Mitochondrial Calcium Homeostasis in the Pathology and Therapeutic Application in Friedreich's Ataxia

Hongting Zhao, Zhuoyuan Li, Yutong Liu, Meng Zhang & Kuanyu Li. Neurosci. Bull. (2022). doi:10.1007/s12264-022-01007-4

Gambling associated risk-taking decision in cerebellar ataxia

Ruo-Yah Lai Natasha A. Desai Christian J. Amlang Chi-Ying R. Lin Tiffany X. Chen Michael J. Minyetty Nadia Amokrane Sheng-Han Kuo;  Parkinsonism & Related Disorders, Volume 0, Issue 0, 105252,  doi:10.1016/j.parkreldis.2022.105252 

People with cerebellar ataxia (CA) can develop impulsive and compulsive behaviors that significantly affect their and their family's quality of life. To further assess the decision-making process associated with these behaviors, we used the Iowa Gambling Task (IGT) to study people with CA.

CA cases obtained significantly lower IGT total scores than controls (−5.30 ± 37.53 vs. 21.30 ± 37.37, p = 0.004). In addition, those with CA made riskier decisions throughout the task compared to controls. Although both CA and controls learned to make decisions with more favorable outcomes over the course of completing the IGT, CA participants never matched the controls' performance. IGT performance did not correlate with ataxia severity or depressive symptoms.

SHAREHOLDER ALERT: Pomerantz Law Firm Investigates Claims On Behalf of Investors of Design Therapeutics, Inc.

NEW YORK, Dec. 26, 2022 /PRNewswire/ -- Pomerantz LLP is investigating claims on behalf of investors of Design Therapeutics, Inc. ("Design" or the "Company") (NASDAQ: DSGN). 

On or around March 24, 2021, Design conducted its initial public offering ("IPO"), selling 12 million shares of stock priced at $20.00 per share. Then, on December 7, 2022, Design reported initial data from a Phase 1 trial of DT-216 in patients with Friedreich ataxia. Among other results, Design said 16 patients on DT-216 and eight on placebo reported at least one treatment-emergent adverse event. On this news, Design's stock price fell sharply during intraday trading on December 8, 2022.

The psychosocial situation of families caring for children with rare diseases during the COVID-19 pandemic: results of a cross-sectional online survey

Lydia Rihm, Mareike Dreier, Farhad Rezvani, Silke Wiegand-Grefe & Jörg Dirmaier; Orphanet J Rare Dis 17, 449 (2022). doi:10.1186/s13023-022-02595-0 

 This study indicates a high psychosocial burden on family caregivers of children with RDs during the early COVID-19 pandemic, characterized by high distress levels and wide-ranging everyday problems, unmet psychosocial information needs, and reduced caregiver-reported HRQoL in children with RDs. The findings highlight the ongoing need for target group-specific, low-threshold support services (e.g., websites) during and after the pandemic.

Social concepts and the cerebellum: behavioural and functional connectivity signatures in cerebellar ataxic patients

Lopes da Cunha Pamela, Fittipaldi Sol, González Campo Cecilia, Kauffman Marcelo, Rodríguez-Quiroga Sergio, Yacovino Darío Andrés, Ibáñez Agustín, Birba Agustina and García Adolfo M. 2023; Phil. Trans. R. Soc., B3782021036420210364, doi:10.1098/rstb.2021.0364 

We compared behavioural outcomes between groups and examined their association with cerebellar connectivity. CA patients showed deficits in social text comprehension and normal scores in the non-social text. Also, social text outcomes in controls selectively correlated with connectivity between the cerebellum and key regions subserving multi-modal semantics and social cognition, including the superior and medial temporal gyri, the temporal pole and the insula. Conversely, brain-behaviour associations involving the cerebellum were abolished in the patients. Thus, cerebellar structures and connections seem involved in processing social concepts evoked by naturalistic discourse. Such findings invite new theoretical and translational developments integrating social neuroscience with embodied semantics.

Protection of dystrophic muscle cells using Idebenone correlates with the interplay between calcium, oxidative stress and inflammation

Amanda Harduim Valduga, Daniela Sayuri Mizobuti, Fernanda dos Santos Rapucci Moraes, Rafael Dias Mâncio, Luis Henrique Rapucci Moraes, Túlio de Almeida Hermes, Aline Barbosa Macedo, Elaine Minatel; Int J Exp Path. 2022; 00: 1- 9. doi:10.1111/iep.12463 

The Idebenone treatment was able to reduce the levels of oxidative stress markers, such as H2O2 and 4-HNE, as well as decreasing intracellular calcium influx in the dystrophic muscle cells. Regarding Idebenone effects on the anti-oxidant defence system, an up-regulation of catalase levels, glutathione reductase (GR), glutathione peroxidase (GPx) and superoxide dismutase (SOD) activity was observed in the dystrophic muscle cells. In addition, the Idebenone treatment was also associated with reduction in inflammatory molecules, such as nuclear factor kappa-B (NF-κB) and tumour necrosis factor (TNF) in mdx muscle cells.

Astrocytic mitochondrial frataxin—A promising target for ischemic brain injury

Hazra, R, Novelli, EM, Hu, X.; CNS Neurosci Ther. 2022; 00: 1- 6. doi:10.1111/cns.14068 

In the ischemic brain, hypoxia leads to mitochondrial dysfunction, insufficient energy production, and astrocyte activation. Yet, most studies investigating mitochondrial dysfunction in cerebral ischemia have focused exclusively on neurons. This review will highlight the importance of the morphological, molecular, and functional heterogeneity of astrocytes in their role in brain injuries and explore how activated astrocytes exhibit calcium imbalance, reactive oxygen species overproduction, and apoptosis. In addition, special focus will be given to the role of the mitochondrial protein frataxin in activated astrocytes during ischemia and its putative role in the pharmacological management of cerebral ischemia.

Study traces shared and unique cellular hallmarks found in 6 neurodegenerative diseases

ScienceDaily, 21 December 2022. Arizona State University. 

In a study appearing in the current issue of Alzheimer's & Dementia: The Journal of the Alzheimer' Association, corresponding author Carol Huseby of Arizona State University and her colleagues look at cellular alterations in six distinct neurodegenerative diseases: amyotrophic lateral sclerosis or Lou Gehrig's disease, Alzheimer's disease, Friedreich's ataxia, frontotemporal dementia, Huntington's disease and Parkinson's disease. The selected RNA transcripts reveal eight common themes across the six neurodegenerative diseases: transcription regulation, degranulation (a process involved in inflammation), immune response, protein synthesis, cell death or apoptosis, cytoskeletal components, ubiquitylation/proteasome (involved in protein degradation) and mitochondrial complexes (which oversee energy usage in cells). The eight cellular dysfunctions uncovered are associated with identifiable pathologies in the brain characteristic of each disease.

Blood RNA transcripts reveal similar and differential alterations in fundamental cellular processes in Alzheimer's disease and other neurodegenerative diseases

Carol J. Huseby, Elaine Delvaux, Danielle L. Brokaw, Paul D. Coleman; Alzheimer's & Dementia, 2022; DOI: 10.1002/alz.12880 

 We report that transcripts of the blood transcriptome selected for each of the neurodegenerative diseases represent fundamental biological cell processes including transcription regulation, degranulation, immune response, protein synthesis, apoptosis, cytoskeletal components, ubiquitylation/proteasome, and mitochondrial complexes that are also affected in the brain and reveal common themes across six neurodegenerative diseases.

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

Pandolfo M, Reetz K, Darling A, Rodriguez de Rivera FJ, Henry PG, Joers J, Lenglet C, Adanyeguh I, Deelchand D, Mochel F, Pousset F, Pascual S, Van den Eede D, Martin-Ugarte I, Vilà-Brau A, Mantilla A, Pascual M, Martinell M, Meya U, Durr A.; Neurol Genet. 2022 Nov 1;8(6):e200034. doi: 10.1212/NXG.0000000000200034. 

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

Design and Delivery of SINEUP: A New Modular Tool to Increase Protein Translation

Arnoldi M, Zarantonello G, Espinoza S, Gustincich S, Di Leva F, Biagioli M.; Methods Mol Biol. 2022;2434:63-87. doi: 10.1007/978-1-0716-2010-6_4. 

Synthetic SINEUP is thus a novel molecular tool that potentially may be used for any industrial or biomedical application to enhance protein production, also as possible therapeutic strategy in haploinsufficiency-driven disorders.Here, we describe a detailed protocol to (1) design a specific BD directed to a gene of interest and (2) assemble and clone it with the ED to obtain a functional SINEUP molecule. Then, we provide guidelines to efficiently deliver SINEUP into mammalian cells and evaluate its ability to effectively upregulate target protein translation.

Recurrent repeat expansions in human cancer genomes

Erwin, G.S., Gürsoy, G., Al-Abri, R. et al.; Nature (2022). doi:10.1038/s41586-022-05515-1 

Expansions of tandem DNA repeats (TRs) are known to cause more than 50 devastating human diseases, including Huntington’s disease and fragile X syndrome1,2. TR tracts that cause human disease are typically large (more than 100 bp)1. However, identifying large TRs with short-read DNA sequencing methods is difficult because the repeat sequences are ubiquitous in the genome and many are too large—larger than the typical sequencing read length—to uniquely map to the reference genome9. Thus, many large TRs go undetected with current genomic technologies, and, despite their importance to monogenic disease, the frequency and function of recurrent repeat expansions (rREs) are unknown in complex human genetic diseases such as cancer.

Researchers may have found a new path for halting cancer cell production

Stanford Medicine; December 14, 2022; 

The project began not with cancer, but with a rare, neurodegenerative disease without a cure, Friedreich ataxia. Five years ago, Erwin, then a graduate student at the University of Wisconsin-Madison, was exploring the genetic underpinnings of Friedreich ataxia in hopes of filling the therapeutic void. Erwin knew that DNA mutations called repeat expansions cause Friedreich ataxia, along with dozens of other serious conditions, many neurological. 

Repeat expansions are stretches of DNA that erroneously repeat themselves dozens to thousands of times in the genome. 

 Testing the molecule in cells from a Friedreich ataxia patient, Erwin saw that Syn-TEF1 successfully targeted the repeat expansion, helping RNA polymerase move through it to transcribe the FXN gene, bringing frataxin to normal levels. Due to its success in cells, researchers are now testing the safety and dosage of a version of Syn-TEF1 in Friedreich ataxia patients.

Kaleibe launched by Replay to target genetic brain disorders with gene therapy

14-12-2022​. Replay, a genome writing company reprogramming biology by writing and delivering big DNA, has announced the launch of Kaleibe, a herpes simplex virus (HSV) gene therapy company targeting genetic brain disorders. It is the third product company to launch since Replay’s formation in July and will leverage its high payload capacity HSV delivery vector, synHSVTM, to target genetic brain disorders. 

The initial development programs will focus on genetic Parkinson’s disease (PD) and Friedreich’s ataxia (FRDA). These diseases have a high unmet medical need and known genetic causes. The target genes, 33kb and 135kb, respectively, far exceed the 5kb payload capacity of adeno-associated virus (AAV) vectors.

G-rich motifs within phosphorothioate-based antisense oligonucleotides (ASOs) drive activation of FXN expression through indirect effects

Feng Wang, Ezequiel Calvo-Roitberg, Julia M Rembetsy-Brown, Minggang Fang, Jacquelyn Sousa, Zachary J Kartje, Pranathi Meda Krishnamurthy, Jonathan Lee, Michael R Green, Athma A Pai, Jonathan K Watts; Nucleic Acids Research, 2022;, gkac1108, doi:10.1093/nar/gkac1108 

The phosphorodiamidate morpholino oligomer analogs of our ASOs did not activate FXN, pointing to a PS-backbone-mediated effect. Our study demonstrates the importance of multiple, detailed control experiments and target validation in oligonucleotide studies employing novel mechanisms such as gene activation.

