Omaveloxolone approved for patients aged 16 years and older with Friedreich ataxia (FRDA): A therapeutics bulletin of the American College of Medical Genetics and Genomics (ACMG)

Arthur Lenahan, Sho Yano, Brett Graham, Kuntal Sen, Omaveloxolone approved for patients aged 16 years and older with Friedreich ataxia (FRDA): A therapeutics bulletin of the American College of Medical Genetics and Genomics (ACMG), Genetics in Medicine Open, Volume 1, Issue 1, 2023, 100832, ISSN 2949-7744, doi:10.1016/j.gimo.2023.100832. 

Omaveloxolone (trade name: SKYCLARYS) is a Nrf2 activator that increases cellular resilience to oxidative stress that has been FDA approved for patients with FRDA who are 16 years and older. Omaveloxolone received orphan drug, fast track, priority review, and rare pediatric disease designations. Omaveloxolone is a semisynthetic triterpenoid administered orally once daily.

CO105 A Retrospective Study Characterizing Age at Loss of Ambulation Among Patients With Friedreich Ataxia Using Health Administrative Claims Data in the United States

A. Salvucci, C. Qian, L. Powell, D. Lynch, G. Vasco, K. Johnston, I. Tomazos, CO105 A Retrospective Study Characterizing Age at Loss of Ambulation Among Patients With Friedreich Ataxia Using Health Administrative Claims Data in the United States, Value in Health, Volume 26, Issue 12, Supplement, 2023, Pages S33-S34, ISSN 1098-3015, doi:10.1016/j.jval.2023.09.177. 

 In this cross-sectional analysis, most patients who were diagnosed with FA before the ages of 24 years experienced LOA and wheelchair use before the age of 16 years. While limitations exist in ascertainment of LOA using claims data, findings suggest that those who had earlier onset of FA also had earlier LOA.

Mitochondrial impairment, decreased sirtuin activity and protein acetylation in dorsal root ganglia in Friedreich Ataxia models

Arabela Sanz-Alcázar, Elena Britti, Fabien Delaspre, Marta Medina-Carbonero, Maria Pazos-Gil, Jordi Tamarit, Joaquim Ros & Elisa Cabiscol​. Mitochondrial impairment, decreased sirtuin activity and protein acetylation in dorsal root ganglia in Friedreich Ataxia models. Cell. Mol. Life Sci. 81, 12 (2024). doi:10.1007/s00018-023-05064-4 

 The NAD+/NADH ratio was reduced and sirtuin activity was impaired. We identified alpha tubulin as the major acetylated protein from DRG homogenates whose levels were increased in FXNI151F mice compared to WT mice. In the mitochondria, superoxide dismutase (SOD2), a SirT3 substrate, displayed increased acetylation in frataxin-deficient DRG neurons. Since SOD2 acetylation inactivates the enzyme, and higher levels of mitochondrial superoxide anion were detected, oxidative stress markers were analyzed. Elevated levels of hydroxynonenal bound to proteins and mitochondrial Fe2+ accumulation was detected when frataxin decreased. Honokiol, a SirT3 activator, restores mitochondrial respiration, decreases SOD2 acetylation and reduces mitochondrial superoxide levels. Altogether, these results provide data at the molecular level of the consequences of electron transport chain dysfunction, which starts negative feedback, contributing to neuron lethality. This is especially important in sensory neurons which have greater susceptibility to frataxin deficiency compared to other tissues.

Predictors of Survival in Friedreich's Ataxia: A Prospective Cohort Study

Indelicato, E., Reetz, K., Maier, S., Nachbauer, W., Amprosi, M., Giunti, P., Mariotti, C., Durr, A., de Rivera Garrido, F.J.R., Klopstock, T., Schöls, L., Klockgether, T., Bürk, K., Pandolfo, M., Didszun, C., Grobe-Einsler, M., Nanetti, L., Nenning, L., Kiechl, S., Dichtl, W., Ulmer, H., Schulz, J.B., Boesch, S. and (2023), Predictors of Survival in Friedreich's Ataxia: A Prospective Cohort Study. Mov Disord. doi:10.1002/mds.29687 

Arrhythmias, progressive neurological disability, and diabetes mellitus influence the overall survival in FA. We built a survival prognostic score which identifies patients meriting closer surveillance and who may benefit from early invasive cardiac monitoring and therapy.

Generation and characterization of two human iPSC lines, IGIBi014-A and IGIBi015-A, from Friedreich's ataxia (FRDA) patients with pathogenic (GAA/TTC)n repeat expansion in first intron of the Frataxin (FXN) gene

Ahmad I, Kapoor H, Kumar Srivastava A, Faruq M. Generation and characterization of two human iPSC lines, IGIBi014-A and IGIBi015-A, from Friedreich's ataxia (FRDA) patients with pathogenic (GAA/TTC)n repeat expansion in first intron of the Frataxin (FXN) gene. Stem Cell Res. 2023 Dec 16;74:103289. doi: 10.1016/j.scr.2023.103289. Epub ahead of print. PMID: 38141359. 

We generated two iPSC lines from FRDA patients with biallelic expansion of GAA repeats in the first intron ofFXNgene.IGIBi014-A and IGIBi015-Aboth iPSC lines demonstrated characteristics of pluripotency, normal karyotypes (46, XY),the capacity to differentiate into all three germ layers, and the ability to sustain the GAA repeat expansion with decreased FXN mRNA expression. These cell lines will be utilized to comprehend the pathophysiology of the illness and the FRDA's predictive phenotypes.

Loss of filamentous actin, tight junction protein expression, and paracellular barrier integrity in Frataxin-deficient human brain microvascular endothelial cells -implications for blood-brain barrier physiology in Friedreich's Ataxia

Frances M. SMITH, Daniel Kosman; Front. Mol. Biosci. Sec. Lipids, Membranes and Membranous Organelles, Volume 10 - 2023 | doi:10.3389/fmolb.2023.1299201

We identified that insufficient FXN levels in the hBMVEC BBB model causes changes in cytoskeletal architecture and tight junction protein abundance, coincident with increased barrier permeability. Changes in the integrity of the BBB may be related to patient brain iron accumulation, neuroinflammation, neurodegeneration, and stroke. Furthermore, our findings implicate other barrier cells, e.g., the cardiac microvasculature, as loci of disease pathology in FRDA.

EFICACIA Y SEGURIDAD DE LA OMAVELOXOLONA EN LA ATAXIA DE FRIEDREICH

Resumen-SIIC en castellano:  Disorders 38(2):313-320. Autores: Lynch D R, Chin MP, Meyer CJ 

Filadelfia, EE.UU. En pacientes con ataxia de Friedreich, el tratamiento prolongado con omaveloxolona se asocia con beneficios sostenidos; se pone de manifiesto la importante del inicio precoz del tratamiento, ya que los pacientes que lo hacen tardíamente no llegaron a presentar la misma mejoría, respecto de los tratados tempranamente con omaveloxolona.

Conclusión Los resultados de la fase abierta de extensión del MOXIE confirman los beneficios sostenidos del tratamiento con omaveloxolona, sobre el curso natural de la enfermedad, en pacientes con AF. Se demuestra también la importancia del inicio temprano del tratamiento, ya que los beneficios observados en los pacientes del grupo omaveloxolona-omaveloxolona no fueron alcanzados por los pacientes originalmente asignados a placebo. Los pacientes que recibieron omaveloxolona desde el principio, presentaron mejora sostenida de la evolución natural de la enfermedad, al cabo de más de 2.5 años de tratamiento.

JNS-101 by Jupiter Neurosciences for Friedreich Ataxia: Likelihood of Approval

December 21, 2023. JNS-101 is under clinical development by Jupiter Neurosciences and currently in Phase II for Friedreich Ataxia. According to GlobalData, Phase II drugs for Friedreich Ataxia does not have sufficient historical data to build an indication benchmark PTSR for Phase II. 

JNS-101 is under development for the treatment of Friedreich’s ataxia. The drug candidate is a micronized formulation of pharmaceutical grade trans-resveratrol. The drug candidate is administered through oral route. It acts by targeting frataxin.

MIB-626 by Metro International Biotech for Friedreich Ataxia: Likelihood of Approval

December 21, 2023. MIB-626 is under clinical development by Metro International Biotech and currently in Phase II for Friedreich Ataxia. According to GlobalData, Phase II drugs for Friedreich Ataxia does not have sufficient historical data to build an indication benchmark PTSR for Phase II. 

MIB-626 is under development for the treatment of Friedreich’s ataxia (FA), coronavirus disease 2019 (COVID-19), acute renal failure (ARF) (acute kidney injury), mild dementia and Leber’s hereditary optic neuropathy. The drug candidate is a crystallized precursor of nicotinamide adenine dinucleotide (NAD+). It is administered through oral route. 

