many molecular aspects of ferroptosis, by upstream regulating glutathione homeostasis, mitochondrial function and lipid metabolism. As Nrf2 is down-regulated in FRDA, targeting Nrf2-mediated ferroptosis in FRDA may be an attractive option to counteract neurodegeneration in such disease, thus paving the way to new therapeutic opportunities. In this study, we evaluated ferroptosis hallmarks in frataxin-silenced mouse myoblasts, in hearts of a frataxin Knockin/Knockout (KIKO) mouse model, in skin fibroblasts and blood of patients, particularly focusing on ferroptosis-driven gene expression, mitochondrial impairment and lipid peroxidation. The efficacy of Nrf2 inducers to neutralize ferroptosis has been also evaluated.

PPAR gamma agonist leriglitazone improves frataxin-loss impairments in cellular and animal models of Friedreich Ataxia

Laura Rodríguez-Pascau, Elena Britti, Pablo Calap-Quintana, Yi Na Dong, Cristina Vergara, Fabien Delaspre, Marta Medina, Jordi Tamarit, Federico V. Pallardó, Pilar Gonzalez-Cabo, Joaquim Ros, David R. Lynch, Marc Martinell, Pilar Pizcueta, Neurobiology of Disease, 2020, 105162, doi:10.1016/j.nbd.2020.105162. 

Here we assess whether MIN-102 (INN: leriglitazone), a novel brain penetrant and orally bioavailable PPARγ agonist with an improved profile for central nervous system (CNS) diseases, rescues phenotypic features in cellular and animal models of FRDA. In frataxin-deficient dorsal root ganglia (DRG) neurons, leriglitazone increased frataxin protein levels, reduced neurite degeneration and α-fodrin cleavage mediated by calpain and caspase 3, and increased survival. Leriglitazone also restored mitochondrial membrane potential and partially reversed decreased levels of mitochondrial Na+/Ca2+ exchanger (NCLX), resulting in an improvement of mitochondrial functions and calcium homeostasis. In frataxin-deficient primary neonatal cardiomyocytes, leriglitazone prevented lipid droplet accumulation without increases in frataxin levels. Furthermore, leriglitazone improved motor function deficit in YG8sR mice, a FRDA mouse model. In agreement with the role of PPARγ in mitochondrial biogenesis, leriglitazone significantly increased markers of mitochondrial biogenesis in FRDA patient cells. Overall, these results suggest that targeting the PPARγ pathway by leriglitazone may provide an efficacious therapy for FRDA increasing the mitochondrial function and biogenesis that could increase frataxin levels in compromised frataxin-deficient DRG neurons. Alternately, leriglitazone improved the energy metabolism by increasing the fatty acid β-oxidation in frataxin-deficient cardiomyocytes without elevation of frataxin levels. This could be linked to a lack of significant mitochondrial biogenesis and cardiac hypertrophy. The results reinforced the different tissue requirement in FRDA and the pleiotropic effects of leriglitazone that could be a promising therapy for FRDA.

Electrocardiogram in Friedreich's ataxia: A short‐term surrogate endpoint for treatment efficacy

Sandra Mastroianno MD Michele Germano MD Angela Maggio MD Raimondo Massaro MD Domenico Rosario Potenza MD Aldo Russo MD Massimo Carella PhD Giuseppe Di Stolfo MD, PhD; Ann Noninvasive Electrocardiol. 2020; 00:e12813. doi:10.1111/anec.12813 

We describe the case of a 21‐year‐old patient affected by Friedreich's ataxia on wheel‐chair, with initial cardiac involvement and electrocardiographic features characterized by thiamine treatment‐related negative T wave and QTc variations. We discuss plausible physiopathology and potential ECG role implications as an intermediate marker of treatment response in future clinical trials considering patients affected by Friedreich's ataxia.

Effect of Mitochondrial and Cytosolic FXN Isoform Expression on Mitochondrial Dynamics and Metabolism

Agrò, M.; Díaz-Nido, J. , Int. J. Mol. Sci. 2020, 21, 8251. doi:10.3390/ijms21218251 (registering DOI)

Alternative forms of frataxin have been described, with different cellular localization and tissue distribution, including a cerebellum-specific cytosolic isoform called FXN II. Here, we explored the functional roles of FXN II in comparison to the mitochondrial FXN I isoform, highlighting the existence of potential cross-talk between cellular compartments. To achieve this, we transduced two human cell lines of patient and healthy subjects with lentiviral vectors overexpressing the mitochondrial or the cytosolic FXN isoforms and studied their effect on the mitochondrial network and metabolism. We confirmed the cytosolic localization of FXN isoform II in our in vitro models. Interestingly, both cytosolic and mitochondrial isoforms have an effect on mitochondrial dynamics, affecting different parameters. Accordingly, increases of mitochondrial respiration were detected after transduction with FXN I or FXN II in both cellular models. Together, these results point to the existence of a potential cross-talk mechanism between the cytosol and mitochondria, mediated by FXN isoforms. A more thorough knowledge of the mechanisms of action behind the extra-mitochondrial FXN II isoform could prove useful in unraveling FRDA physiopathology.

European Investment Bank provides Minoryx with up to €25 million to support development of breakthrough therapies in orphan neurodegenerative diseases

Press release, 30 October 2020, Barcelona.

 The European Investment Bank (EIB) today announced that it has approved €25 million financing for Minoryx Therapeutics, a Phase 3 clinical stage biotech company focused on the development of differentiating treatment options for orphan central nervous system (CNS) disorders.

The EU bank will grant long-term financing to Minoryx to drive the company's research activities in orphan genetic diseases for which there are currently no approved drugs available. The EIB investments will specifically support the development of Minoryx's leriglitazone, a disease-modifying treatment (PPAR-γ agonist) currently being evaluated in three late-stage clinical trials:......Phase 2 FRAMES study in Friedreich's Ataxia (FRDA), a life threatening disease characterised by neurodegeneration resulting in loss of coordination, muscle strength, and cardiomyopathy.

EL BANCO EUROPEO DE INVERSIONES PROPORCIONA €25M A MINORYX PARA APOYAR EL DESARROLLO DE TERAPIAS INNOVADORAS EN ENFERMEDADES RARAS NEURODEGENERATIVAS.

Mataró (Barcelona, España) y Charleroi (Bélgica), 30 de octubre de 2020. Minoryx Therapeutics, una empresa biotecnológica en fase clínica III especializada en el desarrollo de tratamientos diferenciales para enfermedades raras del sistema nervioso central (CNS), ha anunciado hoy que el Banco Europeo de Inversiones (BEI) ha aprobado una financiación de 25 millones de euros. El banco de la UE concederá financiación a largo plazo a Minoryx para impulsar las actividades de investigación y desarrollo de la entidad en enfermedades genéticas huérfanas para las que actualmente no se dispone de medicamentos aprobados.

 Las inversiones del BEI apoyarán específicamente el desarrollo de la leriglitazona, un agonista PPAR gamma diferenciado y con potencial de modificar el curso de la enfermedad que actualmente se está evaluando en tres ensayos clínicos en fase avanzada. Estudio FRAMES de fase II en ataxia de Friedreich (FRDA).