Retinal and Visual Pathways Involvement in Carriers of Friedreich’s Ataxia

Ziccardi, L.; Barbano, L.; Antonelli, G.; Cioffi, E.; Di Renzo, A.; Gioiosa, V.; Marcotulli, C.; Grzybowski, A.; Casali, C.; Parisi, V. ; Diagnostics 2022, 12, 3135. doi:10.3390/diagnostics12123135 

Therefore, our data suggest that, in C-FRDA, a dysfunction of retinal elements without morphological macular impairment may occur. In addition, a morphological impairment of RNFL associated with an abnormal neural conduction along the visual pathways can be also detected.

Double blind trial of a deuterated form of linoleic acid (RT001) in Friedreich ataxia

David R. Lynch, Katherine D. Mathews, Susan Perlman, Theresa Zesiewicz, Sub Subramony, Omid Omidvar, Adam P. Vogel, Ana Krtolica, Nadia Litterman, Lex van der Ploeg, Frederic Heerinckx, Peter Milner & Mark Midei; J Neurol (2022). doi:10.1007/s00415-022-11501-4 

The results of this study provide no evidence for a significant benefit of RT001 at the dosages tested in this Friedreich ataxia patient population.

Ataxia Rating Scales: Content Analysis by Linking to the International Classification of Functioning, Disability and Health

Etoom, M.; Jahan, A.M.; Alghwiri, A.; Lena, F.; Modugno, N.; Healthcare 2022, 10, 2459. doi:10.3390/healthcare10122459

The content analysis of ataxia rating scales would help clinicians and researchers select the most appropriate scale and understand ataxic symptoms and their impact on function. It seems that SARA is the optimal scale for rapid assessment of ataxia or in busy clinical settings. UMSARS or FARS are more appropriate for the investigating the impact of ataxia on overall health, and monitoring ataxia progression and disability.

Clinical Drug-Drug Interaction Between Vatiquinone, a 15-Lipoxygenase Inhibitor, and Rosuvastatin, a Breast Cancer Resistance Protein Substrate

Lee, L., Murase, K., Ma, J. and Thoolen, M. (2022); Clin Pharmacol Drug Dev. doi:10.1002/cpdd.1199

These results demonstrate that vatiquinone has no clinically relevant effect on the pharmacokinetics of rosuvastatin.

Ataxia Rating Scales Reflect Patient Experience: an Examination of the Relationship Between Clinician Assessments of Cerebellar Ataxia and Patient-Reported Outcomes

Michele H. Potashman, Miranda L. Mize, Melissa W. Beiner, Samantha Pierce, Vladimir Coric & Jeremy D. Schmahmann; Cerebellum (2022). doi:10.1007/s12311-022-01494-1 

Ataxia rating scales are observer administered clinical outcome assessments (COAs) of the cerebellar motor syndrome. It is not known whether these COAs mirror patient experience of their disease. Here we test the hypothesis that ataxia COAs are related to and reflect patient reported symptoms and impact of illness.

CIRM grant $4.8m to fund gene therapy for rare disease

6 December 2022. CIRM grant will fund novel gene therapy that aims for single lifelong treatment of Friedreich’s ataxia, a progressive neuromuscular disorder; a second CIRM grant will advance efforts to leverage UC San Diego research on another rare disease. 

I n 2020, Cherqui and her team, in a new study, found that specifically described how CRISPR-Cas9 gene editing of hematopoietic stem cells from patients with FA could work. Hematopoietic stem cells are capable of developing into all types of blood cells. CRISPR-Cas9 is a technology that allows scientists to edit parts of the genome by removing, adding or altering sections of the DNA sequence. 

 In November 2022, the California Institute for Regenerative Medicine (CIRM) awarded Cherqui and the team a grant of $4.8 million, to move this approach closer to clinical trials. The funding will be used to develop a therapy based on gene-edited hematopoietic stem and progenitor cells derived from FA patients, which would be re-infused as a one-time, lifelong treatment.

Form S-1/A JUPITER NEUROSCIENCES,

December 7, 2022; UNITED STATES SECURITIES AND EXCHANGE COMMISSION. REGISTRATION STATEMENT UNDER THE SECURITIES ACT OF 1933. 

JOTROL™ was developed together with our technology partner Aquanova AG, Darmstadt, Germany. JOTROL™ is formulated with a unique patented micellar technology that is projected to increase the bioavailability profile of resveratrol. Manufacturing technology transfers were completed in 2017 and manufacturing procedures and clinical trial supply manufacturing has been completed at Catalent Pharmaceutical Services, Inc., St Petersburg, Florida. JOTROL™ is a micellar non-aqueous solution of resveratrol delivered in a softgel capsule. Each capsule includes 100mg of resveratrol. Pre-clinical trials in mice and rats were conducted comparing JOTROL™ to micronized resveratrol, labeled to have the highest bioavailability in the nutritional market, to demonstrate that we could achieve a significantly higher bioavailability. Summary details of these studies are included in the section “Description of Business”. A Phase I dose finding pharmacokinetic (“PK”) study in healthy volunteers was completed during the first half of 2021. The study results met our targeted goals. The results from this study will be used as a cross-reference for all indications where JOTROL™ will be used in Phase II and Phase III clinical trials. The Phase I results and the FDA guidance of cross-referencing is further described in the section “Description of Business”. The Company has not discussed the use of cross-referencing in this manner with the FDA or other comparable regulatory authorities.

Design Therapeutics Reports Positive Data from Single-Ascending Dose Trial of DT-216 for the Treatment of Friedreich Ataxia and Portfolio Progress

CARLSBAD, Calif., Dec. 07, 2022 (GLOBE NEWSWIRE) -- Design Therapeutics, Inc. (Nasdaq: DSGN), a clinical-stage biotechnology company developing treatments for serious degenerative genetic diseases, today reported progress across its portfolio of novel GeneTAC™ small molecules. Today’s updates include initial results on DT-216 from the company’s single-ascending dose (SAD) Phase 1 clinical trial in patients with Friedreich ataxia (FA). The results show that DT-216 was generally well-tolerated and able to overcome the frataxin (FXN) transcription impairment that causes FA, with a greater than two-fold increase in FXN mRNA in the cohort with the highest response. These data support the continued advancement of DT-216 in the ongoing multiple-ascending dose (MAD) Phase 1 trial and the anticipated Phase 2 clinical trial in FA patients, which is on track to begin in 2023.

FDA: B-NMN Can No Longer Be Sold as a Dietary Supplement in the US

December 06, 2022. Recently, the US Food and Drug Administration (FDA) said that beta-nicotinamide mononucleotide (Β-NMN) — a popular longevity supplement ingredient — is under investigation as a potential new drug. Therefore, companies can no longer market it as a dietary supplement. This decision has sparked concern among those who use NMN and the dietary supplement industry.

Ataxia Rating Scales: Content Analysis by Linking to the International Classification of Functioning, Disability and Health

Etoom, M.; Jahan, A.M.; Alghwiri, A.; Lena, F.; Modugno, N. . Healthcare 2022, 10, 2459. doi:10.3390/healthcare10122459 

 The content analysis of ataxia rating scales would help clinicians and researchers select the most appropriate scale and understand ataxic symptoms and their impact on function. It seems that SARA is the optimal scale for rapid assessment of ataxia or in busy clinical settings. UMSARS or FARS are more appropriate for the investigating the impact of ataxia on overall health, and monitoring ataxia progression and disability.

Solid Biosciences Announces Closing of Acquisition of AavantiBio and Concurrent $75 Million Private Placement

CHARLESTOWN, Mass., Dec. 05, 2022 (GLOBE NEWSWIRE) -- Solid Biosciences Inc. (Nasdaq: SLDB), a life sciences company focused on advancing meaningful therapies for Duchenne muscular dystrophy (Duchenne), today announced the closing of its acquisition of AavantiBio, a privately held gene therapy company focused on transforming the lives of patients with Friedreich’s ataxia and rare cardiomyopathies, including its pipeline assets and net cash. The combined company will focus on advancing a portfolio of neuromuscular and cardiac programs, including SGT-003, a differentiated gene transfer candidate, for the treatment of Duchenne, AVB-202, a gene transfer candidate for the treatment of Friedreich’s ataxia, AVB-401 for BAG3 mediated dilated cardiomyopathy, and additional assets for the treatment of undisclosed cardiac diseases.

The French Friedreich's Ataxia Association awards a grant of 28,000 € to the IRBLleida to understand the early stages of this rare disease

Monday, December 5, 2022 

 The French Friedreich's Ataxia Association (AFAF) has awarded a €28,000 grant to the Biochemistry of Oxidative Stress research group at the Institute for Research in Biomedicine of Lleida (IRBLleida) and the University of Lleida (UdL) to better understand the early stages of the disease. This is the third time that the AFAF has financed a Lleida project and on this occasion, it will be used for a comparative study of mice of the I151F model to discern the early stages of the pathogenesis of Friedreich's ataxia.

Tele-Exercise During COVID-19: Effectiveness of an Adaptive Seated Intervention for Adults With Chronic Neurological Impairments

Devina Kumar, Amy Bialek, Ayushi Divecha, Rachel Garn, Kathleen Friel, Talita Campos; Archives of Physical Medicine and Rehabilitation, Volume 103, Issue 12, e54 - e55, doi:10.1016/j.apmr.2022.08.566

The COVID pandemic has influenced in-person physical, social, and emotional engagement for all populations across the lifespan. Individuals with CNI who require regular exercise and physical activity may demonstrate benefits from guided virtual exercise programs that foster social interaction, personal engagement and physical well-being.

Double blind trial of a deuterated form of linoleic acid (RT001) in Friedreich ataxia

David R. Lynch, Katherine D. Mathews, Susan Perlman, Theresa Zesiewicz, Sub Subramony, Omid Omidvar, Adam P. Vogel, Ana Krtolica, Nadia Litterman, Lex van der Ploeg, Frederic Heerinckx, Peter Milner & Mark Midei; J Neurol (2022). doi:10.1007/s00415-022-11501-4

The results of this study provide no evidence for a significant benefit of RT001 at the dosages tested in this Friedreich ataxia patient population.

Clinical evidence of interventions assessed in Friedreich ataxia: a systematic review

Jain P, Badgujar L, Spoorendonk J, Buesch K.; Therapeutic Advances in Rare Disease. 2022;3. doi:10.1177/26330040221139872

 Identified literature showed a considerable unmet need for therapeutic interventions that halt or slow the deteriorating nature of FA. Novel efficacious drugs should be investigated that aim to improve symptoms or slow disease progression.

Friedreich’s ataxia: major trial readouts and regulatory events to watch in 2023

www.clinicaltrialsarena.com; Analysis. November 30, 2022 

The FDA could approve the first treatment for Friedreich’s ataxia, and at least three other major trials have readouts expected by year end. All signs indicate 2023 will prove a pivotal year in Friedreich’s ataxia drug development. Reata’s omaveloxolone, which met its primary endpoint in a Phase II trial, is up for FDA approval on February 28. Meanwhile, a Phase II/III trial of PTC’s vatiquinone, a Phase I/II trial of Stealth Bio’s elamipretide, and a Phase II study of Larimar’s CI-1601 all have key results expected in 2023.