It was also under development for the treatment of muscle endurance (musculoskeletal disorders) and mitochondrial myopathy.

Skyclarys* (omaveloxolone) received a positive opinion from the CHMP for the treatment of Friedreich’s ataxia

Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 11-14 December 2023. Skyclarys* (omaveloxolone) received a positive opinion from the CHMP for the treatment of Friedreich’s ataxia, an inherited disease causing a range of symptoms that worsen over time, including difficulty walking, inability to co-ordinate movements, muscle weakness, speech problems, damage to the heart muscle and diabetes. 

 Skyclarys 

 INN: omaveloxolone 

Marketing-authorisation applicant: Reata Ireland Limited 

Therapeutic indication: Treatment of Friedreich’s ataxia 

Skyclarys: Pending EC decision

Biogen press release: CAMBRIDGE, Mass., Dec. 15, 2023 (GLOBE NEWSWIRE) 

Lexeo Therapeutics Reports Third Quarter 2023 Financial Results and Operational Highlights

NEW YORK, Dec. 11, 2023 (GLOBE NEWSWIRE) --LEXEO Therapeutics, Inc..Received clearance of LX2006 Clinical Trial Application (CTA) in Canada for the treatment of FA cardiomyopathy; activated first clinical trial site outside of the United States. 

 LX2006 for the Treatment of FA Cardiomyopathy: Received clearance of CTA in Canada for LX2006 for the treatment of FA cardiomyopathy and activated the first clinical trial site for the SUNRISE-FA Phase 1/2 clinical trial outside of the United States. 

LX2006 for the treatment of Friedreich’s ataxia cardiomyopathy: Interim data readout in mid-2024

Frataxin analysis using triple quadrupole mass spectrometry: application to a large heterogeneous clinical cohort

Lynch, D.R., Rojsajjakul, T., Subramony, S.H. et al. Frataxin analysis using triple quadrupole mass spectrometry: application to a large heterogeneous clinical cohort. J Neurol (2023). doi:10.1007/s00415-023-12118-x 

The present data show that assay of FXN-M and FXN-E levels in blood provides an appropriate biofluid for assessing their repletion in particular clinical contexts.

Impact of specialist ataxia centres on health service resource utilisation and costs across Europe: cross-sectional survey

Morris, S., Vallortigara, J., Greenfield, J. et al. Impact of specialist ataxia centres on health service resource utilisation and costs across Europe: cross-sectional survey. Orphanet J Rare Dis 18, 382 (2023). doi:10.1186/s13023-023-02971-4 

Within each country, resource use and costs were broadly similar for specialist ataxia centre and non-specialist ataxia centre groups. There were differences between countries in terms of health care contacts and costs.

Human frataxin, the Friedreich ataxia deficient protein, interacts with mitochondrial respiratory chain

Davide D, Federica C, Marco B, Elisa B, Silvia M, Giulia T, Federica D, Ottaviani D, Elena M, Luigi L, Elisa G, Elena Z, Antonella R, Milena B, Geppo S, Donatella C, Leonardo S, Paola C. Human frataxin, the Friedreich ataxia deficient protein, interacts with mitochondrial respiratory chain. Cell Death Dis. 2023 Dec 8;14(12):805. doi: 10.1038/s41419-023-06320-y. PMID: 38062036. 

Using healthy cells and different FRDA cellular models we found that frataxin interacts with these three respiratory complexes. Furthermore, by EPR spectroscopy, we observed that in mitochondria from FRDA patients' cells the decreased level of frataxin specifically affects the FeS cluster content of complex I. Remarkably, we also found that the frataxin-like protein Nqo15 from T. thermophilus complex I ameliorates the mitochondrial respiratory phenotype when expressed in FRDA patient's cells.

Clinical stage and plasma neurofilament concentration in adults with Friedreich ataxia

Magnus Johnsson, Henrik Zetterberg, Kaj Blennow, Christopher Lindberg, Clinical stage and plasma neurofilament concentration in adults with Friedreich ataxia, Heliyon, 2023, e23347, ISSN 2405-8440, doi:10.1016/j.heliyon.2023.e23347. 

(Last) Magnus Johnsson, Henrik Zetterberg, Kaj Blennow, Christopher Lindberg, Clinical stage and plasma neurofilament concentration in adults with Friedreich ataxia, Heliyon, Volume 10, Issue 1, 2024, e23347, ISSN 2405-8440, doi.:10.1016/j.heliyon.2023.e23347.

FRDA is less prevalent in our region of Sweden than could be assumed. In concordance with previous studies from other authors, we find that p-NfL may be increased in patients with FRDA, but less so in older more clinically affected patients. Thus, we conclude that on an individual basis, p-NFL is of uncertain clinical value as a suitable biomarker.

Intensive Multimodal Treatment for A Young Adult with Friedreich Ataxia: A Case Report

Grace Battal, Nicolas Pinsault, Berthe Hanna-Boutros. Intensive Multimodal Treatment for A Young Adult with Friedreich Ataxia: A Case Report. International Journal of Physiotherapy and Research, 2023, 11 (3), pp.4508-4516. 10.16965/ijpr.2023.110 . hal-04134585 

 The FRDA patient displayed improvement in all outcome measures. Strength, ataxia severity and functional abilities were enhanced while a higher level of independence was gained. Our observations suggest that an intensive multimodal approach holds potential in the management of FRDA and call for further research.

A modified mouse model of Friedreich's ataxia with conditional Fxn allele homozygosity delays onset of cardiomyopathy

A modified mouse model of Friedreich's ataxia with conditional Fxn allele homozygosity delays onset of cardiomyopathy; Tyler L Perfitt, Claudia Huichalaf, Renea Gooch, Anna Kuperman, Youngwook Ahn, Xian Chen, Soumya Ullas, Dinesh Hirenallur-Shanthappa, Yutian Zhan, Diana Otis, Laurence O. Whiteley, Christine Bulawa, and Alain Martelli, American Journal of Physiology-Heart and Circulatory Physiology 0 0:0, doi:10.1152/ajpheart.00496.2023 

This modified model reproduced important pathophysiological and biochemical features of FA over a longer timescale than previous cardiac-specific mouse models, offering a larger window for studying potential therapeutics.

Novel intragenic deletion within the FXN gene in a patient with typical phenotype of Friedreich ataxia: may be more prevalent than we think?

Aguilera, C., Esteve-Garcia, A., Casasnovas, C. et al. Novel intragenic deletion within the FXN gene in a patient with typical phenotype of Friedreich ataxia: may be more prevalent than we think?. BMC Med Genomics 16, 312 (2023). doi:10.1186/s12920-023-01743-0 

We describe a patient presenting with novel intragenic deletion and an expansion on the FXN gene who shows the typical progression and clinical features of FRDA. We believe that parental sample testing should be performed in all FRDA patients that present an apparent biallelic expansion in order to offer proper genetic counselling.

Health-Related Quality of Life in Patients with Inherited Ataxia in Ireland

Menon, P.J., Yi, T.X., Moran, S. et al. Health-Related Quality of Life in Patients with Inherited Ataxia in Ireland. Cerebellum (2023). doi:10.1007/s12311-023-01640-3 

 This study is the first cross-sectional study on HRQoL in patients with inherited ataxia in Ireland. It highlights high rates of unemployment, difficulty with daily activities and physical functioning limitations, which is worse than comparative international studies. Given the limited therapeutic options currently available, optimising HRQoL is an important aspect of managing ataxia.

Loss of homeostatic functions in microglia from a murine model of Friedreich's ataxia

Ilaria Della Valle, Martina Milani, Simona Rossi, Riccardo Turchi, Flavia Tortolici, Valentina Nesci, Alberto Ferri, Cristiana Valle, Daniele Lettieri-Barbato, Katia Aquilano, Mauro Cozzolino, Savina Apolloni, Nadia D'Ambrosi, Loss of homeostatic functions in microglia from a murine model of Friedreich's ataxia, Genes & Diseases, 2023, 101178, doi:10.1016/j.gendis.2023.101178. 

 Although several reports correlated microglia morphology to cerebellar degeneration in FRDA in vivo, this work is the first to provide multilayer evidence (phenomics, transcriptomics, and metabolic analysis) that FRDA microglia are dysfunctional, suggesting a contribution of non-cell autonomous mechanisms in FRDA pathogenesis.

Effectiveness of rehabilitation intervention in persons with Friedreich ataxia

Paparella G, Stragà C, Vavla M, Pesenti N, Merotto V, Martorel GA, Zalunardo S, Armellin M, Comiotto J and Martinuzzi A (2023) Effectiveness of rehabilitation intervention in persons with Friedreich ataxia. Front. Neurol. 14:1270296. doi: 10.3389/fneur.2023.1270296 

 We report that the IR significantly improves motor performance and ataxia symptoms in patients with FRDA. Our study shows significant functional improvement in all the outcome measures used, except for NHPT bilaterally. FARS and SARA scores post-IR are significatively reduced when compared (p < 0.001).