30/10/2020. ACN Mataró.-El Banc Europeu d’Inversions (BEI) ha anunciat l’aprovació de 25 milions d’euros en finançament per a Minoryx Therapeutics, una empresa de biotecnologia amb seu a Mataró que es dedica al desenvolupament de noves opcions terapèutiques per a malalties del sistema nerviós central per a les que no hi ha medicaments aprovats, com l’adrenomieloneuropatia, l’adrenoleucodistròfia o l’atàxia de Friedreich. BEI da 25 millones a firma que desarrolla terapia para enfermedades genéticas. Barcelona, 30 oct (EFE).- 

El Banco Europeo de Inversiones (BEI) ha anunciado que financiará con 25 millones de euros a Minoryx Therapeutics, una empresa de biotecnología centrada en el desarrollo de nuevas terapias para enfermedades genéticas huérfanas del sistema nervioso central y con sede en el Tecnocampus de Mataró (Barcelona). El ensayo (FRAMES) estudia la ataxia de Friedreich (AF), una enfermedad potencialmente mortal caracterizada por una neurodegeneración que provoca pérdida de coordinación y de fuerza muscular y cardiomiopatía.

 

[4Fe-4S] cluster trafficking mediated by Arabidopsis mitochondrial ISCA and NFU proteins

Tamanna Azam, Jonathan Przybyla-Toscano, Florence Vignols, Jérémy Couturier, Nicolas Rouhier, and Michael K. Johnson, J. Biol. Chem. jbc.RA120.015726. doi:10.1074/jbc.RA120.015726

 The results demonstrate rapid, unidirectional and quantitative [4Fe-4S]2+ cluster transfer from ISCA1a/2 to NFU4 or NFU5 that further delineates their respective positions in the plant ISC machinery and their contributions to the maturation of client [4Fe-4S] cluster-containing proteins.

An Overview of the Ferroptosis Hallmarks in Friedreich’s Ataxia

Turchi, R.; Faraonio, R.; Lettieri-Barbato, D.; Aquilano, K. Biomolecules 2020, 10, 1489. doi:10.3390/biom10111489 

 Even though ferroptosis has been associated with various neurodegenerative diseases including FRDA, the mechanisms leading to disease onset/progression have not been demonstrated yet. We describe the molecular alterations occurring in FRDA that overlap with those characterizing ferroptosis. Major conclusions: The study of ferroptotic pathways is necessary for the understanding of FRDA pathogenesis, and anti-ferroptotic drugs could be envisaged as therapeutic strategies to cure FRDA.

Gene Therapy Company AavantiBio Launches With $107 Million Series A Financing From Perceptive Advisors, Bain Capital Life Sciences, RA Capital Management and Sarepta Therapeutics

CAMBRIDGE, Mass., Oct. 22, 2020 (GLOBE NEWSWIRE). 

 A premier syndicate of life sciences investors including Perceptive Advisors, Bain Capital Life Sciences (“Bain Capital”), and RA Capital Management (“RA Capital”) (collectively the “Investor Group”) together with Sarepta Therapeutics, Inc. (“Sarepta”) (NASDAQ: SRPT), a leader in precision genetic medicine for rare diseases, today announced a $107 million Series A financing to create AavantiBio, a gene therapy company focused on transforming the lives of patients with rare genetic diseases. The private financing round includes a $15 million equity investment from Sarepta.

Headquartered in the greater Boston area, UF startup and UF Innovate | The Hub resident client AavantiBio, is co-founded by renowned gene therapy researchers Barry Byrne, M.D., Ph.D., and Manuela Corti, P.T., Ph.D., who together bring thirty years of experience to the company. AavantiBio’s lead program is in Friedreich’s Ataxia (FA), a rare inherited genetic disease that causes cardiac and central nervous system dysfunction. AavantiBio’s research efforts expand on foundational research conducted by Drs. Byrne and Corti in Friedreich’s Ataxia, among other rare genetic disorders. AavantiBio will benefit from strategic partnerships with the University of Florida’s renowned Powell Gene Therapy Center and the MDA Care Center at UF Health where Drs. Byrne and Corti maintain their research and clinical practices. Initial funding in AavantiBio was provided by GoFAR, an Italian patient advocacy group, and the Muscular Dystrophy Association Venture Philanthropy Fund.

The French Association of Ataxia in Friedreich renews its 25,000 euro grant to validate the therapeutic potential of calcitriol for treating this rare malaltia

IRBLleida, Friday, October 23, 2020. The French Association of Ataxia of Friedreich has renewed the aid of 25,000 euros to the Oxidative stress biochemistry Research Group of the Biomedical Research Institute of Lleida (IRBLleida) and the University of Lleida (UdL) to validate the therapeutic potential of calcitriol, the active form of vitamin D, to treat this disease. "The entity has decided to continue collaborating due to the advances in research carried out in Lleida, despite the difficulties of working in the laboratory during the confinement and the new normality" explained the principal investigator of this project, Fabien Delaspre.

Sarepta, continuing its gene therapy push, helps launch a startup

BIOPHARMA DIVE, Oct. 22, 2020. AavantiBio joins a couple large, powerful companies in the hunt for a gene therapy to treat Friedreich's ataxia. Pfizer and Novartis are each working on their own programs. Outside of gene therapy, Reata Pharmaceuticals disclosed last year positive data from a study that tested an oral drug, known as omaveloxolone, in patients with Friedreich's ataxia. Reata said it intends to file the drug for approval based on those results.

Design Therapeutics Appoints Industry Veteran, Dr. João Siffert, as Chief Executive Officer

Design Therapeutics. San Diego, Calif., Oct. 20, 2020

Design Therapeutics, a biotechnology company developing a platform of gene targeted chimera (GeneTAC™) small molecules for the treatment of serious degenerative disorders caused by nucleotide repeat expansions, today announced that João Siffert, M.D., has been appointed as chief executive officer and will also join the Board of Directors. Dr. Siffert joins the founding Design Therapeutics team, including Pratik Shah, Ph.D., co-founder and executive chairman; Aseem Ansari, Ph.D., co-founder and director; and Sean Jeffries, Ph.D., chief business officer. Dr. Siffert brings extensive industry knowledge to Design, with 30 years combined experience in the biopharmaceutical industry, clinical practice and academia. 

 Design Therapeutics is a biotechnology company developing a new class of therapies based on a platform of gene targeted chimera (GeneTAC™) small molecules. The company’s lead program is focused on the treatment of Friedreich ataxia and discovery efforts are ongoing in other for serious degenerative disorders caused by nucleotide repeat expansions.

Assessment of Ataxia Rating Scales and Cerebellar Functional Tests: Critique and Recommendations

Perez-Lloret S, van de Warrenburg B, Rossi M, Rodríguez-Blázquez C, Zesiewicz T, Saute JAM, Durr A, Nishizawa M, Martinez-Martin P, Stebbins GT, Schrag A, Skorvanek M; and members of the MDS Rating Scales Review Committee; Mov Disord. 2020 Oct 6. doi: 10.1002/mds.28313

We identified some "recommended" scales and functional tests for the assessment of patients with major hereditary ataxias and other cerebellar disorders. The main limitations of these instruments include the limited assessment of patients in the more severe end of the spectrum and children. Further research in these populations is warranted.

Safety and Efficacy of Omaveloxolone in Friedreich's Ataxia (MOXIe Study)

Lynch, D.R., Chin, M.P., Delatycki, M.B., Subramony, S., Corti, M., Hoyle, J.C., Boesch, S., Nachbauer, W., Mariotti, C., Mathews, K.D., Giunti, P., Wilmot, G., Zesiewicz, T., Perlman, S., Goldsberry, A., O'Grady, M. and Meyer, C.J. (2020). Ann Neurol. Accepted Author Manuscript. doi:10.1002/ana.25934

In the MOXIe trial, omaveloxolone significantly improved neurological function compared to placebo and was generally safe and well tolerated. It represents a potential therapeutic agent in FRDA.