Acceso a medicamentos huérfanos para el tratamiento de la atrofia muscular espinal en España

B. García-Parra, J.M. Guiu, P. Modamio, A. Martínez-Yélamos, E.L. Mariño-Hernández, M. Povedano[REV NEUROL 2022;75:261-267]PMID: 36285446DOI: doi:10.33588/rn.7509.2022298 

La atrofia muscular espinal (AME) es una enfermedad rara cuyo diagnóstico y tratamiento es complejo. En España hay dos medicamentos huérfanos financiados por el Sistema Nacional de Salud, nusinersén y onasemnogén abeparvovec, y un tercero, risdiplam, pendiente. El objetivo fue analizar el acceso a los fármacos modificadores de la AME y detectar posibles causas de inequidad. Materiales y método. Estudio descriptivo realizado en dos fases: revisión bibliográfica y entrevistas semiestructuradas a expertos clínicos en AME de las comunidades autónomas (CC. AA.) de Andalucía, Castilla-La Mancha, Cataluña y Murcia. El número de centros, servicios o unidades de referencia, la disponibilidad de planes autonómicos para enfermedades raras y los programas piloto de cribado neonatal pueden modular el acceso a los nuevos tratamientos farmacológicos. El número de nuevos pacientes diagnosticados al año se estimó entre uno y seis en cada una de las CC. AA. estudiadas. Dos de las cuatro CC. AA. estaban participando en ensayos clínicos. El tiempo desde la prescripción a la administración de nusinersén estaba entre siete y 60 días. Sólo Cataluña comunicó experiencia con onasemnogén abeparvovec a 30 de junio de 2022. Dos CC. AA. de las cuatro estudiadas disponen de plan autonómico para enfermedades raras; no obstante, se identificó como relevante para el tratamiento de la AME sólo en una de ellas.

Repositioning Drugs for Rare Diseases Based on Biological Features and Computational Approaches

Otero-Carrasco, B.; Prieto Santamaría, L.; Ugarte Carro, E.; Caraça-Valente Hernández, J.P.; Rodríguez-González, Healthcare 2022, 10, 1784. doi:10.3390/healthcare10091784 

Rare diseases are a group of uncommon diseases in the world population. To date, about 7000 rare diseases have been documented. However, most of them do not have a known treatment. As a result of the relatively low demand for their treatments caused by their scarce prevalence, the pharmaceutical industry has not sufficiently encouraged the research to develop drugs to treat them. This work aims to analyse potential drug-repositioning strategies for this kind of disease. Drug repositioning seeks to find new uses for existing drugs. In this context, it seeks to discover if rare diseases could be treated with medicines previously indicated to heal other diseases. Our approaches tackle the problem by employing computational methods that calculate similarities between rare and non-rare diseases, considering biological features such as genes, proteins, and symptoms. Drug candidates for repositioning will be checked against clinical trials found in the scientific literature. In this study, 13 different rare diseases have been selected for which potential drugs could be repositioned. By verifying these drugs in the scientific literature, successful cases were found for 75% of the rare diseases studied. The genetic associations and phenotypical features of the rare diseases were examined. In addition, the verified drugs were classified according to the anatomical therapeutic chemical (ATC) code to highlight the types with a higher predisposition to be repositioned. These promising results open the door for further research in this field of study.

Patient-Reported Impact of Symptoms in Friedreich Ataxia

Jamison Seabury, Danae Alexandrou, Nuran Dilek, Brittany Cohen, John Heatwole, Jane Larkindale, David R Lynch, Courtney Park, Spencer Rosero, Sub H Subramony, Anika Varma, Ellen Wagner, Susan Walther, Jennifer Weinstein, McKenzie Wells, Christine Zizzi, Chad Heatwole Neurology Nov 2022, 10.1212/WNL.0000000000201598; DOI: 10.1212/WNL.0000000000201598 

There are a wide variety of symptoms that affect the lives of individuals with FA. These symptoms, many underrecognized, have different levels of importance and occur at different rates in the FA population. The most common and life altering of these symptoms represent potential targets for future therapeutic interventions.

Efficacy of Omaveloxolone in Friedreich's Ataxia: Delayed-Start Analysis of the MOXIe Extension

Lynch, D.R., Chin, M.P., Boesch, S., Delatycki, M.B., Giunti, P., Goldsberry, A., Hoyle, J.C., Mariotti, C., Mathews, K.D., Nachbauer, W., O'Grady, M., Perlman, S., Subramony, S., Wilmot, G., Zesiewicz, T. and Meyer, C.J. (2022), . Mov Disord. doi:10.1002/mds.29286 

 The noninferiority testing demonstrated that the difference in mFARS between omaveloxolone and placebo observed at the end of placebo-controlled MOXIe part 2 (−2.17 ± 1.09 points) was preserved after 72 weeks in the extension (−2.91 ± 1.44 points). In addition, patients previously randomized to omaveloxolone in MOXIe part 2 continued to show no worsening in mFARS relative to their extension baseline through 144 weeks.

METTL17 is an Fe-S cluster checkpoint for mitochondrial translation

Ast T, Itoh Y, Sadre S, McCoy JG, Namkoong G, Chicherin I, Joshi PR, Kamenski P, Suess DLM, Amunts A, Mootha VK.; bioRxiv; 2022. DOI: 10.1101/2022.11.24.517765. 

Friedreich’s ataxia (FA) is the most common monogenic mitochondrial disease. FA is caused by a depletion of the mitochondrial protein frataxin (FXN), an iron-sulfur (Fe-S) cluster biogenesis factor. To better understand the cellular consequences of FA, we performed quantitative proteome profiling of human cells depleted for FXN. Nearly every known Fe-S cluster-containing protein was depleted in the absence of FXN, indicating that as a rule, cluster binding confers stability to Fe-S proteins. Proteomic and genetic interaction mapping identified impaired mitochondrial translation downstream of FXN loss, and specifically highlighted the methyltransferase-like protein METTL17 as a candidate effector. Using comparative sequence analysis, mutagenesis, biochemistry and cryogenic electron microscopy we show that METTL17 binds to the mitoribosomal small subunit during late assembly and harbors a previously unrecognized [Fe 4 S 4 ] 2+ cluster required for its stability on the mitoribosome. Notably, METTL17 overexpression rescued the mitochondrial translation and bioenergetic defects, but not the cellular growth, of FXN null cells. Our data suggest that METTL17 serves as an Fe-S cluster checkpoint: promoting the translation and assembly of Fe-S cluster rich OXPHOS proteins only when Fe-S cluster levels are replete.

Personal factors understood through the Ecological-Enactive Model of Disability and implications for rehabilitation research

Schwab SM, Spencer C, Carver NS, Andrade V, Dugan S, Greve K, Silva PL.; Front Rehabil Sci. 2022 Aug 12;3:954061. doi:10.3389/fresc.2022.954061. 

The International Classification of Functioning, Disability and Health (ICF) recognizes that disability arises from the interaction between an individual with a medical condition and the context in which they are embedded. Context in the ICF is comprised of environmental and personal factors. Personal factors, the background life and lifestyle of an individual, are poorly understood in rehabilitation. There is limited knowledge about how personal and environmental factors interact to shape the contextual conditions critical for explaining functioning and disability. In this paper, we explore how a newly proposed model of disability, the Ecological-Enactive Model of Disability, can enhance understanding of personal factors across multiple rehabilitation disciplines. We draw from a review of evidence and phenomenological interviews of individuals with Friedreich's Ataxia. We consider the practical impact of this understanding on disability and rehabilitation research and pathways for the future focusing on representative design.

Multimodal Analysis of the Visual Pathways in Friedreich's Ataxia Reveals Novel Biomarkers

Thomas-Black, G., Altmann, D.R., Crook, H., Solanky, N., Carrasco, F.P., Battiston, M., Grussu, F., Yiannakas, M.C., Kanber, B., Jolly, J.K., Brett, J., Downes, S.M., Moran, M., Chan, P.K., Adewunmi, E., Gandini Wheeler-Kingshott, C.A., Németh, A.H., Festenstien, R., Bremner, F. and Giunti, P. (2022), Mov Disord. doi:10.1002/mds.29277 

We demonstrate that frataxin level correlates with peripapillary retinal nerve fibre layer thickness and that retinal sectors differ in their degree of degeneration. We also shown that retinal nerve fibre layer is thinner in FRDA patients than controls and that this thinning is influenced by the AAO and GAA1. Furthermore we show that the ganglion cell and inner plexiform layers are affected in FRDA. Our MRI data indicate that there are borderline correlations between retinal layers and areas of the cortex involved in visual processing. 

Our study demonstrates the uneven distribution of the axonopathy in the retinal nerve fibre layer and highlight the relative sparing of the papillomacular bundle and temporal sectors. We show that thinning of the retinal nerve fibre layer is associated with frataxin levels, supporting the use the two biomarkers in future clinical trials design.

Design and Implementation of a Personalizable Alternative Mouse and Keyboard Interface for Individuals with Limited Upper Limb Mobility

Andreas, D.; Six, H.; Bliek, A.; Beckerle, P.; Multimodal Technol. Interact. 2022, 6, 104. doi:10.3390/mti6120104 

 People with neuromuscular diseases often experience limited upper limb mobility, which makes the handling of standard computer mice and keyboards difficult. Due to the importance of computers in private and professional life, this work aims at implementing an alternative mouse and keyboard interface that will allow for their efficient use by people with a neuromuscular disease. Due to the strongly differing symptoms of these diseases, personalization on the hardware and software levels is the focus of our work. The presented mouse alternative is based on a spectacle frame with an integrated motion sensor for head tracking, which enables the control of the mouse cursor position; the keyboard alternative consists of ten keys, which are used to generate word suggestions for the user input. The interface was tested in a user study involving three participants without disabilities, which showed the general functionality of the system and potential room for improvement. With an average throughput of 1.56 bits per second achieved by the alternative mouse and typing speeds of 8.44 words per minute obtained using the alternative keyboard, the proposed interface could be a promising input device for people with limited upper limb mobility.

A natural history study to track brain and spinal cord changes in individuals with Friedreich's ataxia: TRACK-FA study protocol

Georgiou-Karistianis N, Corben LA, Reetz K, Adanyeguh IM, Corti M, Deelchand DK, Delatycki MB, Dogan I, Evans R, Farmer J, França MC, Gaetz W, Harding IH, Harris KS, Hersch S, Joules R, Joers JJ, Krishnan ML, Lax M, Lock EF, Lynch D, Mareci T, Muthuhetti Gamage S, Pandolfo M, Papoutsi M, Rezende TJR, Roberts TPL, Rosenberg JT, Romanzetti S, Schulz JB, Schilling T, Schwarz AJ, Subramony S, Yao B, Zicha S, Lenglet C, Henry PG.; PLoS One. 2022 Nov 21;17(11):e0269649. doi: 10.1371/journal.pone.0269649. PMID: 36410013. 

 Prioritising immediate areas of need, TRACK-FA aims to deliver a set of sensitive, clinical trial-ready neuroimaging biomarkers to accelerate drug discovery efforts and better understand disease trajectory. Once validated, these potential pharmacodynamic biomarkers can be used to measure the efficacy of new therapeutics in forestalling disease progression.

Determinant of the Cerebellar cognitive affective syndrome in Friedreich Ataxia

destrebecq, comet, deveylder, alaerts, naeije.; Research Square; 2022. DOI: 10.21203/rs.3.rs-2279266/v1. 

CCAS is highly prevalent in adult individuals with FRDA. CCAS is predicted by ataxic motor symptoms severity. This finding supports common core cerebellar pathophysiology in both cognitive and motor symptoms in FRDA and warrants screening for CCAS, especially in patients with SARA > 20.

Harmonizing results of ataxia rating scales: mFARS, SARA, and ICARS

Rummey C, Harding IH, Delatycki MB, Tai G, Rezende T, Corben LA.; Ann Clin Transl Neurol. 2022 Nov 16. doi: 10.1002/acn3.51686. Epub ahead of print. PMID: 36394163. 