The Cardiac Calcium Handling Machinery is Remodeled in Friedreich's Ataxia

The Cardiac Calcium Handling Machinery is Remodeled in Friedreich's Ataxia, Roman Czornobil, Obada Abou- Assali, Elizabeth Remily- Wood, David R Lynch, Sami F. Noujaim, Bojjibabu Chidipi bioRxiv 2023.11.09.566141; doi:10.1101/2023.11.09.566141 

Conclusion: The development of left ventricular contractile dysfunction in FA is associated with reduced expression of calcium handling proteins and mitochondrial dysfunction.

Aspectos médico-legales del consentimiento en la nueva regulación de la eutanasia. A propósito de un caso

Fernández Resina, Laura, Repositorio Institucional UIB, Treballs dels estudiants, TFG, Facultat de Medicina, Grau en Medicina (GMED). Fecha: 2023 Fecha de depósito: 2023-11-13. 

 El propósito del presente trabajo es analizar el caso de un paciente postadolescente afectado de ataxia de Friedreich que plantea su deseo de morir para estudiar los aspectos relativos a su consentimiento en relación a la eutanasia.

Emerging small molecule inhibitors of Bach1 as therapeutic agents: Rationale, recent advances, and future perspectives

Hushpulian DM, Kaidery NA, Dutta D, Sharma SM, Gazaryan I, Thomas B. Emerging small molecule inhibitors of Bach1 as therapeutic agents: Rationale, recent advances, and future perspectives. Bioessays. 2023 Nov 2:e2300176. doi: 10.1002/bies.202300176. Epub ahead of print. PMID: 37919861. 

FDA-approved Nrf2 activators, Tecfidera and Skyclarys for patients with multiple sclerosis and Friedreich's ataxia, respectively, are non-specific alkylating agents exerting side effects. Nrf2 is under feedback regulation through its target gene, transcriptional repressor Bach1.

Ataxia de Friedreich, revisión y actualización de la literatura con búsqueda sistemática de casos en Latinoamérica

Alfaro-Olivera, María, Calle-Nuñez, Adriana, Uribe-León, Alfonso, Araujo-Aliaga, Ismael, Aguirre-Quispe, Wilfor, Sarapura-Castro, Elison, & Cornejo-Olivas, Mario. (2023). Ataxia de Friedreich, revisión y actualización de la literatura con búsqueda sistemática de casos en Latinoamérica. Revista de Neuro-Psiquiatría, 86(1), 45-61. Epub 27 de abril de 2023. doi:10.20453/rnp.v86i1.4466 

En esta revisión, se actualizan aspectos epidemiológicos, fisiopatológicos y clínico-terapéuticos y se conduce una búsqueda sistemática de casos de AF reportados en Latinoamérica. La prevalencia de AF en poblaciones caucásicas es estimada entre 2 y 5 casos por 100 000 habitantes. En Latinoamérica se han publicado 35 estudios que reúnen 1481 casos en 6 países.

Thermodynamic Stabilization of Human Frataxin

Thermodynamic Stabilization of Human Frataxin. Reyes Núñez-Franco, Angel Torres-Mozas, Claudio D. Navo, Andreas Schedlbauer, Mikel Azkargorta, Ibon Iloro, Félix Elortza, Gabriel Ortega, Oscar Millet, Francesca Peccati, Gonzalo Jiménez-Osés. bioRxiv 2023.09.08.556816; doi:10.1101/2023.09.08.556816

This case-study highlights the power of our combined computational approach to generate optimized variants, adequate for protein-based therapeutics.

Evaluation of diaphragm functions with diaphragm ultrasound and Evaluation of diaphragm functions with diaphragm ultrasound and pulmonary function tests in individuals with Friedreich?s ataxia pulmonary function tests in individuals with Friedreich?s a

Yetkin, N. A., Yetkin, M. F., Baran Ketencioğlu, B., Oymak, F. S., Gülmez, İ., Yılmaz, İ., ... Tutar, N.(2023). Evaluation of diaphragm functions with diaphragm ultrasound and Evaluation of diaphragm functions with diaphragm ultrasound and pulmonary function tests in individuals with Friedreich?s ataxia pulmonary function tests in individuals with Friedreich?s a. TURKISH JOURNAL OF MEDICAL SCIENCES , vol.53, no.5, 1301-1311. Doi:10.55730/1300-0144.5696 

 Conclusion: Diaphragm ultrasound may reveal respiratory dysfunction better than PFT. Diaphragm excursion and TF are associated with disease scores in individuals with FDRA. Further studies are needed regarding the detection of alveolar hypoventilation.

Free-Water Imaging in Friedreich Ataxia Using Multi-Compartment Models

Fernandez, L., Corben, L.A., Bilal, H., Delatycki, M.B., Egan, G.F. and Harding, I.H. (2023), Free-Water Imaging in Friedreich Ataxia Using Multi-Compartment Models. Mov Disord. doi:10.1002/mds.29648  

This study supports further applications of multi-compartment diffusion modeling, and investigations of free-water as a measure of disease expression and progression in FRDA

Domain-Selective BET Ligands Yield Next-Generation Synthetic Genome Readers/Regulators with Nonidentical Cellular Functions

Domain-Selective BET Ligands Yield Next-Generation Synthetic Genome Readers/Regulators with Nonidentical Cellular Functions; Ashraf Mohammed, M. Brett Waddell, Ieva Sutkeviciute, Adithi Danda, Steven J. Philips, Walter Lang, P. Jake Slavish, Sandra J. Kietlinska, Mangesh Kaulage, Das Sourav, and Aseem Z. Ansari; J. Am. Chem. Soc. 2023, XXXX, XXX, XXX-XXX; Publication Date:November 3, 2023; doi:10.1021/jacs.3c06297 

SynTEF1, a prototype synthetic genome reader/regulator (SynGR), was designed to target GAA triplet repeats and restore the expression of frataxin (FXN) in Friedreich’s ataxia patients. 

SynGRs as chemical probes provide unique insights into the molecular recognition principles utilized by natural factors to precisely regulate gene expression, and they guide the design of more sophisticated synthetic gene regulators with greater therapeutic potential.

Calcitriol treatment is safe and increases frataxin levels in Friedreich Ataxia patients

Calcitriol treatment is safe and increases frataxin levels in Friedreich Ataxia patients. Berta Alemany-Perna, Jordi Tamarit, Daniel Lopez Dominguez, Anna Quiroga-Varela, Miguel Merchan-Ruiz, Lluis Ramio Torrenta, David Genis Batlle, Joaquim Ros; medRxiv 2023.10.28.23297713; doi:10.1101/2023.10.28.23297713 

The treatment was well tolerated by most patients, and only some of them experienced minor adverse effects at the beginning of the trial. Conclusion: Calcitriol dosage used (0.25mcg/24h) is safe for FRDA patients and it increases frataxin levels. We cannot rule out that higher doses administered longer could yield neurological benefits.

The therapeutic potential of targeting ferroptosis in the treatment of mitochondrial cardiomyopathies and heart failure

Cantrell AC, Zeng H, Chen JX. The therapeutic potential of targeting ferroptosis in the treatment of mitochondrial cardiomyopathies and heart failure. J Cardiovasc Pharmacol. 2023 Oct 10. doi: 10.1097/FJC.0000000000001496. Epub ahead of print. PMID: 37816193. 

We provide a brief overview of the potential roles of SIRT3 in mitochondrial iron homeostasis, as well as its contribution to the mitochondrial cardiomyopathy of Friedreich's ataxia (FRDA) and diabetic cardiomyopathy (DCM).

End-of-Life Discussions With Patients and Caregivers Affected By Neurogenetic Diseases

Anne-Claire D, Coarelli G, Heinzmann A, Verdon B, Manuella L, Petit E, Pierron L, Levy-Soussan M, Durr A, Gargiulo M, Ewenczyk C. End-of-Life Discussions With Patients and Caregivers Affected By Neurogenetic Diseases. Neurol Clin Pract. 2023 Dec;13(6):e200199. doi: 10.1212/CPJ.0000000000200199. Epub 2023 Oct 16. PMID: 37854177; PMCID: PMC10581072. DIRAGENE is an observational, cross-sectional, mixed-methods study with a patient-centered component and a primary caregiver-centered component. Observations include disease severity, psychosocial, and emotional scales; in-house questionnaires; and semidirected interviews.

 

Rehabilitation Program on Genetic and Degenerative Ataxia (RAPP)

ClinicalTrials.gov ID NCT06089863. Sponsor Hospices Civils de Lyon.