Reata Pharma Accused in Securities Suit of Hyping Drug Prospects

PHILADELPHIA, Oct. 16, 2020 (GLOBE NEWSWIRE) -- Kehoe Law Firm, P.C. is investigating potential securities claims on behalf of investors of Reata Pharmaceuticals, Inc. (“Reata” or the “Company”) (NASDAQ: RETA) to determine whether the Company engaged in securities fraud or other unlawful business practices. Omaveloxolone, according to the complaint, is “[a]mong Reata’s drug candidates under development . . . which is in Phase 2 clinical development to treat Friedreich’s ataxia (‘FA’). Following the announcement of positive data from the MOXIe Part 2 study of omaveloxolone for FA in October 2019, the Company represented that it would seek submission for marketing approval of omaveloxolone for the treatment of FA in the [United States] with the U.S. Food and Drug Administration (‘FDA’).” The Reata Defendants, according to the complaint, made false and/or misleading statements and/or failed to disclose that: (i) the MOXIe Part 2 study results were insufficient to support a single study marketing approval of omaveloxolone for the treatment of FA in the United States without additional evidence.

Longitudinal Study of Cognitive Functioning in Friedreich’s Ataxia

Atteneri Hernández-Torres, Fernando Montón, Stephany Hess Medler, Érika de Nóbrega and Antonieta Nieto; Longitudinal Study of Cognitive Functioning in Friedreich’s Ataxia. DOI:10.1017/S1355617720000958 Published online by Cambridge University Press: 14 October 2020

At follow-up, cerebellar symptoms had worsened, and patients presented greater disability. Differences between baseline and follow-up were observed in motor and cognitive reaction times, several trials of the Stroop test, semantic fluency, and block designs. No other cognitive changes were observed. Deterioration in simple cognitive reactions times and block designs performance correlated with the progression of cerebellar symptoms. Our study has demonstrated for the first time that patients with FRDA experience a significant decline over time in several cognitive domains. Specifically, after an eight-year period, FRDA patients worsened in processing speed, fluency, and visuoconstructive skills. This progression is unlikely to be due to greater motor or speech impairment.

Larimar Therapeutics Announces Formation of Scientific Advisory Board

BALA CYNWYD, Pa., Oct. 13, 2020 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (Nasdaq:LRMR), a clinical-stage biotechnology company focused on developing treatments for complex rare diseases, today announced the formation of its Scientific Advisory Board (SAB). Larimar’s SAB is comprised of distinguished research scientists, professors and industry experts recognized as key opinion leaders in the fields of rare disease, pediatrics and mitochondrial disease. “Larimar is privileged to have this group of prestigious, multidisciplinary advisors who are committed to advancing the research and development of CTI-1601 for Friedreich’s ataxia,”

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

Vilema-Enríquez G, Quinlan R, Kilfeather P, Mazzone R, Saqlain S, Del Molino Del Barrio I, Donato A, Corda G, Li F, Vedadi M, Németh AH, Brennan PE, Wade-Martins R.; J Biol Chem. 2020 Oct 7:jbc.RA120.015533. doi: 10.1074/jbc.RA120.015533

Here, we identify that SUV4-20 histone methyltransferases, specifically SUV4-20 H1, play an important role in the regulation of FXN expression and represent a novel therapeutic target.

Sexual function, intimate relationships and Friedreich ataxia

Louise A. Corben, Mireille M. Hermans, Alice Marks, Louise M. Crowe & Martin B. Delatycki; J Neurol (2020). https://doi.org/10.1007/s00415-020-10258-y 

 This study confirmed FRDA impacts sexual functioning, sexual satisfaction and the capacity to form intimate relationships. Understanding the nature and extent of SD is critical to developing interventions and recommendations designed to enhance sexual function, sexuality, and intimate relationships for individuals with FRDA.

Sensitivity of Neuroimaging Indicators in Monitoring the Effects of Interferon Gamma Treatment in Friedreich’s Ataxia

Marinela Vavla, Filippo Arrigoni, Nicola Toschi, Denis Peruzzo, Maria Grazia D’Angelo, Sandra Gandossini, Annamaria Russo, Eleonora Diella, Stefania Tirelli, Roberto Salati, Alessandra Rufini, Ivano Condo, Roberto Testi and Andrea Martinuzzi; Front. Neurosci., 09 October 2020; doi:10.3389/fnins.2020.00872 

Advanced MRI imaging (diffusion tensor imaging, DTI; functional MRI, fMRI; and resting-state fMRI, rs-fMRI) and retinal imaging (optical coherence tomography, OCT) were tested longitudinally in a small group of Friedreich’s ataxia patients participating in an open-label clinical trial testing the safety and the efficacy of 6-month treatment with interferon gamma. Preliminary data encourage the use of MRI, in particular fMRI, as a non-invasive method to monitor treatment response in FRDA and to achieve a better understanding of the physiology behind the observed treatment-induced effects.

A Study to Assess the Efficacy and Safety of Vatiquinone for the Treatment of Participants With Friedreich Ataxia

ClinicalTrials.gov Identifier: NCT04577352

Randomized, Parallel-Arm, Double-Blind, Placebo-Controlled Study With Open-Label Extension to Assess the Efficacy and Safety of Vatiquinone for the Treatment of Friedreich Ataxia (MOVE-FA).

Lead Sponsor: PTC Therapeutics. Start Date November 17, 2020, Phase 2/Phase 3, Location Countries: Australia, Canada, Italy, United States. The primary objective of the study is to evaluate the efficacy (using the modified Friedreich Ataxia Rating Scale [mFARS]) and safety of vatiquinone in participants with Friedreich ataxia (FA).

Neurodegenerative Diseases and the Auditory-Vestibular System

Mehta, Zarin PhD; Hale, Troy AuD; McMillan, Raechal BS; Sudaj, Gabriel BS; Pullman, Kelly AuD; Belus, Gail AuD; The Hearing Journal: October 2020 - Volume 73 - Issue 10 - p 38,40,41 doi: 10.1097/01.HJ.0000719804.32573.ea

Physicians and audiologists should consider auditory-vestibular dysfunction in patients with neurodegenerative diseases even when peripheral hearing sensitivity is normal.

Recapitulating the frataxin activation mechanism in an engineered bacterial cysteine desulfurase supports the architectural switch model

Shachin Patra, Cheng-Wei Lin, Manas K. Ghosh, Steven M. Havens, Seth A. Cory, David H. Russell, David P. Barondeau bioRxiv 2020.10.06.326603; doi:10.1101/2020.10.06.326603

Overall, these studies indicate a weakening of the homodimeric interface was a key development during the evolution of the eukaryotic system and provide new insights into the role of FXN.

Expanding the genotype–phenotype correlation of childhood sensory polyneuropathy of genetic origin

Samya Chakravorty, Rachel Logan, Molly J. Elson, Rebecca R. Luke & Sumit Verma; Sci Rep 10, 16184 (2020). doi:10.1038/s41598-020-73219-5 

Our single-center study shows genetic sensory polyneuropathies associated with progressive neurodegenerative disorders such as mitochondrial ataxia, Friedreich ataxia, spinocerebellar ataxia type 2, ataxia telangiectasia, spastic paraplegia, giant axonal neuropathy, and fumarate hydratase deficiency.

Emerging therapies in Friedreich's Ataxia

Zesiewicz TA, Hancock J, Ghanekar SD, Kuo SH, Dohse CA, Vega J. ; Expert Rev Neurother. 2020 Sep 21:1-14. doi:10.1080/14737175.2020.1821654. 

Areas covered include past and emerging therapies for FRDA, including antioxidants and mitochondrial-related agents, nuclear factor erythroid-derived 2-related factor 2 (Nrf2) activators, deuterated polyunsaturated fatty acids, iron chelators, histone deacetylase (HDAC) inhibitors, trans-activator of transcription (TAT)-frataxin, interferon gamma (IFNγ), erythropoietin, resveratrol, gene therapy, and anti-sense oligonucleotides (ASOs), among others.