 The ever-increasing body of ataxia research provides opportunities for large-scale meta-analyses, systematic reviews, and data aggregation. Because multiple standardized scales are used to quantify ataxia severity, harmonization of these measures is necessary for quantitative data pooling. We applied the modified Friedreich Ataxia Rating Scale (mFARS), the Scale for the Assessment and Rating of Ataxia (SARA), and the International Cooperative Ataxia Rating Scale (ICARS) to a large cohort of people with Friedreich's ataxia. We provide regression coefficients for scale interconversion and discuss the reliability of this approach, together with insights into the differential sensitivities of mFARS and SARA to disease progression.

Cerebellar impulsivity–compulsivity assessment scale

Lin, C.-Y.R., Amokrane, N., Chen, S., Chen, T.X., Lai, R.-Y., Trinh, P., Minyetty, M.J., Emmerich, H., Pan, M.-K., Claassen, D.O. and Kuo, S.-H. (2022); Ann Clin Transl Neurol. doi.:10.1002/acn3.51698

Cerebellar ataxia cases with ICBs have threefold higher total preliminary CIA scores than those without ICBs (12.06 ± 5.96 vs. 4.68 ± 3.50, p = 0.038). Cronbach's alpha revealed good internal consistency across all items (α > 0.70). By performing the test–retest reliability and inter-rater reliability on the preliminary version of CIA, we excluded seven questions (r < 0.70) and generated the final version of CIA. Based on the ROC, a score of 8.0 in CIA was chosen as the cut-off for ICBs in individuals with cerebellar ataxia with 81% sensitivity and 81% specificity.

Safety and pharmacokinetics of a highly bioavailable resveratrol preparation (JOTROL TM)

Kemper C, Benham D, Brothers S, Wahlestedt C, Volmar CH, Bennett D, Hayward M.; AAPS Open. 2022;8(1):11. doi: 10.1186/s41120-022-00058-1. Epub 2022 Jun 30. PMID: 35789594; PMCID: PMC9243782. 

 Resveratrol exhibits a wide range of biological properties, including anti-glycation, antioxidant, anti-inflammation, neuroprotective (including against advanced dementia and Alzheimer's disease), anti-cancer, and anti-aging activity in experimental models (Galiniak et al., Acta Biochim Pol 66:13-21, 2019). Unfortunately, this compound exhibits low bioavailability and solubility (Galiniak et al., Acta Biochim Pol 66:13-21, 2019), requiring large doses that can cause nausea and GI distress. JOTROLTM is a micellar 10% resveratrol solubilization formulation that is thought to increase bioavailability of resveratrol via lymphatic system absorption. Jupiter Neurosciences (formerly Jupiter Orphan Therapeutics; "Jupiter") is pursuing the use of resveratrol in mucopolysaccharidosis type 1 (MPS 1), Friedreich's ataxia, and Alzheimer's disease/mild cognitive impairment.

Diagnostic delay in rare diseases: data from the Spanish rare diseases patient registry

Juan Benito-Lozano, Blanca López-Villalba, Greta Arias-Merino, Manuel Posada de la Paz & Verónica Alonso-Ferreira; Orphanet J Rare Dis 17, 418 (2022). doi:10.1186/s13023-022-02530-3 

This is the first study to quantify time to diagnosis of RDs in Spain, based on data from a national registry open to any RD. Since over half of all persons affected by RDs experience delay in diagnosis, new studies are needed to ascertain the factors associated with this delay and the implications this has on the lives of patients and their families.

Criterios de derivación a genética clínica desde Atención Primaria. Documento de consenso, Atención Primaria

Ismael Ejarque Doménech, Purificación Marín Reina, Sixto García-Miñaur Rica, Isabel Chirivella González, María Teresa Martínez Martínez, Ana María García Rodríguez, Sara Álvarez de Andrés, Juan José Tellería Orriols, Volume 54, Issue 12, 2022, 102501, doi:10.1016/j.aprim.2022.102501. La Atención Primaria (AP) es el primer contacto entre el paciente y el médico, por lo que es fundamental tener claro los criterios de sospecha de una enfermedad genética y dónde se debe remitir para su estudio. s Cuatro sociedades científicas: la Sociedad Española de Medicina Familiar y Comunitaria (semFYC), la Asociación Española de Genética Humana (AEGH), la Asociación Española de Pediatría (AEP) y la Sociedad Española de Oncología Médica (SEOM), han revisado los criterios de derivación a los servicios de genética clínica de las diferentes guías publicadas, con el objetivo de elaborar unas recomendaciones para AP.

De acuerdo con las recomendaciones internacionales, y teniendo siempre como objetivo fundamental la protección de los derechos del menor, se desaconseja el estudio genético de portadores (sanos) y de enfermedades de inicio en la edad adulta (sin posibilidad de intervención preventiva) en pacientes menores de edad. 

Glucagon-like Peptide-1 (GLP-1) Receptor Agonists and Neuroinflammation: Implications for Neurodegenerative Disease Treatment

Katherine O. Kopp, Elliot J. Glotfelty, Yazhou Li, Nigel H. Greig; Pharmacological Research, 2022, 106550, DOI:10.1016/j.phrs.2022.106550. Abstract: Chronic, excessive neuroinflammation is a key feature of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). However, neuroinflammatory pathways have yet to be effectively targeted in clinical treatments for such diseases. Interestingly, increased inflammation and neurodegenerative disease risk have been associated with type 2 diabetes mellitus (T2DM) and insulin resistance (IR), suggesting that treatments that mitigate T2DM pathology may be successful in treating neuroinflammatory and neurodegenerative pathology as well. Glucagon-like peptide-1 (GLP-1) is an incretin hormone that promotes healthy insulin signaling, regulates blood sugar levels, and suppresses appetite. Consequently, numerous GLP-1 receptor (GLP-1R) stimulating drugs have been developed and approved by the US Food and Drug Administration (FDA) and related global regulatory authorities for the treatment of T2DM. Furthermore, GLP-1R stimulating drugs have been associated with anti-inflammatory, neurotrophic, and neuroprotective properties in neurodegenerative disorder preclinical models, and hence hold promise for repurposing as a treatment for neurodegenerative diseases. In this review, we discuss incretin signaling, neuroinflammatory pathways, and the intersections between neuroinflammation, brain IR, and neurodegenerative diseases, with a focus on AD and PD. We additionally overview current FDA-approved incretin receptor stimulating drugs and agents in development, including unimolecular single, dual, and triple receptor agonists, and highlight those in clinical trials for neurodegenerative disease treatment. We propose that repurposing already-approved GLP-1R agonists for the treatment of neurodegenerative diseases may be a safe, efficacious, and cost-effective strategy for ameliorating AD and PD pathology by quelling neuroinflammation. 

 FRDA is a heritable neurodegenerative movement disorder fueled and exacerbated by neuroinflammation 290, 291, 292, which could make it a candidate for GLP-1R agonist treatment. Exenatide treatment was found to re-elevate reduced levels of frataxin, a critical mitochondrial protein, in FRDA patients, which can enhance mitochondrial health and function and could, by extension, reduce neuroinflammation and neurodegeneration characteristic of the disease [293]—again, providing a potentially fruitful area of future basic and clinical research. Similarly, studies by Meissner and colleagues [178] demonstrated the presence of impaired insulin/IGF-1 and IR in vulnerable brain regions of multiple system atrophy patients and a related transgenic mouse model, and their mitigation in the latter by exendin-4, likewise suggesting a promising area of future research.

Decreased mitochondrial respiration in cardiac fibers isolated from a mouse model of Friedreich’s ataxia

Peter Vitiello, Paul Pierce, Shirley/Xiu Wang, Alec Cooper, Aristides Rivera, Jared Ailts, Holly Van Remmen, Jacob Brown; Free Radical Biology and Medicine,Volume 192, Supplement 1, 2022, Page 75, doi:10.1016/j.freeradbiomed.2022.10.308.

Characterization of human mitochondrial aconitase and its interaction with frataxin

Santiago Mansilla, Verónica Tórtora, Florencia Pignataro, Santiago Sastre, Ignacio Castro, María Laura Chiribao, Carlos Robello, Ari Zeida, Javier Santos, Laura Castro; Free Radical Biology and Medicine, Volume 192, Supplement 1, 2022, Pages 86-87, doi:10.1016/j.freeradbiomed.2022.10.151.

RNA as a Major-Groove Ligand: RNA-RNA and RNA-DNA Triplexes Formed by GAA and UUC or TTC Sequences

Zhang J, Fakharzadeh A, Roland C, Sagui C.; ACS Omega. 2022 Nov;7(43):38728-38743. DOI: 10.1021/acsomega.2c04358. PMID: 36340174; PMCID: PMC9631886. 

 Friedreich's ataxia is associated with noncanonical nucleic acid structures that emerge when GAA:TTC repeats in the first intron of the FXN gene expand beyond a critical number of repeats. Specifically, the noncanonical repeats are associated with both triplexes and R-loops. Here, we present an in silico investigation of all possible triplexes that form by attaching a third RNA strand to an RNA:RNA or DNA:DNA duplex, complementing previous DNA-based triplex studies. For both new triplexes results are similar. For a pyridimine UUC+ third strand, the parallel orientation is stable while its antiparallel counterpart is unstable. For a neutral GAA third strand, the parallel conformation is stable. A protonated GA+A third strand is stable in both parallel and antiparallel orientations. We have also investigated Na+ and Mg2+ ion distributions around the triplexes. The presence of Mg2+ ions helps stabilize neutral, antiparallel GAA triplexes. These results (along with previous DNA-based studies) allow for the emergence of a complete picture of the stability and structural characteristics of triplexes based on the GAA and TTC/UUC sequences, thereby contributing to the field of trinucleotide repeats and the associated unusual structures that trigger expansion.

Phenotype and management of neurologic intronic repeat disorders (NIRDs)

Finsterer J.; Rev Neurol (Paris). 2022 Nov 9:S0035-3787(22)00793-7. doi: 10.1016/j.neurol.2022.09.004. Epub ahead of print. PMID: 36371266. 

During recent years an increasing number of neurologic disorders due to expanded tri-, tetra-, penta-, or hexa-nucleotide repeat motifs in introns of various genes have been described (neurologic intronic repeat disorders (NIRDs)). The repeat may be pathogenic in the heterozygous or homozygous form. Repeat lengths vary considerably and can be stable or unstable during transmission to the next generation. The most well-known NIRDs are Friedreich ataxia, spinocerebellar ataxia types-10, -31, and -36, CANVAS, C9Orf72 familial amyotrophic lateral sclerosis (fALS), and myotonic dystrophy-2 (MD2). Phenotypically, NIRDs manifest as mono-organ (e.g. spinocerebellar ataxia type 31) or multi-organ disease (e.g. Friedreich ataxia, myotonic dystrophy-2). A number of other more rare NIRDs have been recently detected. This review aims at summarising and discussing previous findings and recent advances concerning the etiology, pathophysiology, clinical presentation, and therapeutic management of the most common NIRDs.

Blood Transcript Biomarkers Selected by Machine Learning Algorithm Classify Neurodegenerative Diseases including Alzheimer’s Disease

Huseby, C.J.; Delvaux, E.; Brokaw, D.L.; Coleman, P.D.; Biomolecules 2022, 12, 1592. doi:10.3390/biom12111592 

A blood-based screen to distinguish and classify neurodegenerative diseases is especially interesting having low cost, minimal invasiveness, and accessibility to almost any world clinic. In this study, we set out to discover a small set of blood transcripts that can be used to distinguish healthy individuals from those with Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, Friedreich’s ataxia, or frontotemporal dementia. Using existing public datasets, we developed a machine learning algorithm for application on transcripts present in blood and discovered small sets of transcripts that distinguish a number of neurodegenerative diseases with high sensitivity and specificity. We validated the usefulness of blood RNA transcriptomics for the classification of neurodegenerative diseases. Information about features selected for the classification can direct the development of possible treatment strategies.