The present protocol aimed at evaluating the Rehabilitation Program in collaboration with partner patient on the symptom intensity, activity and quality of life on genetic and degenerative ataxia. 

This PAMPERO program's effect will be assessed by comparing the difference of Intensity of symptom measured by to Scale for the Assessment and Rating of Ataxia (SARA) at inclusion and 3 months after the end of rehabilitation.

Detection of alternative DNA structures and its implications for human disease

Matos-Rodrigues G, Hisey JA, Nussenzweig A, Mirkin SM. Detection of alternative DNA structures and its implications for human disease. Molecular Cell. 2023 Oct;83(20):3622-3641. DOI: 10.1016/j.molcel.2023.08.018. PMID: 37863029. 

 The most well-known REDs include Huntington’s disease (HD), fragile X syndrome (FXS), and Friedreich’s ataxia (FRDA), which are caused by the expansion of (CAG)n, (CGG)n, and (GAA)n repeats, respectively. Thus, DNA sequences prone to formalternative DNA structures are highly frequent in the human genome and associated with several human diseases.

Therapeutic Biomarkers in Friedreich's Ataxia: a Systematic Review and Meta-analysis

Gavriilaki M, Chatzikyriakou E, Moschou M, Arnaoutoglou M, Sakellari I, Kimiskidis VK. Therapeutic Biomarkers in Friedreich's Ataxia: a Systematic Review and Meta-analysis. Cerebellum. 2023 Oct 27. doi: 10.1007/s12311-023-01621-6. Epub ahead of print. PMID: 37889470.

 Although a large array of biomarkers have been investigated in Friedreich's ataxia (FRDA) trials, the optimal biomarker for assessing disease progression or therapeutic benefit has yet to be identified.

Experimental drugs for Friedrich’s ataxia: progress and setbacks in clinical trials, Expert Opinion on Investigational Drugs

Sylvia Boesch & Elisabetta Indelicato (2023) Experimental drugs for Friedrich’s ataxia: progress and setbacks in clinical trials, Expert Opinion on Investigational Drugs, DOI: 10.1080/13543784.2023.2276758 

 Generally, therapeutic approaches in FA are divided in two categories. One group of therapeutics (including gene therapy) aims at increasing/restoring frataxin levels. The second group encompasses those approaches aiming at reversing the consequence of frataxin loss at a tissue level, for instance mitochondrial failure. The first class of therapeutics may appear the most appealing as they intervene very early in the pathogenic cascade and may be potentially curative. Currently, various gene therapy and genome editing strategies are explored in FA. The likelihood of toxicity issues when overexpressing frataxin and the need for a delivery system with widespread distribution and low immunogenicity are among the hurdles to be addressed. Beyond these biological hinders, it is however not clear when such treatments should be administered to guarantee a reversal or at least a substantial improvement of the clinical phenotype. The presence of a developmental aspect as well as of a neurodegenerative kind of progression after onset suggest that the benefit of gene therapy/genome editing would be limited if applied beyond an early clinical phase.

Quantification of human mature frataxin protein expression in nonhuman primate hearts after gene therapy

Teerapat Rojsajjakul, Juliette J. Hordeaux, Gourav R. Choudhury, Christian J. Hinderer, Clementina Mesaros, James M. Wilson & Ian A. Blair. Quantification of human mature frataxin protein expression in nonhuman primate hearts after gene therapy. Commun Biol 6, 1093 (2023). doi:10.1038/s42003-023-05472-z 

Increasing expression of heart hFXN-M using gene therapy offers a way to prevent early mortality in FRDA. We used rhesus macaque monkeys to test the pharmacology of an adeno-associated virus (AAV)hu68.CB7.hFXN therapy. The advantage of using non-human primates for hFXN-M gene therapy studies is that hFXN-M and monkey FXN-M (mFXN-M) are 98.5% identical, which limits potential immunologic side-effects. 

The dose response is non-linear resulting in a ten-fold increase in monkey heart hFXN-M protein expression with only a three-fold increase in dose of the vector.

PTC Therapeutics Provides Corporate Update and Reports Third Quarter Financial Results

NEWS PROVIDED BY PTC Therapeutics, Inc. , 26 Oct, 2023 

PTC had a type C written-response-only meeting with FDA for vatiquinone for Friedreich ataxia to determine whether the data from the MOVE-FA study would be sufficient to support an NDA for accelerated approval. In their written response, the FDA stated that while they see the value of upright stability as a clinically meaningful endpoint, they believed a confirmatory study would likely be needed to support NDA submission. PTC has requested a follow-up live meeting to address the issues raised by the FDA. PTC is participating in a scientific advice procedure with the EMA to determine if the MOVE-FA data could support a conditional marketing authorization application in the EEA. PTC expects to have the outcome of this procedure in the first quarter of 2024.

Friedreich's Ataxia-Health Index Development and Validation of a Novel Disease-Specific Patient-Reported Outcome Measure

Friedreich's Ataxia-Health Index Development and Validation of a Novel Disease-Specific Patient-Reported Outcome Measure, Jamison Seabury, Spencer Rosero, Anika Varma, Jennifer Weinstein, Charlotte Engebrecht, Nuran Dilek, John Heatwole, Danae Alexandrou, Brittany Cohen, Jane Larkindale, David R. Lynch, Courtney Park, Sub H. Subramony, Ellen Wagner, Susan Walther, McKenzie Wells, Christine Zizzi, Chad Heatwole Neurol Clin Pract Oct 2023, 13 (5) e200180; DOI: 10.1212/CPJ.0000000000200180 

 Participants with FA identified 18 symptomatic themes of importance to be included as subscales in the FA-HI. The FA-HI demonstrates high internal consistency and test-retest reliability, and it was identified by participants as highly relevant, comprehensive, and easy to complete. FA-HI total and subscale scores statistically differentiated between subgroups of participants with varying levels of disease burden.

Frataxin Deficiency Drives a Shift from Mitochondrial Metabolism to Glucose Catabolism, Triggering an Inflammatory Phenotype in Microglia

Frataxin Deficiency Drives a Shift from Mitochondrial Metabolism to Glucose Catabolism, Triggering an Inflammatory Phenotype in Microglia Francesca Sciarretta, Fabio Zaccaria, Andrea Ninni, Veronica Ceci, Riccardo Turchi, Savina Apolloni, Martina Milani, Ilaria Della Valle, Marta Tiberi, Valerio Chiurchiù, Nadia D’Ambrosi, Silvia Pedretti, Nico Mitro, Katia Aquilano, Daniele Lettieri-Barbato bioRxiv 2023.10.18.562916; doi:10.1101/2023.10.18.562916 

 The study also pinpointed Hcar2 (GPR109A) as a potential agent for butyrate anti-inflammatory impact on microglia. Tests on FRDA mice highlighted the neuroprotective attributes of butyrate intake, bolstering neuromotor performance. In essence, our findings shed light on how cerebellar microglia activation contributes to FRDA and highlight butyrate potential to alleviate neuroinflammation, rectify metabolic imbalances, and boost neuromotor capabilities in FRDA and similar conditions.

Effectiveness of rehabilitation intervention in persons with Friedreich ataxia

Gabriella Paparella, Cristina Stragà, Marinela Vavla, Nicola Pesenti, Vasco Merotto, Gian A. Martorel, Sara Zalunardo, Maria Armellin, Jimmy Comiotto, Andrea Martinuzzi; Effectiveness of rehabilitation intervention in persons with Friedreich ataxia. Front. Neurol. Sec. Neurorehabilitation Volume 14 - 2023 | doi: 10.3389/fneur.2023.1270296 

Our study shows significant functional improvement in all the outcome measures used, except for NHPT bilaterally. FARS and SARA scores post-IR are significatively reduced when compared. 

We demonstrate that IR programs in FRDA can provide a meaningful clinical improvement in terms of outcome measures. These findings could be useful when approaching progressive neurological disorders.

Management of Friedreich's Ataxia-Associated Cardiomyopathy in Pregnancy: A Review of the Literature

Ashleigh N. Peterson, Leigh C. Hickerson, E. Rebecca Pschirrer, Lynsy B. Friend, Cynthia C. Taub, Management of Friedreich's Ataxia-Associated Cardiomyopathy in Pregnancy: A Review of the Literature, The American Journal of Cardiology, 2023, doi:10.1016/j.amjcard.2023.10.019. 

 Most patients with FRDA can deliver vaginally, and neuraxial analgesia is recommended during labor due to the risks associated with general anesthesia. Breastfeeding is encouraged, even for those taking cardiac medications.