Mechanism of Iron–Sulfur Cluster Assembly: In the Intimacy of Iron and Sulfur Encounter

Srour, B.; Gervason, S.; Monfort, B.; D’Autréaux, B. . Inorganics 2020, 8, 55.   doi:10.3390/inorganics8100055

In this paper, we review the most recent advances on the mechanism of assembly for the founding member of the Fe–S cluster family, the [2Fe2S] cluster that is the building block of all other Fe–S clusters. The aim is to provide a survey of the mechanisms of iron and sulfur insertion in the scaffold proteins by examining how these processes are coordinated, how sulfide is produced and how the dinuclear [2Fe2S] cluster is formed, keeping in mind the question of the physiological relevance of the reconstituted systems. We also cover the latest outcomes on the functional role of the controversial frataxin protein in Fe–S cluster biosynthesis.

Oxidative stress-dependent frataxin inhibition mediated alcoholic hepatocytotoxicity through ferroptosis

Jingjing Liu, Hui He, Jing Wang, Xiaoping Guo, Hongkun Lin, Huimin Chen, Chunjie Jiang, Li Chen, Ping Yao, Yuhan Tang, Toxicology, 2020, 152584, doi:10.1016/j.tox.2020.152584. Frataxin deficiency enhanced ferroptosis driven by ethanol via evaluating the levels of lactate dehydrogenase, cell morphological changes, mitochondrial labile iron pool, and lipid peroxidation. Conversely, restoring frataxin alleviated the sensitivity to ferroptosis. In addition, frataxin overexpression mitigated the sensitivity of ethanol-induced ferroptosis in HepG2CYP2E1+/+.

Home Based Tele-exercise for People With Chronic Neurological Impairments: COVID and Beyond (Telex)

ClinicalTrials.gov Identifier: NCT04564495. To assess the impact of a 12-week virtual seated physical intervention on cardiovascular health and wellness in people with chronic neurological impairments (CNI). Locations: United States, New York, Burke Neurological Institute, September 25, 2020

Extra-mitochondrial mouse frataxin and its implications for mouse models of Friedreich’s ataxia

Liwei Weng, Laurent Laboureur, Qingqing Wang, Lili Guo, Peining Xu, Leah Gottlieb, David R. Lynch, Clementina Mesaros & Ian A. Blair; Sci Rep 10, 15788 (2020). doi:10.1038/s41598-020-72884-w 

Mature mouse frataxin (78-207) only contributes 7–15% to the total frataxin protein present in mouse tissues. We have also found that truncated mature frataxin (79-207) is present primarily in the cytosol of mouse liver; whereas, frataxin (78-207) is primarily present in the mitochondria. These findings, which provide support for the role of extra-mitochondrial frataxin in the etiology of Friedreich’s ataxia, also have important implications for studies of mitochondrial dysfunction conducted in mouse models of frataxin deficiency.

Apart from our own studies on frataxin isoform E, several other studies have suggested that human mature frataxin can have an extra-mitochondria location. Alternatively, processing of the mature mouse frataxin could proceed in a different manner than in humans. If this is the case, we would suggest that mouse models do not serve as a good model for humans. Finally, as human gene therapy is tested in mouse models, it is possible that the mature human protein will undergo truncations in the mouse tissues, although they will most likely be at different sites because of the differences in amino acid sequence at the amino-terminus compared to mouse frataxin. This will impact on the assessment of efficacy and safety of the human transgene constructs (such as CAG-hFXN-HA) in mouse models.

IXICO joins neuroimaging consortium focused on Friedreich’s Ataxia

24 Sep 2020. IXICO PLC (LON:IXI) said it has entered a five year collaboration with the Friedreich's Ataxia Research Alliance (FARA) to become a member of the TRACK-FA neuroimaging consortium, focused on exploring novel imaging markers for Friedreich’s Ataxia (FA). The company added that it will be an industry member and stakeholder in the consortium and will work alongside academic partners with expertise in neuroimaging and conducting clinical research in FA including Monash University in Australia), the University of Minnesota and Aachen University in Germany.

Biomarker for Friedreich's Ataxia (BioFridA) (BioFridA)

ClinicalTrials.gov Identifier: NCT04548921. Responsible Party: Centogene AG Rostock. Recruitment Status : Recruiting, First Posted : September 15, 2020 International, multicenter, observational, longitudinal monitoring study to identify biomarker/s for Friedreich's Ataxia and to explore the clinical robustness, specificity, and long-term variability of these biomarker/s Locations: Lebanon, American University of Science and Technology, Beirut, Lebanon, 16-6452 Principal Investigator: Andre Megarbane, MD

Altered Secretome and ROS Production in Olfactory Mucosa Stem Cells Derived from Friedreich’s Ataxia Patients

Pérez-Luz, S.; Loria, F.; Katsu-Jiménez, Y.; Oberdoerfer, D.; Yang, O.-L.; Lim, F.; Muñoz-Blanco, J.L.; Díaz-Nido, J.; Int. J. Mol. Sci. 2020, 21, 6662. doi:10.3390/ijms21186662. Human olfactory ecto-mesenchymal stem cells represent a novel model that could prove useful due to their accessibility and neurogenic capacity. Here, we isolated and cultured these stem cells from Friedreich´s ataxia patients and healthy donors, characterizing their phenotype and describing disease-specific features such as reduced cell viability, impaired aconitase activity, increased ROS production and the release of cytokines involved in neuroinflammation. Importantly, we observed a positive effect on patient-derived cells, when frataxin levels were restored, confirming the utility of this in vitro model to study the disease. This model will improve our understanding of Friedreich´s ataxia pathogenesis and will help in developing rationally designed therapeutic strategies.

Iron-Sulfur Cluster Complex Assembly in the Mitochondria of Arabidopsis thaliana

 

Alejandro M. Armas, Manuel Balparda, Agustina Terenzi, Maria V. Busi, Maria A. Pagani and Diego F. Gomez-Casati; Plants 2020, 9(9), 1171, doi:10.3390/plants9091171 (registering DOI) In plants, the cysteine desulfurase (AtNFS1) and frataxin (AtFH) are involved in the formation of Fe-S groups in mitochondria, specifically, in Fe and sulfur loading onto scaffold proteins, and the subsequent formation of the mature Fe-S cluster. We found that the small mitochondrial chaperone, AtISD11, and AtFH are positive regulators for AtNFS1 activity in Arabidopsis. Moreover, when the three proteins were incubated together, a stronger attenuation of the Fenton reaction was observed compared to that observed with AtFH alone. Using pull-down assays, we found that these three proteins physically interact, and sequence alignment and docking studies showed that several amino acid residues reported as critical for the interaction of their human homologous are conserved. Our results suggest that AtFH, AtNFS1 and AtISD11 form a multiprotein complex that could be involved in different stages of the iron–sulfur cluster (ISC) pathway in plant mitochondria.

Rare Disease Trials Require Interactions With KOLs, Patients, & Regulators

 

Clinical Leader, September 9, 2020; Chief Editor: Ed Miseta Minoryx Therapeutics is a small biotech hoping to bring new hope to patients suffering from orphan CNS diseases. The company of 25 employees was founded in 2011 and is seeking treatments for diseases with a high unmet medical need. The company’s leading program is leriglitazone, currently in development for multiple CNS disorders. Leriglitazone is a small-molecule selective PPAR gamma agonist. 

Another example is the company’s Friedreich’s Ataxia study, which required a different interaction with regulators. In that case, the disease was better known to physicians and Minoryx was able to locate more data on the progression of the disease. The company designed a Phase 2 trial and, upon completion of that study, will discuss the results with regulators to determine future steps.