Prediction of the disease course in Friedreich ataxia

Christian Hohenfeld, Ulrich Terstiege, Imis Dogan, Paola Giunti, Michael H. Parkinson, Caterina Mariotti, Lorenzo Nanetti, Mario Fichera, Alexandra Durr, Claire Ewenczyk, Sylvia Boesch, Wolfgang Nachbauer, Thomas Klopstock, Claudia Stendel, Francisco Javier Rodríguez de Rivera Garrido, Ludger Schöls, Stefanie N. Hayer, Thomas Klockgether, Ilaria Giordano, Claire Didszun, Myriam Rai, Massimo Pandolfo, Holger Rauhut, Jörg B. Schulz & Kathrin Reetz. Sci Rep 12, 19173 (2022). doi:10.1038/s41598-022-23666-z 

 We explored whether disease severity of Friedreich ataxia can be predicted using data from clinical examinations. From the database of the European Friedreich Ataxia Consortium for Translational Studies (EFACTS) data from up to five examinations of 602 patients with genetically confirmed FRDA was included. Clinical instruments and important symptoms of FRDA were identified as targets for prediction, while variables such as genetics, age of disease onset and first symptom of the disease were used as predictors. We used modelling techniques including generalised linear models, support-vector-machines and decision trees. The scale for rating and assessment of ataxia (SARA) and the activities of daily living (ADL) could be predicted with predictive errors quantified by root-mean-squared-errors (RMSE) of 6.49 and 5.83, respectively. Also, we were able to achieve reasonable performance for loss of ambulation (ROC-AUC score of 0.83). However, predictions for the SCA functional assessment (SCAFI) and presence of cardiological symptoms were difficult. In conclusion, we demonstrate that some clinical features of FRDA can be predicted with reasonable error; being a first step towards future clinical applications of predictive modelling. In contrast, targets where predictions were difficult raise the question whether there are yet unknown variables driving the clinical phenotype of FRDA.

C-Path and EFACTS Announce Data Sharing Agreement Making RDCA-DAP the Largest Worldwide Database for Friedreich’s Ataxia

TUCSON, Ariz., Nov. 10, 2022 — Critical Path Institute (C-Path) and the European Friedreich’s Ataxia Consortium for Translational Studies (EFACTS) today announced a data sharing agreement to incorporate patient data into C-Path’s Rare Disease Cures Accelerator-Data and Analytics Platform (RDCA-DAP®) solidifying RDCA-DAP as the largest worldwide database for Friedreich’s ataxia. 

 “The Friedreich’s Ataxia Research Alliance (FARA) partnered with C-Path to create a database that could integrate data from natural history studies and clinical trials, FA Integrated Clinical Database (FA-ICD), and we are really excited that this data is now part of RDCA-DAP and that our EFACTS partners are also contributing such informative data,” said FARA CEO Jennifer Farmer, M.S. “The collaboration with EFACTS goes beyond the contribution of this important data as EFACTS concomitantly joins the steering committee of the C-Path’s taskforce for FA and will inform new research. We look forward to the new insights and clinical trial tools that will be derived from having such a robust database shared with the research community.”

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

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

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

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

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

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

Clinical Management Guidelines for Friedreich Ataxia (FRDA)

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

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

11/08/2022​.

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

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

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

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

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

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

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

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

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

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

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

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

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

The objective of this study was to perform a characterization of cervical spinal cord structural damage in a large multisite FRDA cohort. Previous research has shown that increased eccentricity reflects dorsal column (DC) damage, while decreased CSA reflects either DC or corticospinal tract (CST) damage, or both. Hence our data support the hypothesis that damage to the DC and damage to CST follow distinct courses in FRDA: developmental abnormalities likely define the DC, while CST alterations may be both developmental and degenerative. These results provide new insights about FRDA pathogenesis and indicate that CSA of the cervical spinal cord should be investigated further as a potential biomarker of disease progression.

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

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

Graphical abstract

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

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

Children with a rare congenital genetic disorder: a systematic review of parent experiences

von der Lippe, C., Neteland, I. & Feragen, K.B.; Orphanet J Rare Dis 17, 375 (2022). doi:10.1186/s13023-022-02525-0 

 Coordinated care, and a more holistic approach in the follow up of children with rare genetic disorders is needed. International collaboration on research, diagnostics, producing scientific correct and understandable information available for health care professionals and lay people should be prioritized.

Selection of Synthetic Proteins to Modulate the Human Frataxin Function

Pignataro MF, Herrera MG, Fernández N, Aran M, Gentili H, Bataglini F, Santos J.; Biotechnol Bioeng. 2022 Oct 12. doi: 10.1002/bit.28263. Epub ahead of print. PMID: 36225115. 

 Our results suggest quaternary addition may be a new tool to modulate frataxin function in vivo. Nevertheless, more functional experiments under physiological conditions should be carried out to evaluate Affi_224 effectiveness in FRDA cell models.

Reata Pharmaceuticals Announces that the FDA Does Not Plan to Hold an Advisory Committee Meeting to Discuss the NDA for Omaveloxolone for Friedreich’s Ataxia

October 13, 2022. PLANO, Texas--(BUSINESS WIRE)-- Reata Pharmaceuticals, Inc. (Nasdaq: RETA) (“Reata,” the “Company,” “our,” “us,” or “we”), a clinical-stage biopharmaceutical company, announced that the U.S. Food and Drug Administration (“FDA”) has informed the Company that it does not plan to hold an advisory committee meeting in connection with its review of the Company’s New Drug Application (“NDA”) for omaveloxolone for the treatment of patients with Friedreich’s ataxia.

Study to Evaluate Multiple Ascending Dose and Multi-Dose of DT-216 in Adult Patients With Friedreich Ataxia

ClinicalTrials.gov Identifier: NCT05573698. A Phase 1b, Randomized, Double-blind, Placebo-controlled, Multiple Ascending Dose and Multi-Dose Study of DT-216 in Adult Patients With Friedreich Ataxia. Recruitment Status : Recruiting

First Posted : October 10, 2022 

Sponsor: Design Therapeutics

SARS-CoV-2 in patients with Friedreich ataxia

Megan M. Shen, Layne N. Rodden, Kellie McIntyre, Adriana Arias, Victoria Profeta, Kimberly Schadt & David R. Lynch; J Neurol (2022). doi:10.1007/s00415-022-11419-x

On a broader scale, the pandemic’s effects on this cohort are likely more prominent not from infection itself but rather disruptions to physical activity and therapy services. Anecdotally, a substantial proportion of patients have perceived significant declines in global health resulting from these disruptions, consistent with previous reports [1]. Future investigation with an expanded cohort and updated vaccination data as novel SARS-CoV-2 variants emerge will continue to inform adaptations in care.

A promising mouse model for Friedreich Ataxia progressing like human patients

Catherine Gérard, Annabelle Fortin Archambault, Camille Bouchard, Jacques P. Tremblay; Behavioural Brain Research, Volume 436, 2023, 114107, doi:10.1016/j.bbr.2022.114107. 

Jackson Laboratories Inc. developed a new mouse model that has 800 GAA repeats. We demonstrate here that these mice accurately reflect the human disease with a progressive neuromuscular degeneration highlighted by the two beam tests and the beginning of heart hypertrophy at 26 weeks. YG8-800 mice are thus currently a promising mouse model for FRDA.

Diabetes mellitus y ataxia de Friedreich en un niño: una difícil coexistencia [Diabetes mellitus and Friedreich´s ataxia in a child: a complicated coexistence]

Marqués Cabrero A, Expósito Raspeño M, Sánchez Escudero V, Gutiérrez Cruz N, González Vergaz A.; Arch Argent Pediatr. 2022 Oct;120(5):e223-e225. Spanish. doi: 10.5546/aap.2022.e223. Epub 2022 Aug 30. PMID: 36190225. 

The appearance of motor clumsiness, with running and jumping difficulties in a 6-year-old boy prompted the genetic study of Friedreich's ataxia, confirming his diagnosis. After diagnosis, it was evaluated by Pediatric Cardiology, detecting the presence of non-obstructive hypertrophic cardiomyopathy, and by Pediatric Endocrinology, due to overweight. At 9 years of age, he was diagnosed with diabetes mellitus, a regimen of insulin treatment was initiated. During follow-up, he presented significant neurological deterioration, reaching the use of a wheelchair, which hinders adequate metabolic control. This is a report of a pediatric patient with Friedrich ataxia and diabetes mellitus.

Plasma multi-omics analysis reveals very long chain ceramides as validated biomarkers of Friedreich’s ataxia

Dezhen Wang, M. Grazia Cotticelli, Blanca E. Himes, David R. Lynch, Clementina Mesaros; medRxiv 2022.09.27.22280432; doi:10.1101/2022.09.27.22280432

 New plasma lipids biomarkers of Friedreich’s Ataxia (FRDA) were validated using a discovery-validation design with two independent cohorts.

Solid Biosciences Announces Acquisition of AavantiBio and Concurrent $75 Million Private Placement

September 30, 2022 07:00 ET | Source: Solid Biosciences Inc CHARLESTOWN, Mass. and CAMBRIDGE, Mass., Sept. 30, 2022 (GLOBE NEWSWIRE) -- Solid Biosciences Inc. (Nasdaq: SLDB), a life sciences company focused on advancing meaningful therapies for Duchenne muscular dystrophy (Duchenne), and AavantiBio, Inc., a privately-held gene therapy company focused on transforming the lives of patients with Friedreich’s ataxia and rare cardiomyopathies, today announced that the companies have entered into a definitive merger agreement whereby Solid will acquire AavantiBio, including its pipeline assets and net cash. The combined company will focus on advancing a portfolio of neuromuscular and cardiac programs, led by SGT-003, a differentiated gene transfer candidate, for the treatment of Duchenne. Additional pipeline programs include AVB-202, a gene transfer candidate for the treatment of Friedreich’s ataxia, AVB-401 for BAG3 mediated dilated cardiomyopathy, and additional assets for the treatment of undisclosed cardiac diseases. Following approval by Solid stockholders, the combined company will operate as Solid Biosciences, will trade on Nasdaq under the ticker symbol “SLDB” and Bo Cumbo, the current Chief Executive Officer of AavantiBio, will assume the role of President and CEO of Solid Biosciences. 

FA is a rare inherited neuromuscular disease that causes progressive nervous system damage and movement problems. AVB-202, AavantiBio’s lead AAV gene transfer therapy candidate in preclinical development, utilizes a dual route of administration to more rigorously target disease pathology. Preclinical data from three animal models, including mouse and nonhuman primate, supported preclinical proof of concept. Solid is anticipating an IND submission for AVB-202 in the second half of 2024.

Friedreich Ataxia: An expanded access program for Elamipretide treatment

Children's Mercy Kansas City / Children’s Mercy Research Institute. 

Full Study Name: SPIES-006

This study is for participants who are 1 to 80 years old and involves the treatment use of Elamipretide through the expanded access program for treatment of Friedreich Ataxia. This is a compassionate use study. Compassionate use studies are those where the drug is not available to the market and the sponsor is providing the drug to the patient without cost to them in hopes that it will help decrease the progression of their disease state.

Guía de Evaluación Diagnóstica y Discapacidad en Pacientes con Ataxias y Paraparesias Espásticas Hereditarias

Francisco Javier Arpa Gutiérrez, María José Abenza Abildúa, Idoia Rouco Axpe. Sociedad Española de Neurología (2022). ISBN: 978-84-124320-4-6 . https://www.edicionessen.es

El objetivo de este trabajo, dirigido a neurólogos en general y a otros facultativos de especialidades médicas como medicina física y rehabilitadora, atención primaria, medicina interna, medicina del trabajo, etc., es facilitar la correcta valoración diagnóstica y de la discapacidad en los pacientes con AH y PEH. Una gradación completa y homogénea de su situación clínica aumentaría la posibilidad de acceder a recursos sociales y legales adecuados a su situación.