Skeletal muscle proteome analysis underpins multifaceted mitochondrial dysfunction in Friedreich´s Ataxia

Elisabetta Indelicato, Klaus Faserl, Matthias Amprosi, Wolfgang Nachbauer, Rainer Schneider, Julia Wanschitz, Bettina Sarg, Sylvia Boesch. Skeletal muscle proteome analysis underpins multifaceted mitochondrial dysfunction in Friedreich´s Ataxia; Front. Neurosci. Sec. Neuropharmacology Volume 17 - 2023 | doi: 10.3389/fnins.2023.1289027. 

Principal component analysis showed a clear separation between FRDA and control samples. Interactome analysis revealed clustering of DE proteins in oxidative phosphorylation, ribosomal elements, mitochondrial architecture control and fission/fusion pathways. DE findings in the muscle-specific proteomics suggested a shift towards fasttwitching glycolytic fibers. Notably, most DE proteins (169/228, 74%) are target of the transcription factor nuclear factor-erythroid 2.Our data corroborate a mitochondrial biosignature of FRDA, which extends beyond a mere oxidative phosphorylation failure. Skeletal muscle proteomics highlighted a derangement of mitochondrial architecture and maintenance pathways and a likely adaptive metabolic shift of contractile proteins.The present findings are relevant for the design of future therapeutic strategies and highlight the value of skeletal muscle -omics as disease state readout in FRDA.

Skeletal muscle proteome analysis underpins multifaceted mitochondrial dysfunction in Friedreich´s Ataxia

Correction to Safety and Efficacy of Omaveloxolone in Friedreich Ataxia (MOXIe Study)

Lynch D. Correction to Safety and Efficacy of Omaveloxolone in Friedreich Ataxia (MOXIe Study). Ann Neurol. 2023 Oct 5. doi: 10.1002/ana.26808. Epub ahead of print. Erratum for: Ann Neurol. 2021 Feb;89(2):212-225. PMID: 37795909.

 In the Results section, the text should read: “Within the mFARS assessment, omaveloxolone improved each component (bulbar, upper limb coordination, lower limb coordination, and upright stability) relative to placebo, although the greatest effects were on upper limb coordination, followed by upright stability.

Disease Delineation for Multiple Sclerosis, Friedreich Ataxia, and Healthy Controls Using Supervised Machine Learning on Speech Acoustics

Schultz BG, Joukhader Z, Nattala U, et al. Disease Delineation for Multiple Sclerosis, Friedreich Ataxia, and Healthy Controls Using Supervised Machine Learning on Speech Acoustics. IEEE Transactions on Neural Systems and Rehabilitation Engineering : a Publication of the IEEE Engineering in Medicine and Biology Society. 2023 Oct;PP. DOI: 10.1109/tnsre.2023.3321874. PMID: 37792655.

 Results showed that Friedreich ataxia, multiple sclerosis and healthy controls were all identified with high accuracy (over 82%). Twenty-one acoustic features were strong markers of neurodegenerative diseases, falling under the categories of spectral qualia, spectral power, and speech rate. We demonstrated that speech markers can delineate neurodegenerative diseases and distinguish healthy speech from pathological speech with high accuracy.

Vestibular Pathology as Early Finding of Friedreich’s Ataxia in a 16 Years Old Woman

Fernández, A.G. Vestibular Pathology as Early Finding of Friedreich’s Ataxia in a 16 Years Old Woman. Indian J Otolaryngol Head Neck Surg (2023). doi:10.1007/s12070-023-04249-4 

Friedreich’s ataxia is degenerative disease frequently starting around puberty and it’s characterized by a progressive gait ataxia, limb weakness, apparition of Babinsky sign, loss of deep tendon reflex, dysarthria and skeletal deformities. The development of vestibular pathology is common but not completely understood. A 16 years old woman with early vestibular defects in relation to a latter Friedreich’s ataxia diagnosis is reported.

Social cognition in degenerative cerebellar ataxias

Simona Karamazovova, Veronika Matuskova, Natalie Svecova, Martin Vyhnalek, Social cognition in degenerative cerebellar ataxias, Current Opinion in Behavioral Sciences, Volume 54, 2023, 101313, doi:10.1016/j.cobeha.2023.101313.

Social cognition (SC) refers to a set of skills necessary for successful social communication and interpersonal relationships. Accumulating evidence points toward a crucial role of the cerebellum in SC. This narrative review summarizes and discusses the social cognitive impairment in cerebellar ataxias (CA), a group of hereditary neurodegenerative diseases of the cerebellum. Substantial impairment in emotion recognition and theory of mind, two essential components of SC, is present in CA. The social cognitive impairment is largely independent of the motor disability, general cognitive deficit, or neuropsychiatric symptoms. Since the impairment reaches comparable levels to autism or schizophrenia, it can substantially impact patients’ quality of life and deserves further attention in future research.

FDA Clears Exploration Trial for Higher Dose of CTI-1601 for Friedreich Ataxia

October 2, 2023. After the company released positive phase 2 data earlier this year, Larimar Therapeutics announced that the FDA has cleared a 4-week, placebo-controlled exploration trial (NCT05579691) assessing its investigational Friedrich ataxia (FA) agent CTI-1601 in doses of 50 mg. The company’s open-label extension (OLE), which will assess 25 mg of CTI-1601 daily, was also cleared for initiation by the FDA.

The OLE, expected to begin in Q1 2024, will include those who completed treatment in the phase 2 dose exploration trial or a prior trial of CTI-1601. In the OLE, investigators will assess safety, tolerability, and pharmacokinetics of the agent, as well as measures of frataxin (FXN) levels and other pharmacodynamic markers. Other objectives include the evaluation of the effects of long-term subcutaneous administration of CTI-1601 on measures of clinical function. Data from the OLE will be compared with a matched set of untreated patients from the Friedreich’s Ataxia Clinical Outcome Measures Study (FACOMS) database.

Neurologic orphan diseases: Emerging innovations and role for genetic treatments

Kioutchoukova IP, Foster DT, Thakkar RN, Foreman MA, Burgess BJ, Toms RM, Molina Valero EE, Lucke-Wold B. Neurologic orphan diseases: Emerging innovations and role for genetic treatments. World J Exp Med 2023; 13(4): 59-74  doi: 10.5493/wjem.v13.i4.59

 Emerging innovations and the role of genetic treatments open a new window of opportunity for the treatment of neurologic orphan diseases.

Benefits of Adaptive Sport on Physical and Mental Quality of Life in People with Physical Disabilities: A Meta-Analysis

Isidoro-Cabañas E, Soto-Rodríguez F, Morales-Rodríguez F, Pérez-Mármol J. Benefits of Adaptive Sport on Physical and Mental Quality of Life in People with Physical Disabilities: A Meta-Analysis; Healthcare (Basel, Switzerland). 2023 Sep;11(18). PMCID: PMC10531072. doi:10.3390/healthcare11182480 

The engagement in adaptive sports showed a positive impact on the mental quality of life among adults with physical disabilities. However, the positive effect of adaptive sports practice on physical quality of life was shown only in the pre–post-test analysis. Further studies are required to validate the obtained findings.

Comparison of Live and Remote Video Ratings of the Scale for Assessment and Rating of Ataxia

Taheri Amin A, Faber J, Önder D, et al. Comparison of Live and Remote Video Ratings of the Scale for Assessment and Rating of Ataxia; Movement Disorders Clinical Practice. 2023 Aug;10(9):1404-1407. PMCID: PMC10525045. DOI: 10.1002/mdc3.13843 

Live and remote video ratings showed a high level of agreement for the complete score (bias = 0.09, with standard deviation = 2.00) and all single SARA items (bias<0.20 for all items).

Conclusion: Remote video ratings of SARA are a reliable means to assess severity of ataxia.

Pre-Validation of a Virtual Reality Tool to Quantify the Severity of Friedreich's Ataxia

K. Chenier, A. Duquette, L. Touma, M. T. Le and D. R. Labbe, "Pre-Validation of a Virtual Reality Tool to Quantify the Severity of Friedreich's Ataxia," 2023 IEEE 11th International Conference on Serious Games and Applications for Health (SeGAH), Athens, Greece, 2023, pp. 1-7, doi: 10.1109/SeGAH57547.2023.10253802.

 The results of this study demonstrate the feasibility of using VR with FA patients, although adaptation of the technology may be necessary for those with more severe impairments.

CRISPR/Cas9-Based Edition of Frataxin Gene in Dictyostelium discoideum

Hernan Gustavo Gentili, María Florencia Pignataro, Justo Facundo Olmos, María Florencia Paván, Lorena Itatí Ibáñez, Javier Santos, Francisco Velazquez Duarte; CRISPR/Cas9-Based Edition of Frataxin Gene in Dictyostelium discoideum. Biochem J 2023; BCJ20230244. doi:10.1042/BCJ20230244 

The results of the study suggest that this new D. discoideum strain offers a wide range of possibilities to easily explore diverse FA FXN variants. This can facilitate the development of straightforward drug screenings to look for new therapeutic strategies.