Ataxia: Hope starts with measurement

The Florey Institute of Neuroscience and Mental Health. News and media. 03 Sep 2020.
The team will be developing a prototype device to measure ataxia thanks to funding received from the Biomedical Translation Bridge program administered by MTP Connect.
The $500,000 in funding was announced today by the Minister for Health, the Hon. Greg Hunt MP, with US-based advocacy organisation Friedreich Ataxia Research Alliance (FARA) confirming they will match the government’s investment.
“Whilst there are multiple treatments in development for heredity forms of ataxia in particular, without clinicians being able to make objective measurements for the condition it makes it difficult to understand the effectiveness of these. We believe that developing a device which uses sensors and sophisticated algorithms to assess ataxia progression will allow these treatments to be fast tracked,” said Associate Professor Corben.

Molecular and Cellular Substrates for the Friedreich Ataxia. Significance of Contactin Expression and of Antioxidant Administration

Bizzoca, A.; Caracciolo, M.; Corsi, P.; Magrone, T.; Jirillo, E.; Gennarini, G.; Molecules 2020, 25, 4085. doi:10.3390/molecules25184085

In this study, the neural phenotype is explored in rodent models of the spinocerebellar disorder known as the Friedreich Ataxia (FA), which results from mutations within the gene encoding the Frataxin mitochondrial protein. For this, the M12 line, bearing a targeted mutation, which disrupts the Frataxin gene exon 4 was used, together with the M02 line, which, in addition, is hemizygous for the human Frataxin gene mutation (Pook transgene), implying the occurrence of 82–190 GAA repeats within its first intron. The mutant mice phenotype was compared to the one of wild type littermates in regions undergoing differential profiles of neurogenesis, including the cerebellar cortex and the spinal cord by using neuronal (β-tubulin) and glial (Glial Fibrillary Acidic Protein) markers as well as the Contactin 1 axonal glycoprotein, involved in neurite growth control. Morphological/morphometric analyses revealed that while in Frataxin mutant mice the neuronal phenotype was significantly counteracted, a glial upregulation occurred at the same time. Furthermore, Contactin 1 downregulation suggested that changes in the underlying gene contributed to the disorder pathogenesis. Therefore, the FA phenotype implies an alteration of the developmental profile of neuronal and glial precursors. Finally, epigallocatechin gallate polyphenol administration counteracted the disorder, indicating protective effects of antioxidant administration.

Registries for orphan drugs: generating evidence or marketing tools?

Carla E. M. Hollak, Sandra Sirrs, Sibren van den Berg, Vincent van der Wel, Mirjam Langeveld, Hanka Dekker, Robin Lachmann & Saco J. de Visser; Orphanet J Rare Dis 15, 235 (2020). doi:10.1186/s13023-020-01519-0

Independent disease registries for pre-and post-approval of novel treatments for rare diseases are increasingly important for healthcare professionals, patients, regulators and the pharmaceutical industry. Current registries for rare diseases to evaluate orphan drugs are mainly set up and owned by the pharmaceutical industry which leads to unacceptable conflicts of interest. To ensure independence from commercial interests, disease registries should be set up and maintained by healthcare professionals and patients. Public funding should be directed towards an early establishment of international registries for orphan diseases, ideally well before novel treatments are introduced. Regulatory bodies should insist on the use of data from independent disease registries rather than company driven, drug-oriented registries.

Broad Institute launches new effort to study rare neuromuscular disorder

Broad Institute, NEWS / 09.3.20. By Leah Eisenstadt.
A new research and drug discovery effort at the Broad Institute of MIT and Harvard is taking aim at the rare, inherited movement disorder Friedreich’s ataxia (FA), which causes progressive damage to the nervous system. FA arises from genetic mutations that lead to dysfunction of the cell’s energy-producing organelles called mitochondria.
“The goal of the Friedreich's Ataxia Accelerator is to nucleate a small group of investigators who will bring the power of genomics to this debilitating disease,” said Mootha, who is also a Howard Hughes Medical Institute investigator and professor of medicine at Harvard Medical School and Massachusetts General Hospital.

Impact of the therapeutic positioning report in the P&R process in Spain: analysis of orphan drugs approved by the European Commission and reimbursed in Spain from 2003 to 2019

Xavier Badia, Tania Vico, John Shepherd, Alicia Gil, José Luis Poveda-Andrés & César Hernández; Orphanet J Rare Dis 15, 224 (2020). doi:10.1186/s13023-020-01507-4

This study shows that the therapeutic positioning report plays a key role in the pricing and reimbursement process in Spain. A positive conclusion of the therapeutic positioning report seems to favourably affect pricing and reimbursement decisions in Spain and, since its introduction, has also contributed to reduce pricing and reimbursement approval timelines in Spain.

AveXis renamed Novartis Gene Therapies, signifying the growing importance of gene therapy to Novartis corporate strategy

Novartis, Sep 02, 2020

Novartis has renamed the previously acquired AveXis to Novartis Gene Therapies. The change signifies the growing importance of gene therapy to building a leading, focused medicines company with advanced therapy platforms.

The change to Novartis Gene Therapies is the natural evolution as the company scales up to deliver Zolgensma globally and expand its reach via a robust pipeline of AAV-based gene therapies for rare genetic diseases including investigational treatments for Rett syndrome, a genetic form of amyotrophic lateral sclerosis (ALS) and Friedreich’s ataxia. Novartis Gene Therapies also establishes a seamless global presence for Zolgensma and the gene therapies to come. Instead of alternating between the AveXis and Novartis umbrella brands by market, the company comes together under one banner as a unified entity.

Reata Announces the Presentation of the Pivotal MOXIe Part 2 Study of Omaveloxolone in Friedreich’s Ataxia at the American Academy of Neurology

September 03, 2020 06:45 ET | Source: Reata Pharmaceuticals, Inc.

PLANO, Texas, Sept. 03, 2020 (GLOBE NEWSWIRE) -- Reata Pharmaceuticals, Inc. (Nasdaq: RETA) (“Reata,” the “Company,” or “we”), a clinical-stage biopharmaceutical company, today announced the forthcoming presentation of efficacy and safety results from the pivotal MOXIe Part 2 study, a randomized, double-blind, placebo-controlled trial of omaveloxolone in Friedreich’s ataxia.

The presentation will take place on September 24, 2020 as part of the 2020 Emerging Science presentations hosted by the American Academy of Neurology (AAN). David Lynch, M.D., Ph.D., will present the data. Dr. Lynch is an attending physician at the Children’s Hospital of Philadelphia (CHOP), professor of neurology at the Perelman School of Medicine at the University of Pennsylvania, and the principal investigator of the MOXIe study.

Separately, Dr. Lynch will present the results of the MOXIe Part 2 study at the FARA 2020 Biomarker & Clinical Endpoint Meetin

High levels of frataxin overexpression leads to mitochondrial and cardiac toxicity in mouse models

Brahim Belbellaa, Laurence Reutenauer, Nadia Messaddeq, Laurent Monassier, Hélène Puccio; Molecular Therapy - Methods & Clinical Development, 2020, doi:10.1016/j.omtm.2020.08.018.

this study underlines the need, during the development of gene therapy approaches, to consider appropriately vector expression level, long term safety and biomarkers to monitor such events.

The uses of resveratrol for neurological diseases treatment and insights for nanotechnology based-drug delivery systems

Bruno Fonseca-Santos, Marlus Chorilli, International Journal of Pharmaceutics, 2020, 119832, doi:10.1016/j.ijpharm.2020.119832.