The Use of Enhanced Recovery After Surgery Protocols and Sugammadex in a Friedreich Ataxia Patient Who Underwent Robotic Surgery: A Case Report of a Patient Who Required No Postoperative Opioids and Was Discharged Home Earlier Than Anticipated

Lori P. Russo, Daniel Haddad, Daniel Bauman, Mina M. Fam (September 26, 2022). Cureus 14(9): e29590. doi:10.7759/cureus.29590

Anesthesia in general must be carefully planned in FRDA patients to allow for the best possible recovery and minimize complications. Due to the underlying neuromuscular compromise seen in these patients, their ability to recover from the pharmacologic and physiologic changes associated with anesthesia can be more difficult. They are prone to sensitivity to opioids, sedatives, and neuromuscular blocking agents (NMBAs) and are less likely to tolerate hemodynamic changes. Our review revealed no literature to suggest the routine use of Enhanced Recovery After Surgery (ERAS) protocols in FRDA patients or in patients with neuromuscular disease in general. The use of sugammadex has also been shown to be safe, and literature suggests superiority in both the general population and those with neuromuscular conditions. Our understanding is that there is very limited literature in regard to the safe use of sugammadex in FRDA patients.

The inherited cerebellar ataxias: an update

Coarelli G, Wirth T, Tranchant C, Koenig M, Durr A, Anheim M.; J Neurol. 2022 Sep 24. doi: 10.1007/s00415-022-11383-6. 

We describe new therapeutic leads: antisense oligonucleotides approach in polyglutamine SCAs and viral gene therapy in Friedreich ataxia. This review provides support for diagnosis, genetic counseling and therapeutic management of ICAs in clinical practice.

Diagnostic Delay and Clinical Features in Friedreich’s Ataxia

Mehmet Fatih Yetkin, Murat Gültekin, Merve Akcakoyunlu, Recep Baydemir, Ayse Çağlar Sarılar, Mehmet Canpolat, Hüseyin Per; Turk Noroloji Dergisi, cilt.28, sa.2, ss.97-101, 2022 (Hakemli Dergi). DOI:10.4274/tnd.2022.26780

Conclusion: This study is the first study to evaluate the diagnosis delay in patients with FRDA in our country. Although FRDA was the most common hereditary ataxia, in our study, it was shown that there was a significant delay in diagnosis in patients with FRDA. There is a need for studies that will raise awareness of public and health professionals about FRDA.

FRIEDREICH'S ATAXIA AND ITS CARDIOVASCULAR MANIFESTATIONS

Bryam Esteban Coello Garcia, Karina Noemi Contreras Garcia, Priscila Jazmin Sarango Lapo, Tatiana Carolina Espinoza Coyago, Johanna Belen Illescas Aguilera, Bonny Maria Montalvan Nivicela, Karen Sofia Suscal Pelaez; EPRA International Journal of Multidisciplinary Research (IJMR) -Volume: 8, Issue: 9, September 2022, DOI:10.36713/epra11261 

 The aim of this bibliographic review is to inform the scientific community of the presence of systemic manifestations, especially cardiovascular, in Friedreich's Ataxia; since this disease is not only characterized by the presence of neurological alterations, but also of affections to different apparatuses and systems of the human body, such as the heart, due to the cellular alteration that Friedreich's Ataxia causes.

Gene Expression Quantification to Assess Frataxin Replacement Therapies in Friedreich’s Ataxia

M. Baile, D. Schecter, A. Miller, T. Galas, N. Scherer, R. Chen, N. Ruiz, D. Bettoun.; Mov Disord. 2022; 37 (suppl 1). Meeting: 2022 International Congress (September 15-18, 2022. Madrid, Spain) 

 Quantitation of expression levels of a small number of genes in buccal cells can be used to discriminate between healthy individuals and patients with FRDA. Treatment with CTI-1601 is effective in restoring the expression levels of 6 of those genes to levels similar to those observed in healthy individuals.

Tissue Frataxin Increases After Administration of CTI-1601, a Frataxin Replacement Therapy in Development for the Treatment of Friedreich’s Ataxia

D. Bettoun, T. Galas, D. Schecter, N. Ruiz, R. Clayton, J. Farmer.; Mov Disord. 2022; 37 (suppl 1).Meeting: 2022 International Congress (September 15-18, 2022. Madrid, Spain) 

In this first clinical study of CTI-1601, a therapy intended to increase FXN in patients with FRDA, increases in FXN levels were seen in multiple tissues. These observed increases in FXN after 7 days of QD dosing of 50 or 100 mg CTI-160 are potentially clinically relevant since 2- to 3-fold increases in FXN in patients with FRDA may achieve FXN levels observed in asymptomatic heterozygous carriers [1, 2]. CTI-1601 was generally well-tolerated. These data support the continued study of CTI-1601 as a treatment for patients with FRDA.

Activation of a type I interferon response associated with acute frataxin knockdown in iPSC-derived cardiomyocytes

Cotticelli MG, Xia S, Truitt R, Doliba NM, Rozo AV, Tobias JW, Lee T, Chen J, Napierala JS, Napierala M, Yang W, Wilson RB.; Dis Model Mech. 2022 Sep 15:dmm.049497. doi: 10.1242/dmm.049497 

We confirmed that in iPSC-derived cardiomyocytes, loss of frataxin leads to mitochondrial dysfunction. The type I interferon response was activated in multiple cell types following acute frataxin knockdown and was caused, at least in part, by release of mitochondrial DNA into the cytosol, activating the cGAS-STING sensor pathway.

The power and the promise of CRISPR/Cas9 genome editing for clinical application with gene therapy

Ning Guo, Ji-Bin Liu, Wen Li, Yu-Shui Ma, Da Fu; Journal of Advanced Research, Volume 40, 2022, Pages 135-152, doi:10.1016/j.jare.2021.11.018. 

CRISPR/Cas9 also provides a possible therapeutic strategy for Friedreich's ataxia (FRDA). For example, removing the GAA expansions of the frataxin gene (FXN) in vitro and in vivo alleviates related symptoms dramatically but with some unexpected side effects like p53-mediated cell proliferation delay.

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

ClinicalTrials.gov Identifier: NCT05515536

The primary objective of this study is to assess the long-term safety of vatiquinone in participants with Friedreich ataxia (FA) previously exposed to vatiquinone in Study PTC743-NEU-003-FA (NCT04577352) or Study PTC743-NEU-005-FA

Phase 3 

Study Type : Interventional (Clinical Trial) 

Estimated Enrollment : 140 participants 

Allocation: N/A 

Intervention Model: Single Group Assignment 

Masking: None (Open Label) 

Primary Purpose: Treatment 

Official Title: Long-Term Open-Label Study to Assess the Safety and Efficacy of Vatiquinone in Patients With Friedreich Ataxia 

Estimated Study Start Date : November 1, 2022 

Estimated Primary Completion Date : December 31, 2027 

Estimated Study Completion Date : December 31, 2027

Consideration of oral health in rare disease expertise centres: a retrospective study on 39 rare diseases using text mining extraction method

Friedlander, L., Vincent, M., Berdal, A. et al.; Orphanet J Rare Dis 17, 317 (2022). doi:10.1186/s13023-022-02467-7 

Five networks we studied fill in the patient database while their phenotypes predict that dental and oral phenotypes may raise difficulties. The analysis of the collected data suggests a lack of connection with oral professionals during early childhood and adult transition. These networks are BRAIN-TEAM with Friedreich ataxia (Rare diseases with motor or cognitive expression of the central nervous system)......

Resveratrol from Dietary Supplement to a Drug Candidate: An Assessment of Potential

Khattar, Shivani, Sauban Ahmed Khan, Syed Amir Azam Zaidi, Mahdi Darvishikolour, Uzma Farooq, Punnoth Poonkuzhi Naseef, Mohamed Saheer Kurunian, Mohammed Zaafar Khan, Athar Shamim, Mohd Masih Uzzaman Khan, Zeenat Iqbal, and Mohd. Aamir Mirza. 2022.; Pharmaceuticals 15, no. 8: 957. doi:10.3390/ph15080957

In Australia, RVT as an option for the treatment of Friedreich ataxia was assessed ( NCT01339884, A Study of Resveratrol as Treatment for Friedreich Ataxia, Phase 1, Phase 2)

Perspectives on current models of Friedreich's ataxia

Kelekçi S, Yıldız AB, Sevinç K, Çimen DU, Önder T. Perspectives on current models of Friedreich's ataxia. Frontiers in Cell and Developmental Biology. 2022 ;10:958398. DOI: 10.3389/fcell.2022.958398 

We discuss the current challenges in using FRDA animal models and patient-derived cells. Additionally, we provide a brief overview of how iPSC-based models of FRDA were used to investigate the main pathways involved in disease progression and to screen for potential therapeutic agents for FRDA. The specific focus of this perspective article is to discuss the outlook and the remaining challenges in the context of FRDA iPSC-based models.

Comorbidities in Friedreich ataxia: incidence and manifestations from early to advanced disease stages

Fichera M, Castaldo A, Mongelli A, Marchini G, Gellera C, Nanetti L, Mariotti C.; Neurol Sci. 2022 Sep 2. doi: 10.1007/s10072-022-06360-w 

 Incidence of FA-related medical conditions varies according to disease duration. In patients with very long disease duration, we observed an unexpectedly high incidence of visual and auditory pseudo-hallucinations that were not previously reported in FA patients. We hypothesized that these late complications may be possibly related to the severe sensory deafferentation syndrome observed in the advanced stages of FA disease.

The immune system as a driver of mitochondrial disease pathogenesis: a review of evidence

Hanaford A, Johnson SC. Orphanet Journal of Rare Diseases. 2022 Sep;17(1):335. DOI: 10.1186/s13023-022-02495-3.

Inflammation appears to play a role in the pathogenesis of the mitochondria-associated iron accumulation disease Friedreich ataxia (FRDA). Microgliosis has been reported in the dorsal root ganglia of FRDA patients, a known site of FRDA neuropathology. Microglial activation has also been reported in FRDA patients in brain regions associated with neuropathology using PET scanning for 18F-FEMPA, a high-affinity ligand for the microglia-specific 18-kDa Translocator protein (TPSO). 18F-FEMPA signal intensity correlates with age of disease onset, supporting a causal role for neuroinflammation in FRDA symptoms. FRDA patients also show elevated plasma IL-6, and FRDA patient blood transcriptomic profiles show upregulated innate immune responses.

Identifying project topics and requirements in a citizen science project in rare diseases: a participative study

Michaela Neff, Holger Storf, Jessica Vasseur, Jörg Scheidt, Thomas Zerr, Andreas Khouri & Jannik Schaaf. Orphanet J Rare Dis 17, 357 (2022). doi:10.1186/s13023-022-02514-3 

Due to their low prevalence (< 5 in 10,000), rare diseases are an important area of research, with the active participation of those affected being a key factor. In the Citizen Science project “SelEe” (Researching rare diseases in a citizen science approach), citizens collaborate with researchers using a digital application, developed as part of the project together with those affected, to answer research questions on rare diseases. The aim of this study was to define the rare diseases to be considered, the project topics and the initial requirements for the implementation in a digital application.

Advancing qualitative rare disease research methodology: a comparison of virtual and in-person focus group formats

Andrew A. Dwyer, Melissa Uveges, Samantha Dockray & Neil Smith; Orphanet J Rare Dis 17, 354 (2022). doi:10.1186/s13023-022-02522-3 

Geographically dispersed patients have posed significant roadblocks for rare disease research resulting in small sample sizes and underpowered studies. As rare disease patients have been referred to as internet “power users”, web-enabled technologies hold promise for reaching dispersed rare disease patients and surmounting geographic barriers for many. To our knowledge, the present study is the first to support the validity of virtual focus groups for qualitative rare disease research. Moreover, the present findings suggest the anonymity afforded by the internet can facilitate discussion of highly sensitive and intimate topics. This observation is important as feelings of stigma and shame are frequently experienced by patients living with a rare disease—particularly in a condition like CHH that has a psychosexual/sexual health component. The present findings support methodologic rigor of using web-enabled technologies for qualitative research using focus groups in rare diseases.