Long non-coding RNA TUG1 is down-regulated in Friedreich's ataxia

Long non-coding RNA TUG1 is down-regulated in Friedreich's ataxia. Mert Koka, Hui Li, Rumana Akther, Susan Perlman, Darice Wong, Brent L Fogel, David R Lynch, Vijayendran Chandran, bioRxiv 2023.09.22.558879; doi: 10.1101/2023.09.22.558879 

This suggests that elevated TUG1 levels correlate with earlier onset and more severe cases. In summary, this study highlights Tug1 as a crucial blood-based biomarker for FRDA. Tug1's consistent expression variance across human and mouse tissues is closely associated to disease severity and key FRDA pathways. It also correlates strongly with Fxn levels, making it a promising early, non-invasive marker. TUG1 offers potential for FRDA monitoring and therapeutic development, warranting further clinical research.

Innovative thinking of clinical investigation for rare disease drug development

Wang, P., Chow, SC. Innovative thinking of clinical investigation for rare disease drug development. Orphanet J Rare Dis 18, 299 (2023). doi:10.1186/s13023-023-02909-w 

Many clinical trials for drug development are powered on effectiveness only, and safety issue is considered as the secondary objective. This practice has made some approved drugs have safety concerns, and some are even withdrawn or recalled. One possible reason for researchers not power on safety is that testing for safety requires a much larger sample size. As for orphan drug development, this problem is even worse due to the limited availability of participants.

Periodontal Treatment of Norwegian Patients With Rare Diseases: A Commentary

Øystein Fardal, Irene Skau, Jostein Grytten, Periodontal Treatment of Norwegian Patients With Rare Diseases: A Commentary, International Dental Journal, 2023, doi:10.1016/j.identj.2023.07.009. 

 An autosomal recessive disease that causes neurodegeneration. It results in muscle weakness and loss of sensation and proprioception, causing problems with movement as well as impaired speech. The symptoms tend to worsen as time progresses, so many patients end up in wheelchairs, lose their vision and hearing, and experience other medical complications such as diabetes mellitus and scoliosis. The cause of the disease is a reduction in frataxin, which is necessary for the production of mitochondrial adenosine triphosphate (ATP) and the management of iron stores. No previous connections with periodontal complications have been reported; however, diabetes is a known risk factor. In addition, the inability to perform adequate oral hygiene due to the disability may be an important risk factor.

Analytical Method and Stability Study for Oral Suspension of Idebenone in Syrspend

Porru, E.; Piro, F.; Comito, R.; Mosendz, A.; Minniti, E.; Conti, M.; Stancari, A.; Violante, F.S. Analytical Method and Stability Study for Oral Suspension of Idebenone in Syrspend. Separations 2023, 10, 517. doi:10.3390/separations10090517 

The greatest disadvantage of IDB is its low solubility in water, resulting in low bioavailability. Galenic preparations of IDB in customized doses are common for pediatric patients, which can often prove to be the only option for access to therapy. As an antioxidant, the chemical stability of IDB is an essential guarantee for exerting the desired antioxidant action. Stability studies are essential to know the effect of storage conditions of a galenic product. For the first time, a stability-indicating LC-MS method has been developed to define the stability of IDB suspensions in SyrSpend® Sugar-Free Unflavored (Fagron), a carrier phase formulated for setting up suspensions of active pharmaceutical ingredients (APIs) insoluble or poorly insoluble in water and compatible with it.

Patient-derived iPSC models of Friedreich ataxia: a new frontier for understanding disease mechanisms and therapeutic application

Maheshwari S, Vilema-Enríquez G, Wade-Martins R. Patient-derived iPSC models of Friedreich ataxia: a new frontier for understanding disease mechanisms and therapeutic application. Transl Neurodegener. 2023 Sep 20;12(1):45. doi: 10.1186/s40035-023-00376-8. PMID: 37726850. 

These models enable studies of the molecular mechanisms underlying GAA-induced pathology, as well as providing an exciting tool for the screening and testing of novel disease-modifying therapies. This review explores how the use of iPSCs to study FRDA has developed over the past decade, as well as discussing the enormous therapeutic potentials of iPSC-derived models, their current limitations and their future direction within the field of FRDA research.

Butyrate prevents visceral adipose tissue inflammation and metabolic alterations in a Friedreich’s ataxia mouse model

Turchi R, Sciarretta F, Ceci V, Tiberi M, Audano M, Pedretti S, Panebianco C, Nesci V, Pazienza V, Ferri A, Carotti S, Chiurchiù V, Mitro N, Lettieri-Barbato D, Aquilano K. Butyrate prevents visceral adipose tissue inflammation and metabolic alterations in a Friedreich's ataxia mouse model. iScience. 2023 Aug 28;26(10):107713. doi: 10.1016/j.isci.2023.107713. PMID: 37701569; PMCID: PMC10494209.  

Metagenomic analysis indicated a reduction in fecal butyrate-producing bacteria, known to exert antidiabetic effects. A butyrate-enriched diet restrained vWAT abnormalities and mitigated diabetes features in KIKO mice. Our work emphasizes the role of vWAT in FA-related metabolic issues and suggests butyrate as a safe and promising adjunct for FA management.

Neurologic orphan diseases: Emerging innovations and role for genetic treatments

Kioutchoukova IP, Foster DT, Thakkar RN, Foreman MA, Burgess BJ, Toms RM, Molina Valero EE, Lucke-Wold B. Neurologic orphan diseases: Emerging innovations and role for genetic treatments. World J Exp Med 2023; 13(4): 59-74 [DOI: 10.5493/wjem.v13.i4.59]. 

 Neurologic orphan diseases are rare conditions that impact a small percentage of the population. Through new advances in technology and research, the use of genetic treatment for these conditions is increasing. Recent advances in clustered regularly interspaced palindromic repeats/Cas9, adeno-associated viral vectors, antisense oligonucleotides, and mammalian target of rapamycin inhibitors have shown improvements in the care of patients and their quality of life.

SIRT3 Regulates Clearance of Apoptotic Cardiomyocytes by Deacetylating Frataxin

Jing Gao, Chenglin Huang, Linghui Kong, Wugang Zhou, Mengwei Sun, Tong Wei and Weili Shen; SIRT3 Regulates Clearance of Apoptotic Cardiomyocytes by Deacetylating Frataxin. Circulation ResearchVolume 133, Issue 7, 15 September 2023; Pages 631-647 doi:1161/CIRCRESAHA.123.323160  

The SIRT3-FXN axis has the potential to resolve cardiac inflammation by increasing macrophage efferocytosis and anti-inflammatory activities.

Friedreich's ataxia: new insights

Krasilnikova MM, Humphries CL, Shinsky EM. Friedreich's ataxia: new insights. Emerg Top Life Sci. 2023 Sep 12:ETLS20230017. doi: 10.1042/ETLS20230017. Epub ahead of print. PMID: 37698160. 

 Friedreich ataxia (FRDA) is an inherited disease that is typically caused by GAA repeat expansion within the first intron of the FXN gene coding for frataxin. This results in the frataxin deficiency that affects mostly muscle, nervous, and cardiovascular systems with progressive worsening of the symptoms over the years. This review summarizes recent progress that was achieved in understanding of molecular mechanism of the disease over the last few years and latest treatment strategies focused on overcoming the frataxin deficiency.

Comparative multi-omics analyses of cardiac mitochondrial stress in three mouse models of frataxin deficiency

Nicole M. Sayles, Jill S. Napierala, Josef Anrather, Nadège Diedhiou, Jixue Li, Marek Napierala, Hélène Puccio, Giovanni Manfredi; Comparative multi-omics analyses of cardiac mitochondrial stress in three mouse models of frataxin deficiency. Dis Model Mech 2023; dmm.050114. doi: doi:10.1242/dmm.050114

Transcriptional changes were found in all models, but differentially expressed genes consistent with cardiomyopathy and ISRmt were only identified in FxnG127V hearts. However, these changes were surprisingly mild even at an advanced age (18-months), despite a severe decrease in FXN levels to 1% of WT. These findings indicate that the mouse heart has low reliance on FXN, highlighting the difficulty in modeling genetically relevant FA cardiomyopathy.