Due to the insolubility of this compound; the use of nanotechnology-based systems has been proposed for the incorporation of RES and RES-loaded nanocarriers have been designed for intranasal administration, oral or parenteral routes to deliver it to the brain. In general, these nanosystems have shown to be effective in many studies, pharmacological and pharmacokinetic assays, as well as some cell studies. The outcomes show that RES has been reported in human clinical trials for some neurological diseases, although no studies were performed in humans using nanocarriers, animal and/or cellular models have been reported to show good results regarding therapeutics on neurological diseases. Thus, the use of this nutraceutical has shown true for neurological diseases and its loading into nanocarriers displaying good results on the stability, delivery and targeting to the brain.

An Optimally Weighted User- and Item-based Collaborative Filtering Approach to Predicting Baseline Data for Friedreich’s Ataxia Patients

Wenbin Yue, Zidong Wang, Weibo Liu, Bo Tian, Stanislao Lauria, Xiaohui Liu, Neurocomputing, 2020, doi:10.1016/j.neucom.2020.08.031.

In this paper, a modified collaborative filtering (MCF) algorithm with improved performance is developed for recommendation systems with application in predicting baseline data of Friedreich’s Ataxia (FRDA) patients. The proposed MCF algorithm combines the individual merits of both the user-based collaborative filtering (UBCF) method and the item-based collaborative filtering (IBCF) method, where both the positively and negatively correlated neighbors are taken into account. The weighting parameters are introduced to quantify the degrees of utilizations of the UBCF and IBCF methods in the rating prediction, and the particle swarm optimization algorithm is applied to optimize the weighting parameters in order to achieve an adequate tradeoff between the positively and negatively correlated neighbors in terms of predicting the rating values. To demonstrate the prediction performance of the proposed MCF algorithm, the developed MCF algorithm is employed to assist with the baseline data collection for the FRDA patients. The effectiveness of the proposed MCF algorithm is confirmed by extensive experiments and, furthermore, it is shown that our algorithm outperforms some conventional approaches.

Plasma and red blood cell membrane accretion and pharmacokinetics of RT001 (bis-allylic 11,11-D2-linoleic acid ethyl ester) during long term dosing in patients

J. Thomas Brenna, Genevieve James, Mark Midei, Frederic Heerinckx, Paldeep Atwal, Peter Milner, Karsten Schmidt, Lex van der Ploeg, Robert Fielding, Mikhail S. Shchepinov, Journal of Pharmaceutical Sciences, 2020, doi:10.1016/j.xphs.2020.08.019.

RT001 is the di-deutero isotopologue of linoleic acid ethyl ester (D2-LA). Resistance to oxidative damage at the carbon-deuterium bond depends upon the concentration of D2-LA as a percentage of total LA. We report here on the plasma and red cell (RBC) pharmacokinetics (PK) of D2-LA, and its metabolite 13,13-D2-arachidonic acid (D2-AA), in patients with multiple neurodegenerative diseases (total of 59 participants). In Friedreich’s ataxia patients, D2-LA was absorbed and transported similarly to dietary LA, peaking at about 6 h after oral dosing. Plasma D2-LA concentrations approached steady state after 28 days of dosing. After 6 months of daily dosing in subjects with other disorders, D2-LA and D2-AA levels were at or above the 20% of total (D2-LA/ total LA, or D2-AA/ total AA) therapeutic targets for most subjects. We conclude that chronic dosing of RT001 and associated dietary guidance can be maintained over many months to achieve target plasma and RBC levels, forming a basis for therapeutic dosing across a broad range of conditions. RT001 has been safe and well-tolerated in 59 different participants treated across 10 different neurodegenerative diseases in multiple clinical trials for up to 36 months with no significant drug related adverse events limiting use.

Friedreich Ataxia: current state-of-the-art, and future prospects for mitochondrial-focused therapies

Federico V. Pallardó, Giovanni Pagano, Laura R. Rodríguez, Pilar Gonzalez-Cabo, Alex Lyakhovich, Marco Trifuoggi; Translational Research,
2020, doi:10.1016/j.trsl.2020.08.009.

The present mini review is aimed at evaluating the basic and clinical reports on the roles and the use of a set of iron chelators, antioxidants and some cofactors involved in the key mitochondrial functions. Extensive literature has focused on the protective roles of iron chelators, coenzyme Q10 and analogs, and vitamin E, altogether with varying outcomes in clinical studies. Other studies have suggested mitoprotective roles for other mitochondrial cofactors, involved in Krebs cycle, such as alpha-lipoic acid and carnitine, involved in acyl transport across the mitochondrial membrane.

Frataxin gene editing rescues Friedreich’s ataxia pathology in dorsal root ganglia organoid-derived sensory neurons

Pietro Giuseppe Mazzara, Sharon Muggeo, Mirko Luoni, Luca Massimino, Mattia Zaghi, Parisa Tajalli-Tehrani Valverde, Simone Brusco, Matteo Jacopo Marzi, Cecilia Palma, Gaia Colasante, Angelo Iannielli, Marianna Paulis, Chiara Cordiglieri, Serena Gea Giannelli, Paola Podini, Cinzia Gellera, Franco Taroni, Francesco Nicassio, Marco Rasponi & Vania Broccoli; Nat Commun 11, 4178 (2020). doi:10.1038/s41467-020-17954-3

These results strongly suggest that removal of the repressed chromatin flanking the GAA tract might contribute to rescue FXN total expression and fully revert the pathological hallmarks of FRDA DRG neurons.

Atypical structures of GAA/TTC trinucleotide repeats underlying Friedreich’s ataxia: DNA triplexes and RNA/DNA hybrids

Jiahui Zhang, Ashkan Fakharzadeh, Feng Pan, Christopher Roland, Celeste Sagui; Nucleic Acids Research, gkaa665, doi:10.1093/nar/gkaa665

The authors intended the study to provide a ‘rationale for the discovery and characterization of the non-B DNA regulatory structures involved in the formation of the RNA:DNA interactome’. However, experimental data with molecular resolution for these non-B DNA structures is noticeably scarce. We believe that structural studies such as ours can meaningfully contribute in the creation of such a roadmap.

Clinical presentation and survival of childhood hypertrophic cardiomyopathy: a retrospective study in United Kingdom

Gabrielle Norrish, Ella Field, Karen Mcleod, Maria Ilina, Graham Stuart, Vinay Bhole, Orhan Uzun, Elspeth Brown, Piers E F Daubeney, Amrit Lota, Katie Linter, Sujeev Mathur, Tara Bharucha, Khoon Li Kok, Satish Adwani, Caroline B Jones, Zdenka Reinhardt, Juan Pablo Kaski; European Heart Journal, Volume 40, Issue 12, 21 March 2019, Pages 986–993, doi:10.1093/eurheartj/ehy798

This study describes the clinical characteristics and outcomes of childhood HCM over four decades in a well-characterized United Kingdom cohort.
Aetiology was: non-syndromic (n = 433, 63%), RASopathy (n = 126, 18.3%), Friedreich’s ataxia (n = 59, 8.6%) or inborn errors of metabolism (IEM) (n = 64, 9%). In infants (n = 159, 23%) underlying aetiology was more commonly a RASopathy (42% vs. 11.2%, P < 0.0001) or IEM (18.9% vs. 6.4% P < 0.0001)

Multiple Ascending Dose Study of CTI-1601 Versus Placebo in Subjects With Friedreich's Ataxia

ClinicalTrials.gov Identifier: NCT04519567 Responsible Party: Larimar Therapeutics, Inc. First Posted: August 19, 2020

A Phase 1 Multiple Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Subcutaneous CTI-1601 Versus Placebo in Subjects With Friedreich's Ataxia

Actual Study Start Date: July 31, 2020
Estimated Primary Completion Date: June 30, 2021
Estimated Study Completion Date: June 30, 2021

Validation of low-cost system for gait assessment in children with ataxia

S. Summa, G. Tartarisco, M. Favetta, A. Buzachis, A. Romano, G.M. Bernava, A. Sancesario, G. Vasco, G. Pioggia, M. Petrarca, E. Castelli, E. Bertini, T. Schirinzi; Computer Methods and Programs in Biomedicine, 2020, 105705, Doi:10.1016/j.cmpb.2020.105705.