A promissing mouse model for Friedreich Ataxia progressing like human patients

Catherine Gérard, Annabelle Fortin Archambault, Camille Bouchard, Jacques P. Tremblay; Behavioural Brain Research, 2022, 114107, doi:10.1016/j.bbr.2022.1141

Jackson Laboratories Inc. developed a new mouse model that has 800 GAA repeats. We demonstrate here that these mice accurately reflect the human disease with a progressive neuromuscular degeneration highlighted by the two beam tests and the beginning of heart hypertrophy at 26 weeks. YG8-800 mice are thus currently a promising mouse model for FRDA.

Larimar Therapeutics Announces FDA Clearance to Initiate the 25 mg Cohort of a Phase 2 Dose Exploration Trial of CTI-1601 in Friedreich’s Ataxia Patients

BALA CYNWYD, Pa., Sept. 14, 2022 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (“Larimar”) today announced that the U.S. Food and Drug Administration (FDA) has cleared the initiation of the 25 mg cohort of a Phase 2, four-week, placebo-controlled, dose exploration trial of CTI-1601 in Friedreich’s ataxia (FA) patients. In a written communication to Larimar, the FDA indicated it was lifting its full clinical hold on the CTI-1601 program and imposing a partial hold. The design of the upcoming Phase 2 trial is identical to the design proposed by Larimar, with the exception of a requirement for the FDA to review data from the 25 mg cohort prior to escalating the dose in the second cohort. Larimar expects to begin the Phase 2 trial in Q4 2022, with top-line data expected in 2H 2023.

The C-Terminal Cross-linked Telopeptide of Type I Collagen (CTX-I) as a Potential Cardiomyopathy Biomarker in Friedreich Ataxia Patients

Chiara Pane, Assunta Trinchillo, Andrea Salzano, Angela Marsili, Giorgia Puorro, Antonio Cittadini, Francesco Saccà & Cinzia Valeria Russo; Cerebellum (2022). doi:10.1007/s12311-022-01475-4 

CTX-I, a biomarkers of collagen turnover, is elevated in FRDA and should provide complementary information to identify patients with high cardiological risk even if longitudinal studies are needed to define the role of this serologic marker of collagen metabolism in the natural history of cardiomyopathy in FRDA patients.

A non-synonymous single nucleotide polymorphism in SIRT6 predicts neurological severity in Friedreich ataxia

Rodden LN, Rummey C, Dong YN, Lagedrost S, Regner S, Brocht A, Bushara K, Delatycki MB, Gomez CM, Mathews K, Murray S, Perlman S, Ravina B, Subramony SH, Wilmot G, Zesiewicz T, Bolotta A, Domissy A, Jespersen C, Ji B, Soragni E, Gottesfeld JM and Lynch DR; (2022). Front. Mol. Biosci. 9:933788. doi: 10.3389/fmolb.2022.933788

People with FRDA in the CT SIRT6 group have less severe neurological and visual dysfunction than those in the TT SIRT6 group. Biochemical analyses indicate that the benefit conferred by T to C SNP in SIRT6 does not come from altered expression or enzymatic activity of SIRT6 or frataxin but is associated with changes in the transcriptome.

Hyperactivation of mTOR and AKT in a cardiac hypertrophy animal model of Friedreich ataxia

Wing-Hang Tong, Hayden Ollivierre, Audrey Noguchi, Manik C. Ghosh, Danielle A. Springer, Tracey A. Rouault; Heliyon, Volume 8, Issue 8, 2022. 

 We observed increased phosphorylation of AKT and dysregulation of multiple downstream effectors of mTORC1, including S6K1, S6, ULK1 and 4EBP1, in a cardiac/skeletal muscle specific FRDA conditional knockout (cKO) mouse model and in human cell lines depleted of ISC biogenesis factors.

Respiratory Function in Friedreich’s Ataxia

Vinante, E.; Colombo, E.; Paparella, G.; Martinuzzi, M.; Martinuzzi, A. Children 2022, 9, 1319. https://doi.org/10.3390/children9091319

Respiratory function is impaired at various degrees in FRDA. The complex condition of inco-ordination and hyposthenia in FRDA affects daytime and night-time respiratory efficiency. We believe that the respiratory deficit and the inefficiency of cough are indeed a clinical problem deserving consideration, especially in the context of the concomitant postural difficulty and the possible presence of dysphagia. Therefore, the rehabilitation project for the subject with FRDA should also consider the respiratory function.

Preservation of bioenergetics and inhibition of ferroptosis with the novel compound SBT-588 in Friedreich’s ataxia cell models

Laura E. Kropp, Hatim Zariwala, Yunmi Park, Martin Redmon, David A. Brown, Alyssa Handler; Biochimica et Biophysica Acta (BBA) - Bioenergetics, Volume 1863, Supplement, 2022, doi:10.1016/j.bbabio.2022.148869.

Frataxin deficiency disrupts mitochondrial respiration and pulmonary endothelial cell function

Miranda K Culley, Monica Mehta, Jingsi Zhao, Dror Perk, Yi Yin Tai, Ying Tang, Sruti Shiva, Marlene Rabinovitch, Mingxia Gu, Thomas Bertero, Stephen Y Chan; bioRxiv 2022.08.22.504849; doi:org/10.1101/2022.08.22.504849

Our data highlight an Fe-S-driven metabolic shift separate from previously described replication stress whereby FXN knockdown diminished mitochondrial respiration and increased glycolysis and oxidative species production. In turn, FXN-deficient endothelial cells exhibited a vasoconstrictive phenotype consistent with PH. These data were observed in both primary pulmonary endothelial cells after pharmacologic inhibition of FXN and inducible pluripotent stem cell-derived endothelial cells from patients with FXN mutations. Altogether, this study defines FXN as a shared upstream driver of pathologic aberrations in both metabolism and genomic stability. Moreover, our study highlights FXN-specific vasoconstriction, suggesting available and future therapies may be beneficial and targeted for PH subtypes with FXN deficiency.

A systematic review of disease prevalence, health-related quality of life, and economic outcomes associated with Friedreich’s Ataxia

Katherine Buesch & Rongrong Zhang (2022) , Current Medical Research and Opinion, DOI: 10.1080/03007995.2022.2112870 

Findings from this systematic review revealed several knowledge gaps that would preclude the conduct of a robust assessment of the benefits and outcomes associated with a disease-modifying FA therapy. Additional understanding regarding patient and caregiver HRQoL and costs is required.

Direct utility of natural history data in analysis of clinical trials: Propensity match-based analysis of Omaveloxolone in Friedreich ataxia using the FA-COMS dataset

David Lynch, Angie Goldsberry, Christian Rummey, Jennifer Farmer, Sylvia Boesch, martin delatycki, Paola Giunti, j chad Hoyle, Caterina Mariotti, Katherine Mathews, Susan Perlman, SH Subramony, George Wilmot, Theresa Zesiwiecz, Lisa Weissfeld, Colin Meyer medRxiv 2022.08.12.22278684; doi: 10.1101/2022.08.12.22278684 

These results suggest a clinically meaningful slowing of FRDA progression with omaveloxolone, and consequently details how propensity-matched analysis contributes to the understanding of the effects of therapeutic agents. This demonstrates the direct value of natural history studies in the evaluation of clinical trials.

Replication dependent and independent mechanisms of GAA repeat instability

Chiara Masnovo, Ayesha F. Lobo, Sergei M. Mirkin; DNA Repair, Volume 118, 2022, 103385, doi:10.1016/j.dnarep.2022.103385. 

Here, we provide a brief historical overview on the discovery of (GAA)n repeat expansions and their association to FRDA, followed by recent advances in the identification of triplex H-DNA formation and replication fork stalling. The main body of this review focuses on the last decade of progress in understanding the mechanism of (GAA)n repeat instability during DNA replication and/or DNA repair. We propose that the discovery of additional mechanisms of (GAA)n repeat instability can be achieved via both comparative approaches to other repeat expansion diseases and genome-wide association studies. Finally, we discuss the advances towards FRDA prevention or amelioration that specifically target (GAA)n repeat expansions.

An open-label pilot study of recombinant granulocyte-colony stimulating factor in Friedreich’s ataxia

Kevin C. Kemp, Anastasia Georgievskaya, Kelly Hares, Juliana Redondo, Steven Bailey, Claire M. Rice, Neil J. Scolding, Chris Metcalfe & Alastair Wilkins; Nat Commun 13, 4655 (2022). doi:10.1038/s41467-022-31450-w 

 Pharmacological interventions to increase frataxin expression and reverse the deleterious effects of frataxin deficiency are attractive therapeutic approaches in FA. We have shown that a course of G-CSF therapy in participants with FA is safe, is associated with effective HSC mobilisation, and leads to significant elevations in frataxin together with improvements in biochemical deficits associated with FA. Nevertheless, the need for future assessment of G-CSF administration on affected tissues, such as the heart and brain, using a range of dose levels and dosing frequencies is required. The long-term safety of sustained G-CSF administration in people with FA is also unknown. The natural rate of disease progression in FA necessitates prolonged trial periods to sufficiently detect changes in clinical measures. This study provides proof-of-principle evidence to support an efficacy study of G-CSF administration in FA, using repeated courses over a longer period.

 

An open-label pilot study of recombinant granulocyte-colony stimulating factor in Friedreich’s ataxia

FDA Extends Review of Omaveloxolone in Friedreich Ataxia

August 9, 2022. After Reata Pharmaceuticals submitted an analysis from the MOXIe extension study of the investigational agent as part of the NDA submission, the FDA extended the PDUFA date to February 2023.

Reata continues to hit FDA roadblocks with its Friedreich’s ataxia candidate, noting regulator 'concerns'

Endpoints News. August 8, 2022. 

Reata Pharmaceuticals is facing an FDA wall on its small molecule candidate to treat Friedreich’s ataxia, omaveloxolone. According to the company’s Q2 report, the FDA might still not be sold on the drug. 

 “[The FDA] continues to have concerns regarding the strength of the efficacy evidence. The FDA did not identify any significant clinical safety issues. The FDA stated that the safety review is ongoing, and they are continuing to evaluate the cardiac safety of omaveloxolone in patients with Friedreich’s ataxia. They have not identified any other major safety concerns at this stage of their review,” the Q2 report said. 

 The FDA is expected to make its decision by Nov. 30. Reata stressed it’s still waiting to receive formal minutes from its mid-cycle review meeting with regulators.

Design Therapeutics Highlights Upcoming Milestones and Reports Second Quarter 2022

CARLSBAD, Calif., Aug. 08, 2022 (GLOBE NEWSWIRE) -- Design Therapeutics, Inc. (Nasdaq: DSGN), a clinical-stage biotechnology company developing treatments for serious degenerative genetic diseases, today highlighted anticipated upcoming milestones across its clinical and research-stage pipeline of novel GeneTAC™ small molecules and reported second quarter 2022 financial results.

Initial Data from Single-Ascending Dose Portion of Phase 1 trial for DT-216 Expected in the Fourth Quarter of 2022: DT-216, Design’s lead GeneTAC™ molecule, is designed to treat FA by specifically targeting the GAA repeat expansion mutation, the underlying cause of disease, and restore frataxin (FXN) gene expression. DT-216 is being evaluated in a Phase 1 clinical trial in adult patients with FA. The company plans to report initial data, including safety, tolerability, pharmacokinetics and FXN levels from the single-ascending dose portion of the trial in the fourth quarter of 2022. Design expects to initiate dosing of DT-216 in the multiple-ascending dose portion of the Phase 1 study in the second half of 2022.