Propensity matched comparison of omaveloxolone treatment to Friedreich ataxia natural history data

Lynch, D.R., Goldsberry, A., Rummey, C., Farmer, J., Boesch, S., Delatycki, M.B., Giunti, P., Hoyle, J.C., Mariotti, C., Mathews, K.D., Nachbauer, W., Perlman, S., Subramony, S.H., Wilmot, G., Zesiewicz, T., Weissfeld, L. and Meyer, C. (2023), Propensity matched comparison of omaveloxolone treatment to Friedreich ataxia natural history data. Ann Clin Transl Neurol. doi:10.1002/acn3.51897 

These results suggest a meaningful slowing of Friedreich ataxia progression with omaveloxolone, and consequently detail how propensity-matched analysis may contribute to understanding of effects of therapeutic agents. This demonstrates the direct value of natural history studies in clinical trial evaluations.

Proprioceptive and tactile processing in individuals with Friedreich Ataxia, an fMRI study

Destrebecq Virginie, Rovai Antonin, Trotta Nicola, Comet Camille, Gilles Naeije, Front. Neurol. Sec. Movement Disorders, Volume 14 - 2023, doi: 10.3389/fneur.2023.1224345

Our study captured the difference between tactile and proprioceptive impairments in FA using somatosensory fMRI paradigms. The lack of correlation between the proprioceptive paradigm and ataxia clinical parameters supports a low contribution of afferent ataxia to FA clinical severity

SIRT3 Regulates Clearance of Apoptotic Cardiomyocytes by Deacetylating Frataxin

Jing Gao, Chenglin Huang, Linghui Kong, Wugang Zhou, Mengwei Sun, Tong Wei and Weili Shen. Circulation Research. 2023;0. Originally published 30 Aug 2023 doi:10.1161/CIRCRESAHA.123.323160  

We showed that SIRT3 deficiency exacerbated Ang II–induced downregulation of the efferocytosis receptor MerTK (c-Mer tyrosine kinase) and proinflammatory cytokine production, accompanied by disrupted mitochondrial iron homeostasis in cardiac macrophages. Quantitative acetylome analysis revealed that SIRT3 deacetylated FXN (frataxin) at lysine 189. Ang II attenuated SIRT3 activity and enhanced the acetylation level of FXN K189. Acetylated FXN further reduced the synthesis of ISCs (iron-sulfur clusters), resulting in mitochondrial iron accumulation. Phagocytic internalization of apoptotic cardiomyocytes increased myoglobin content, and derived iron ions promoted mitochondrial iron overload and lipid peroxidation. An iron chelator deferoxamine improved the levels of MerTK and efferocytosis, thereby attenuating proinflammatory macrophage activation. FXNK189R mice showed improved macrophage efferocytosis, reduced cardiac inflammation, and suppressed cardiac fibrosis.

Replication Stalling at Friedreich's Ataxia (GAA)n Repeats In Vivo

Maria M. Krasilnikova & Sergei M. Mirkin (2004) Replication Stalling at Friedreich's Ataxia (GAA)n Repeats In Vivo, Molecular and Cellular Biology, 24:6, 2286-2295, DOI: 10.1128/MCB.24.6.2286-2295.2004

 We believe that repeat-caused replication attenuation in vivo is due to triplex formation. The apparent link between the replication stalling and length polymorphism of the repeat points to a new model for the repeat expansion.

Longitudinal changes of SARA scale in Friedreich ataxia: Strong influence of baseline score and age at onset

Porcu, L., Fichera, M., Nanetti, L., Rulli, E., Giunti, P., Parkinson, M.H., Durr, A., Ewenczyk, C., Boesch, S., Nachbauer, W., Indelicato, E., Klopstock, T., Stendel, C., Rodríguez de Rivera, F.J., Schöls, L., Fleszar, Z., Giordano, I., Didszun, C., Castaldo, A., Rai, M., Klockgether, T., Pandolfo, M., Schulz, J.B., Reetz, K., Mariotti, C. and (2023), Longitudinal changes of SARA scale in Friedreich ataxia: Strong influence of baseline score and age at onset. Ann Clin Transl Neurol. doi:10.1002/acn3.51886 

 Analyses of statistical properties of SARA suggest a variable sensitivity of the scale at different disease stages, and provide important information for population selection and result interpretation in future clinical trials.

Sarepta Therapeutics to Collaborate With Lexeo on Heart Disease Gene Therapy Pipeline

Aug 28, 2023, NEW YORK – Sarepta Therapeutics has invested an undisclosed sum in Lexeo Therapeutics, and the two companies on Monday said they will explore opportunities to further develop gene therapies in Lexeo's preclinical pipeline for cardiovascular disease.

Halogens engineering-based design of agonists for boosting expression of frataxin protein in Friedreich's ataxia

Naveed, M., Ali, I., Aziz, T., Ain, N., Shabbir, M. A., Javed, K., Alharbi, M., Alshammari, A., Alasmari, A. F., Alharbi, S. A., & Alharbi, M. S. (2023). Halogens engineering-based design of agonists for boosting expression of frataxin protein in Friedreich's ataxia. European review for medical and pharmacological sciences, 27(15), 6972–6984. doi:10.26355/eurrev_202308_33269 

 The selected agonist is one of the most potent compounds in increasing Frataxin protein expression. Furthermore, optimization with halogens can be a productive approach to improve the candidate's drug efficacy. The development of effective medications for the treatment of Friedreich ataxia would be aided by the results of these computational investigations.

The optimized agonist 9-[1-[(1S, 5R)-8, 8-dimethyl-8-azoniabicyclo[3.2.1]octan-3-yl]triazol-4-yl]fluoren-9-ol has higher binding energy of -10.4Kcal/mol with molecular weight of 705.63 g/mol. Drug-like properties are identified through ADMET profiling, having water solubility of about -7.59, skin permeation -7.08 cm/s, bioavailability score 0.17, and high GI absorption. The candidate fulfills the Lipinski rule of five and portrays efficient molecular dynamic stimulations.

Design Therapeutics Reports Initial Results from Phase 1 Multiple-Ascending Dose Study of DT-216 for the Treatment of Friedrich Ataxia

CARLSBAD, Calif., Aug. 14, 2023 (GLOBE NEWSWIRE) -- Design Therapeutics, Inc. (Nasdaq: DSGN), a clinical-stage biotechnology company developing treatments for serious degenerative genetic diseases, today reported initial results from the company’s Phase 1 multiple-ascending dose (MAD) clinical trial of DT-216 in patients with Friedrich ataxia (FA). As of a data cutoff date of August 7, 2023, results showed that DT-216 was generally well-tolerated and achieved a statistically significant and dose-related increase in frataxin (FXN) mRNA levels in skeletal muscle biopsies.

Epidemiological research on rare diseases using large-scale online search queries and reported case data

Zhang, L., Jin, Y., Li, J. et al. Epidemiological research on rare diseases using large-scale online search queries and reported case data. Orphanet J Rare Dis 18, 236 (2023). doi:10.1186/s13023-023-02839-7

 Rare diseases have become a major public health concern worldwide. However, detailed epidemiological data are lacking. With the development of the Internet, search queries have played an important role in disease surveillance. In this study, we explored a new method for the epidemiological research on rare diseases, using large-scale online search queries and reported case data. We distilled search logs related to rare diseases nationwide from 2016 to 2019. The case data were obtained from China’s national database of rare diseases during the same period.

Finding an Appropriate Mouse Model to Study the Impact of a Treatment for Friedreich Ataxia on the Behavioral Phenotype

Bouchard, C.; Gérard, C.; Yanyabé, S.G.-f.; Majeau, N.; Aloui, M.; Buisson, G.; Yameogo, P.; Couture, V.; Tremblay, J.P. Finding an Appropriate Mouse Model to Study the Impact of a Treatment for Friedreich Ataxia on the Behavioral Phenotype. Genes 2023, 14, 1654. doi:10.3390/genes14081654

 The YG8sR mice are Knock-Out (KO) for their murine frataxin gene but contain a human frataxin transgene derived from an FRDA patient with 300 GAA repeats. These mice are used as a FRDA model but even with a low frataxin concentration, their phenotype is mild. We aimed to find an optimized mouse model with a phenotype comparable to the human patients to study the impact of therapy on the phenotype. We compared two mouse models: the YG8sR injected with an AAV. PHP.B coding for a shRNA targeting the human frataxin gene and the YG8-800, a new mouse model with a human transgene containing 800 GAA repeats.

Why Is Design Therapeutics Stock Moving Lower Today?

Aug. 15, 2023, Design Therapeutics planned to reformulate its Friedreich ataxia drug following injection site reactions in a Phase 1 study. The company plans to begin a new multiple-dose Phase 1 study in the second half of 2024, with initial data in the first half of 2025. Based on current methods and procedures, the treatment effect of DT-216 on FXN protein was inconclusive due to high intra-individual variability, consistent with what was seen in the observational study.