This study aims to test the usability of the Kinect system for assessing ataxia severity, exploring the potentiality of clustering algorithms and validating this system with a standard motion capture system.
The spatio-temporal parameters measured by Kinect cannot be used interchangeably with those parameters acquired with standard motion capture system in clinical practice but can still provide fundamental information. Specifically, these results might bring to the development of a novel system to perform easy and quick evaluation of gait in young patients with ataxia, useful for patients stratification in terms of clinical severity and diagnosis.

LARIMAR THERAPEUTICS : Management's Discussion and Analysis of Financial Condition and Results of Operations (form 10-Q) share with twitter share with LinkedIn share with facebook

MarketScreener; 08/14/2020.
CTI-1601 is currently being evaluated in Phase 1 clinical trials in patients with Friedreich's Ataxia. We have received orphan drug status, fast track designation and rare pediatric disease designation, from the U.S. Food and Drug Administration (the "FDA"), for CTI­1601. In addition, the European Medicines Agency ("EMA") Committee for Orphan Medicinal Products ("COMP") issued a positive opinion on the Company's application for orphan drug designation for CTI-1601. The receipt of such designations or positive opinions may not result in a faster development process, review or approval compared to products considered for approval under conventional FDA or EMA procedures and does not assure ultimate approval by the FDA or EMA.

Larimar Therapeutics (LRMR) Investor Presentation - Slideshow

Seeking Alpha Aug. 13, 2020 6:05 PM ET | About: Larimar Therapeutics, Inc. (LRMR)

About CTI-1601

Identification of a Novel Oleic Acid Analog with Protective Effects in Multiple Cellular Models of Friedreich Ataxia

M Grazia Cotticelli, Roberto Forestieri, Shujuan Xia, Sipak Joyasawal, Taehee Lee, Kexin Xu, Amos B Smith Iii, Donna M Huryn, Robert B Wilson; ACS Chem Neurosci. 2020 Aug 11. doi: 10.1021/acschemneuro.0c00323. Online ahead of print.

Friedreich ataxia (FRDA) is an inherited neurodegenerative disorder for which there is no cure or approved treatment. It is characterized by the loss or impaired activity of frataxin protein, which is involved in the biogenesis of iron-sulfur clusters. Our previous studies suggested that cell death in FRDA may involve ferroptosis, an iron-dependent form of cell death requiring lipid peroxidation. Based on reports that oleic acid acts as a ferroptosis inhibitor, we evaluated whether it, other fatty acids, and fatty acid derivatives could rescue viability in cellular models of FRDA. We identified a trifluoromethyl alcohol analog of oleic acid that was significantly more potent than oleic acid itself. Further evaluation indicated that the effects were stereoselective, although a specific molecular target has not yet been identified. This work provides a potential starting point for therapeutics to treat FRDA, as well as a valuable probe molecule to interrogate FRDA pathophysiology.

Test–retest reliability of the Friedreich’s ataxia rating scale

Christian Rummey Theresa A. Zesiewicz Santiago Perez‐Lloret Jennifer M. Farmer Massimo Pandolfo David R. Lynch; Ann Clin Transl Neurol. doi:10.1002/acn3.51118

The modified Friedreich Ataxia Rating Scale (mFARS) is a disease specific, exam‐based neurological rating scale commonly used as a outcome measure in clinical trials. While extensive clinimetric testing indicates it’s validity in measuring disease progression, formal test–retest reliability was lacking. To fill this gap, we acquired results from screening and baseline visits of several large clinical trials and calculated intraclass correlation coefficients, coefficients of variance, standard error, and the minimally detectable changes. This study demonstrated excellent test–retest reliability of the mFARS, and it’s upright stability subscore.

UPDATED: Reata suggests Friedreich's ataxia program could be delayed, sending stock plunging

August 10, 2020 05:07 PM EDT; Reata Pharmaceuticals $RETA made waves last October when its drug omaveloxolone produced positive trial results in treating a rare neurological disorder, but the candidate’s path forward became much murkier Monday.
In a report of quarterly earnings, the biotech divulged that the FDA is considering delaying omaveloxolone’s NDA pending completion of a second trial. That could push back approval by at least a year given that the target population, individuals with Friedreich’s ataxia, is limited and progression of the hard-to-treat illness is notoriously slow. The Covid-19 pandemic would also hinder Reata’s ability to complete an additional trial.

FDA 'not convinced' MOXIe data sufficient

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 B. Schulz, Sylvia Boesch & on behalf of the EFACTS (European Friedreich’s Ataxia Consortium for Translational Studies); Orphanet J Rare Dis 15, 198 (2020). doi:10.1186/s13023-020-01475-9

Six hundred eleven genetically confirmed FRDA patients were recruited within a multicentric natural history study conducted by the EFACTS (European FRDA Consortium for Translational Studies, ClinicalTrials.gov-Identifier NCT02069509). Age at first symptoms as well as age at first suspicion of FRDA by a physician were collected retrospectively at the baseline visit.
In the genetic era, presentation with non-neurological features or in the adulthood still leads to a significant diagnostic delay in FRDA. Well-known correlations between GAA1 repeat length and disease milestones are not valid in case of atypical presentations or positive family history.

A Drosophila model of Friedreich Ataxia with CRISPR/Cas9 insertion of GAA repeats in the frataxin gene reveals in vivo protection by N-acetyl cysteine

Maria Russi, Elodie Martin, Benoit D’Autréaux, Laura Tixier, Hervé Tricoire, Véronique Monnier; Human Molecular Genetics, ddaa170, doi:10.1093/hmg/ddaa170 

 Friedreich Ataxia (FA) is caused by GAA repeat expansions in the first intron of FXN, the gene encoding frataxin, which results in decreased gene expression. Thanks to the high degree of frataxin conservation, the Drosophila melanogaster fruitfly appears as an adequate animal model to study this disease and to evaluate therapeutic interventions. Here, we generated a Drosophila model of FA with CRISPR/Cas9 insertion of approximately 200 GAA in the intron of the fly frataxin gene fh. These flies exhibit a developmental delay and lethality associated with decreased frataxin expression. We were able to by-pass preadult lethality using genetic tools to overexpress frataxin only during the developmental period. These frataxin-deficient adults are short-lived and present strong locomotor defects. RNA-Seq analysis identified deregulation of genes involved in amino-acid metabolism and transcriptomic signatures of oxidative stress. In particular, we observed a progressive increase of Tspo expression, fully rescued by adult frataxin expression. Thus, Tspo expression constitutes a molecular marker of the disease progression in our fly model and might be of interest in other animal models or in patients. Finally, in a candidate drug screening, we observed that N-acetyl cysteine improved the survival, locomotor function, resistance to oxidative stress and aconitase activity of frataxin-deficient flies. Therefore, our model provides the opportunity to elucidate in vivo the protective mechanisms of this molecule of therapeutic potential. This study also highlights the strength of the CRISPR/Cas9 technology to introduce human mutations in endogenous orthologous genes, leading to Drosophila models of human diseases with improved physiological relevance.