Ataxia de friedreich, lucha por la supervivencia

Beatriz Miguel Palacios. Diplomada en Fisioterapia. Hospital Universitario Miguel Servet. Zaragoza, Nuria Bedoya Chocán. Celadora. Hospital Tres Mares. Reinosa, Cantabria., Nuria Sánchez Garrigós. Diplomada en Enfermería. Hospital General de Valdepeñas. Ciudad Real., María Teresa Bartolomé Bueno. FP2 Administrativo. Clínica del Pilar. Zaragoza., Noelia Loren Valles. Técnico en Cuidados Auxiliares de Enfermería. Hospital Miguel Servet. Zaragoza., José Antonio Ortín Clavería. Grado en Fisioterapia. Hospital Universitario Miguel Servet. Zaragoza.; REVISTA SANITARIA DE INVESTIGACIÓN, 5 agosto 2022, ISSN: 2660-7085 

PALABRAS CLAVE: Ataxias hereditarias, fisioterapia, ataxia cerebelosa, marcha, enfermedades cardiovasculares.

Lexeo to start phase I/II clinical trial for patients with FA cardiomyopathy.

5 ago 2022

Importance of an echocardiogram in the evaluation of ataxia

Stokreef S, Lemos M, Quintas S.; BMJ Case Reports CP 2022;15:e248691. doi:10.1136/bcr-2021-248691

We present the case of a boy in his middle childhood with gait ataxia and loss of reflexes with a 1-year onset. He had a background of an autism spectrum disorder but was otherwise healthy. A paediatric cardiology assessment was requested to investigate possible cardiac involvement associated to his neurological symptoms. Even though he had no cardiac symptoms and a normal electrocardiography, the echocardiogram revealed severe asymmetric left ventricle hypertrophy consistent with hypertrophic cardiomyopathy. This prompted genetic testing and the diagnosis of Friedreich’s ataxia was confirmed.

Unleashing the potential of AAV gene therapy

Biopharma Dealmakers (Biopharm Deal). 18/7/2022.

Voyager Therapeutics is unlocking the potential of adeno-associated virus gene therapy to treat a range of neurological disorders, broadening the therapeutic window while ensuring efficacy and safety. The company has already secured capsid option and license agreements with Novartis and Pfizer for target-specific use with CNS and cardiac muscle targets. Voyager also has an ongoing collaboration with Neurocrine Biosciences on a preclinical Friedreich’s ataxia (FA) program and two undisclosed discovery programs in which the company’s novel capsids may be deployed.

SCouT: Synthetic Counterfactuals via Spatiotemporal Transformers for Actionable Healthcare

Bhishma Dedhia, Roshini Balasubramanian, Niraj K. Jha; arXiv:2207.04208v1 [cs.AI] for this version); doi:10.48550/arXiv.2207.04208 (Computer Science > Artificial Intelligence)

We also generate actionable healthcare insights at the population and patient levels by simulating a state-wide public health policy to evaluate its effectiveness, an in silico trial for asthma medications to support randomized controlled trials, and a medical intervention for patients with Friedreich's ataxia to improve clinical decision-making and promote personalized therapy.

We simulate synthetic counterfactuals under a Calcitriol supplement intervention for a Friedreich’s ataxia (FA) patient.

Cardiovascular Research in Friedreich Ataxia

R. Mark Payne; J Am Coll Cardiol Basic Trans Science. null2022, 0 (0); doi:10.1016/j.jacbts.2022.04.005

Patients can develop a cardiomyopathy associated with heart failure and death. • A single gene defect decreases expression of FXN and may be amenable to therapy. • A need exists for greater basic and clinical investigations to advance therapies.

Cerebrospinal Fluid Proteomics in Friedreich Ataxia Reveals Markers of Neurodegeneration and Neuroinflammation

Imbault, Virginie; Dionisi, Chiara; Naeije, Gilles; Communi, David; Pandolfo, Massimo (2022). Frontiers. Collection. doi:10.3389/fnins.2022.885313 

This study supports the hypothesis that the quantitative analysis CSF proteins may provide robust biomarkers for clinical trials as well as shed light on pathogenic mechanisms. Interestingly, DEPs in FA patients CSF point to neurodegeneration and neuroinflammation processes that may respond to treatment.

EE146 Cost and Resource Utilization in Friedreich Ataxia: A Systematic Literature Review

R Zhang, K Buesch; Value in Health, Volume 25, Issue 7, Supplement, 2022, Page S363, doi:10.1016/j.jval.2022.04.396. 

The search retrieved 57 studies, of which 5 fulfilled the eligibility criteria. Among these, 2 reported resource utilization, and 5 reported cost data. No economic evaluation was identified. Neurologists and cardiologists were the most frequently visited physicians, seen by 61-86% and 57-86% of FA patients, respectively. About 23-46% of FA patients were hospitalized for an average of 5-9 days per year. Mean annual direct medical and non-medical cost per patient ranged from £8.893 in the UK to...

CO49 Clinical Efficacy and Safety of Therapeutic Interventions Used in Friedreich Ataxia: A Systematic Review

P Jain, L Badgujar, JA Spoorendonk, K Buesch; Value in Health, Volume 25, Issue 7, Supplement, 2022, Pages S312-S313, doi:10.1016/j.jval.2022.04.147. 

 In total, 32 relevant publications were identified, of which 24 were randomized controlled trials. These publications investigated idebenone (n=11), recombinant erythropoietin (n=6), omaveloxolone (n=3), amantadine hydrochloride (n=2), and A0001, CoQ10, creatine, deferiprone, interferon-γ-1b, L-cartinine levorotatory form of 5-hydroxytryptophan, luvadaxistat, resveratrol, RT001, vatiquinone (all n=1). Age of study participants ranged from 8 to 73 years and disease duration ranged from 4 to 19.

Natural History of Friedreich's Ataxia: Heterogeneity of Neurological Progression and Consequences for Clinical Trial Design

Christian Rummey, Louise A Corben, Martin Delatycki, George Wilmot, Sub H Subramony, Manuela Corti, Khalaf Bushara, Antoine Duquette, Christopher Gomez, J Chad Hoyle, Richard Roxburgh, Lauren Seeberger, Grace Yoon, Katherine Mathews, Theresa Zesiewicz, Susan Perlman, David R Lynch; Neurology Jul 2022, 10.1212/WNL.0000000000200913; DOI: 10.1212/WNL.0000000000200913

Understanding of the diversity within Friedreich's ataxia populations and their patterns of functional decline provides an essential foundation for future clinical trial design including patient selection and facilitates the interpretation of the clinical relevance of progression detected in Friedreich's ataxia.

Rare motor disorder: International study investigates living situation of people with Friedreich’s Ataxia

AAAS and EurekAlert. NEWS RELEASE 11-JUL-2022 DZNE - GERMAN CENTER FOR NEURODEGENERATIVE DISEASES 

The study aims to investigate and evaluate the health-related, psychosocial and economic impacts of the disease. The results of the interdisciplinary project, which combines clinical expertise with expertise in health economics, health care research and psychosocial research, are intended to provide a basis for improving treatment, care and support. In this project, the DZNE works closely with international partners from France (Paris Brain Institute) and Canada (McMaster University) as well as with the healthtech company Aparito and various European university hospitals. "PROFA" is being carried out in six study centers in Europe. It is planned that more than 200 patients aged 12 years and older will participate in the study.

셀리버리 “올해 코로나19·아토피 2상 진입 기대…무증 적절”

[KBIC 2022] 조대웅 대표 발표 

프리드리히 운동실조증(FRDA) 치료제 ‘AAV-FXN-aMTD‘는 TSDT를 적용한 세포·조직투과성 aMTD-융합 Frataxin(FXN) 재조합단백질이다. 조 대표는 “현재 다케다 제약과 공동 연구개발을 진행하고 있다”며 “3단계 마일스톤 효능평가를 미국에서 진행하고 있으며, 기술이전 협의도 동시에 진행 중”이라고 했다.

HTA decision-making for drugs for rare diseases: comparison of processes across countries

Tania Stafinski, Judith Glennie, Andrea Young & Devidas Menon; Orphanet J Rare Dis 17, 258 (2022). doi:10.1186/s13023-022-02397-4 

There is no “magic bullet” solution to address the challenges inherent in the HTA evaluation and reimbursement of DRDs. A variety of approaches are being used by different jurisdictions to address the evaluation of DRDs, in additional to various mechanisms for enabling reimbursement and patient access. As reimbursement and pricing processes for DRDs are being revisited in Canada, the insights gleaned related to stakeholder engagement, the collection of robust real-world data to support innovative reimbursement schemes, and the role that different financing models could play in efforts to achieve equitable access should be considered.

A Phase 1/2 Study of the Safety and Efficacy of LX2006 Gene Therapy in Participants With Cardiomyopathy Associated With Friedreich's Ataxia

ClinicalTrials.gov Identifier: NCT05445323; Sponsor: Lexeo Therapeutics

Intervention/treatment: 

Genetic: Low dose LX2006 Adeno-associated viral vector encoding the FXN gene (AAVrh.10hFXN) Genetic: High Dose LX2006 Adeno-associated viral vector encoding the FXN gene (AAVrh.10hFXN)

Large-scale expansions of Friedreich′s ataxia GAA·TTC repeats in human cells are prevented by LNA-DNA oligonucleotides and PNA oligomers

Anastasia Rastokina, Negin Mozafari, Jorge Cebrian, Edvard Smith, Sergei M. Mirkin, Rula Zain; bioRxiv 2022.07.04.498742; doi:10.1101/2022.07.04.498742 

The human disease Friedreich′s ataxia (FRDA) is caused by expansions of GAA·TTC repeats in the first intron intron of the frataxin (FXN) gene, and both intergenerational and somatic expansions are crucial for disease development. We and others have shown earlier that expanded GAA·TTC repeats can form an intramolecular triplex structure (H-DNA). Here we studied the effects of locked nucleic acid (LNA)-DNA mixmer oligonucleotides and peptide nucleic acid (PNA) oligomers on the expansion of GAA·TTC repeats in cultured human cells. Our experimental system employes a mammalian/yeast shuttle plasmid containing a selectable cassette to detect repeat expansions. Using our in-house in vitro triplex-specific DNA cleavage assay, we first confirmed H-DNA formation by the (GAA)100·(TTC)100 repeat in the selectable cassette and demonstrated that the designed LNA-DNA oligonucleotides as well as PNA oligomers are able to disrupt this structure. We then found that both LNA-DNA mixmers and PNA oligomers prevent repeat expansions in human cells. In the accompanying paper, we show that expansions of GAA·TTC repeats in this experimental system occur during replication fork stalling, regression and restart at the repetitive run. We hypothesize, therefore, that triplex DNA formation by the GAA·TTC repeats is a key to their instability, while LNA-DNA oligonucleotides and PNA oligomers counteract repeat expansions by disrupting the triplex at the fork or preventing triplex formation upon fork reversal.

Efficacy of plant extracts against Friedreich’s ataxia

Magisetty Obulesu, Plant Extracts in Neurodegenerative Diseases, Academic Press, Chapter 4, Pages 47-60, 2022, doi:10.1016/B978-0-323-95762-5.00006-0.

Friedreich’s ataxia (FA) is a rare neurodegenerative disease (ND). Its prevalence is usually found in those of Indo-European and Afro-Asiatic origin. Frataxin (FXN), a low-molecular-weight protein of 23kDa found in mitochondria, plays a pivotal role in the etiopathogenesis of FA. Therefore, a wide array of therapeutics has been targeted at FXN. This chapter throws light on multifarious therapeutics employed to combat FA in cell and animal models and human subjects. A few possible mechanistic roles of plant-based compounds and dietary ingredients have been discussed. It also emphasizes the pitfalls in current therapeutics that need more attention.