Toward quantitative neuroimaging biomarkers for Friedreich's ataxia at 7 Tesla: Susceptibility mapping, diffusion imaging, R2 and R1 relaxometry

Sina Straub Stephanie Mangesius Julian Emmerich Elisabetta Indelicato Wolfgang Nachbauer Katja S. Degenhardt Mark E. Ladd Sylvia Boesch Elke R. Gizewski; J Neurosci Res. 2020; 00: 1– 13. doi:10.1002/jnr.24701


VBM revealed significant white matter atrophy within regions of the brainstem, and the cerebellum. These regions overlapped partially with brain regions for which significant differences between healthy controls and patients were found in the VOI‐based quantitative MRI evaluation. It was shown that two independent analyses provided overlapping results. Moreover, positive results on correlations with disease characteristics were found, indicating that these quantitative MRI parameters could provide more detailed information and assist the search for effective treatments. Positive results on correlations with disease characteristics were found, indicating that these quantitative MRI parameters could provide more detailed information and assist the search for effective treatments.

Antioxidant Defense Mechanisms and its Dysfunctional Regulation in the Mitochondrial Disease, Friedreich’s Ataxia

S. Chiang, M.L.H. Huang, K.C. Park, D.R. Richardson, Free Radical Biology and Medicine, 2020, doi.org/10.1016/j.freeradbiomed.2020.07.019.

 Considering FA, which is due to the decreased expression of the mitochondrial protein, frataxin, this iron accumulation does not occur within protective storage proteins such as mitochondrial ferritin. Instead, it forms unbound biomineral aggregates composed of high spin iron(III), phosphorous and sulfur, which probably contributes to the observed redox stress. There is also a dysregulated response to the ensuing redox assault, as the master regulator of oxidative stress, nuclear factor erythroid 2-related factor-2 (Nrf2), demonstrates marked down-regulation. The dysfunctional response of Nrf2 in FA is due to multiple mechanisms including: (1) up-regulation of Keap1 that is involved in Nrf2 degradation; (2) activation of the nuclear Nrf2 export/degradation machinery via glycogen synthase kinase-3β (Gsk3β) signaling; and (3) inhibited nuclear translocation of Nrf2. More recently, increased microRNA (miRNA) 144 expression has been demonstrated to down-regulate Nrf2 in several disease states, including an animal model of FA. Other miRNAs have also demonstrated to be dysregulated upon frataxin depletion in vivo in humans and animal models of FA. Collectively, frataxin depletion results in multiple, complex responses that lead to detrimental redox effects that could contribute to the mechanisms involved in the pathogenesis of FA.

Larimar Therapeutics Announces Positive Opinion on Orphan Drug Designation Received from the European Medicines Agency for CTI-1601 for the Treatment of Friedreich’s Ataxia

BALA CYNWYD, Pa., July 28, 2020 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (Nasdaq:LRMR), a clinical-stage biotechnology company focused on developing treatments for complex rare diseases, today announced that the European Medicines Agency (EMA) Committee for Orphan Medicinal Products (COMP) issued a positive opinion on the company’s application for orphan drug designation for CTI-1601, a potential treatment for Friedreich’s ataxia (FA), a rare, progressive, multi-symptom genetic disease that affects the functioning of multiple organs and systems. CTI-1601 is a recombinant fusion protein intended to deliver human frataxin into the mitochondria of patients with FA who are unable to produce enough of this essential protein. The U.S. Food and Drug Administration (FDA) previously granted Orphan Drug, Fast Track and Rare Pediatric Disease designations to CTI-1601 for the treatment of FA. Larimar expects that the European Commission, based on this positive opinion of the COMP, will formally grant the orphan drug designation for the European Union (EU) this year.

Antioxidant Therapies and Oxidative Stress in Friedreich´s Ataxia: The Right Path or Just a Diversion?

R. Rodríguez, L.; Lapeña, T.; Calap-Quintana, P.; Moltó, M.D.; Gonzalez-Cabo, P.; Navarro Langa, J.A.; Antioxidants 2020, 9, 664. doi:10.3390/antiox9080664

Friedreich´s ataxia is the commonest autosomal recessive ataxia among population of European descent. Despite the huge advances performed in the last decades, a cure still remains elusive. One of the most studied hallmarks of the disease is the increased production of oxidative stress markers in patients and models. This feature has been the motivation to develop treatments that aim to counteract such boost of free radicals and to enhance the production of antioxidant defenses. In this work, we present and critically review those “antioxidant” drugs that went beyond the disease´s models and were approved for its application in clinical trials. The evaluation of these trials highlights some crucial aspects of the FRDA research. On the one hand, the analysis contributes to elucidate whether oxidative stress plays a central role or whether it is only an epiphenomenon. On the other hand, it comments on some limitations in the current trials that complicate the analysis and interpretation of their outcome. We also include some suggestions that will be interesting to implement in future studies and clinical trials.

Relationship between activity and stability: Design and characterization of stable variants of human frataxin

Ignacio Hugo Castro, Mauro Bringas, Davide Doni, Martin Ezequiel Noguera, Luciana Capece, Martín Aran, Matías Blaustein, Paola Costantini, Javier Santos; Archives of Biochemistry and Biophysics, 2020, 108491, doi:10.1016/j.abb.2020.108491.


In this study, we prepared a set of FXN variants spanning a broad range of conformational stabilities. Variants S160I, S160 M and A204R were more stable than the wild-type and showed similar biological activity. We concluded that the contribution of particular side chains to the conformational stability of FXN might be highly subordinated to their impact on both the protein function and the stability of the functional supercomplex.

Cardiolipin-deficient Cells Have Decreased Levels of the Iron-Sulfur Biogenesis Protein Frataxin

Yiran Li, Wenjia Lou, Alexander Grevel, Lena Böttinger, Zhuqing Liang, JiajiaJi Ji, Vinay A. Patil, Jenney Liu, Cunqi Ye, Maik Hüttemann, Thomas Becker and Miriam L. Greenberg; [published online ahead of print, 2020 Jul 6]. J Biol Chem. 2020;jbc.RA120.013960. doi:10.1074/jbc.RA120.013960

Cardiolipin (CL) is the signature phospholipid of mitochondrial membranes, where it is synthesized locally and plays an important role in mitochondrial bioenergetics. Previous studies in the yeast model have indicated that CL is required for optimal iron homeostasis, which is disrupted by a mechanism not yet determined in the yeast CL mutant, crd1Δ. This finding has implications for the severe genetic disorder, Barth syndrome (BTHS), in which CL metabolism is perturbed because of mutations in the CL-remodeling enzyme, tafazzin. Here, we investigate the effects of tafazzin-deficiency on iron homeostasis in the mouse myoblast model of BTHS, TAZ-KO (tafazzin knockout) cells. Similarly to CL-deficient yeast cells, TAZ-KO cells exhibited elevated sensitivity to iron as well as to H2O2, which was alleviated by the iron chelator deferoxamine. TAZ-KO cells exhibited increased expression of the iron exporter ferroportin and decreased expression of the iron importer transferrin receptor, likely reflecting a regulatory response to elevated mitochondrial iron. Reduced activities of mitochondrial iron-sulfur cluster (Fe-S) enzymes suggested that the mechanism underlying perturbation of iron homeostasis was defective Fe-S biogenesis. We observed decreased levels of Yfh1/frataxin, an essential component of the Fe-S biogenesis machinery, in mitochondria from TAZ-KO mouse cells and in CL-deleted yeast crd1Δ cells, indicating that the role of CL in Fe-S biogenesis is highly conserved. Yeast crd1Δ cells exhibited decreased processing of the Yfh1 precursor upon import, which likely contributes to the iron homeostasis defects. Implications for understanding the pathogenesis of BTHS are discussed.