Rationale and protocol of a double-blind, randomized, placebo-controlled trial to test the efficacy, safety and tolerability of Dimethyl Fumarate in Friedreich Ataxia (DMF-FA-201)

Chiara Pane1, Alberto M. Marra, Ludovica Aliberti, Mario Campanile, Federica Coscetta, Giulia Crisci, Roberta D'Assante, Angela Marsili, Giorgia Puorro, Andrea Salzano, Antonio Cittadini, Francesco Saccà; Rationale and protocol of a double-blind, randomized, placebo-controlled trial to test the efficacy, safety and tolerability of Dimethyl Fumarate in Friedreich Ataxia (DMF-FA-201). Front. Neurosci. Sec. Neuropharmacology, Volume 17 - 2023 | doi: 10.3389/fnins.2023.1260977 

 Conclusions: this is the first study aimed at exploring the ability of DMF, an already available treatment for MS and psoriasis, to correct the biological deficits of FRDA and potentially improve mitochondrial respiration in-vivo.

Interferon Gamma Enhances Cytoprotective Pathways via Nrf2 and MnSOD Induction in Friedreich’s Ataxia Cells

Luffarelli, R.; Panarello, L.; Quatrana, A.; Tiano, F.; Fortuni, S.; Rufini, A.; Malisan, F.; Testi, R.; Condò, I. Interferon Gamma Enhances Cytoprotective Pathways via Nrf2 and MnSOD Induction in Friedreich’s Ataxia Cells. Int. J. Mol. Sci. 2023, 24, 12687. doi:10.3390/ijms241612687 

The cytokine interferon gamma (IFN-γ) has been shown to increase frataxin expression in FRDA cells and to improve functional deficits in FRDA mice. Currently, IFN-γ represents a potential therapy under clinical evaluation in FRDA patients. Here, we show that IFN-γ induces a rapid expression of Nrf2 and MnSOD in different cell types, including FRDA patient-derived fibroblasts. Our data indicate that IFN-γ signals two separate pathways to enhance Nrf2 and MnSOD levels in FRDA fibroblasts. MnSOD expression increased through an early transcriptional regulation, whereas the levels of Nrf2 are induced by a post-transcriptional mechanism. We demonstrate that the treatment of FRDA fibroblasts with IFN-γ stimulates a non-canonical Nrf2 activation pathway through p21 and potentiates antioxidant responses under exposure to hydrogen peroxide. Moreover, IFN-γ significantly reduced the sensitivity to hydrogen peroxide-induced cell death in FRDA fibroblasts. Collectively, these results indicate the presence of multiple pathways triggered by IFN-γ with therapeutic relevance to FRDA.

Omaveloxolone for the Treatment of Friedreich’s Ataxia

Riley Kessler, Sonal Sharma, David R Lynch, Omaveloxolone for the Treatment of Friedreich’s Ataxia, Published Online: Aug 9th 2023 touchREVIEWS in Neurology. 2023;19(2):Online ahead of journal publication. 

 This review discusses the underlying cellular pathology and proposed mechanism of omaveloxolone in FRDA. The MOXIe study is presented in detail, including a discussion of the challenges faced in clinical trials in FRDA, and rare diseases more broadly. Finally, other therapies under investigation are reviewed briefly.

CRISPR/Cas9 Genome Editing for Tissue-Specific In Vivo Targeting: Nanomaterials and Translational Perspective

Sahel DK, Vora LK, Saraswat A, et al. CRISPR/Cas9 Genome Editing for Tissue-Specific In Vivo Targeting: Nanomaterials and Translational Perspective. Advanced Science (Weinheim, Baden-wurttemberg, Germany). 2023 Jul;10(19):e2207512. DOI: 10.1002/advs.202207512. PMID: 37166046; PMCID: PMC10323670. 

Despite DSBs, they have also been explored through epigenome editing and biosensor applications. However, its in vivo delivery is still a major challenge. Interestingly, ample nonviral nanocarriers have been developed and explored for the in vivo delivery of CRISPR components, but they are limited to some immune-prone organs of the body, such as the liver, lungs, or spleen. 

However, various pharmaceutical companies are showing interest in the CRISPR therapeutics area, and therefore, it will be interesting to watch the progress in this field. Since both ethical and social implications are associated with the usage of CRISPR, we need to move forward very responsibly.

Preparing for Disease-Modification Trials in Degenerative Cerebellar Ataxias: Which Endpoints to Choose?

Maas RPPWM. Preparing for Disease-Modification Trials in Degenerative Cerebellar Ataxias: Which Endpoints to Choose? Movement Disorders : Official Journal of the Movement Disorder Society. 2023 Jun;38(6):917-923. DOI: 10.1002/mds.29388. PMID: 37475615.

Brain MRI detects early-stage alterations and disease progression in Friedreich ataxia

Adanyeguh IM, Joers JM, Deelchand DK, et al. Brain MRI detects early-stage alterations and disease progression in Friedreich ataxia. Brain Communications. 2023 ;5(4):fcad196. DOI: 10.1093/braincomms/fcad196. PMID: 37483529. 

 We show that fixel-based analysis of diffusion MRI data is particularly sensitive to longitudinal change in the cerebellar peduncles, as well as motor and sensory white matter tracts. In combination with other morphometric measures, they may therefore provide sensitive imaging biomarkers of disease progression for clinical trials.

Recent advances in small molecules for improving mitochondrial disorders

Meng L, Wu G. Recent advances in small molecules for improving mitochondrial disorders. RSC Advances. 2023 Jul;13(30):20476-20485. DOI: 10.1039/d3ra03313a. PMID: 37435377; PMCID: PMC10331567. 

 This review focuses on the latest advances in developing bioactive compounds for treating mitochondrial disease, aiming to provide a broader perspective of fundamental studies that have been carried out to evaluate the effects of small molecules in regulating mitochondrial function. Novel-designed small molecules ameliorating mitochondrial functions are urgent for further research.

Patient-reported, health economic and psychosocial outcomes in patients with Friedreich ataxia (PROFA): protocol of an observational study using momentary data assessments via mobile health app

Buchholz M, Weber N, Borel S, et alPatient-reported, health economic and psychosocial outcomes in patients with Friedreich ataxia (PROFA): protocol of an observational study using momentary data assessments via mobile health appBMJ Open 2023;13:e075736. doi: 10.1136/bmjopen-2023-075736 

The symptoms affect the patients’ health-related quality of life (HRQoL) and psychosocial health. FA leads to an increasing need for care, associated with an economic burden. Little is known about the impact of FA on daily lives and HRQoL. To fill that gap, we will assess patient-reported, psychosocial and economic outcomes using momentary data assessment via a mobile health application (app).

The use of digital outcome measures in clinical trials in rare neurological diseases: a systematic literature review

Poleur, M., Markati, T. & Servais, L. The use of digital outcome measures in clinical trials in rare neurological diseases: a systematic literature review. Orphanet J Rare Dis 18, 224 (2023). doi:10.1186/s13023-023-02813-3 

 We found two studies of patients with FRDA that used inertial technology. Remote monitoring of several voice parameters, upper limb function through 14 parameters that can be grouped into parameters related to movement velocity, spectral frequency, and parameters related to deviation of the ideal trajectory, and 15 spatiotemporal gait parameters was feasible over 1 week. The sensitivity of an upper limb composite score, the AIM-S, obtained through sensors contained in a spoon designed to detect deterioration in upper limb function, was greater than other measures.

Biogen to Acquire Reata Pharmaceuticals

CAMBRIDGE, Mass. and PLANO, Texas, July 28, 2023 (GLOBE NEWSWIRE) -- Biogen Inc. (Nasdaq: BIIB) and Reata Pharmaceuticals, Inc. (Nasdaq: RETA) today announced the companies have entered into a definitive agreement under which Biogen has agreed to acquire Reata for $172.50 per share in cash, reflecting an enterprise value of approximately $7.3 billion. 

Reata has made significant advancements developing therapeutics that regulate cellular metabolism and inflammation in serious neurologic diseases. Reata’s FDA-approved SKYCLARYS® (omaveloxolone) is the first and only approved treatment for Friedreich’s ataxia (FA) in the United States, with a commercial launch underway, and European regulatory review ongoing. In addition, Reata is developing a portfolio of innovative products for a range of neurological diseases.

Larimar Therapeutics Receives FDA Clearance to Proceed to 50 mg Cohort in CTI-1601’s Phase 2 Friedreich's Ataxia Trial and to Initiate Open Label Extension Trial

BALA CYNWYD, Pa., July 25, 2023 (GLOBE NEWSWIRE). Larimar Therapeutics, Inc.. Today announced that the U.S. Food and Drug Administration (FDA) has cleared the Company’s four-week, placebo-controlled, Phase 2 dose exploration trial of CTI-1601 in patients with Friedreich's ataxia (FA) to proceed to a 50 mg cohort in which participants will be dosed daily for the first 14 days, and then every other day until day 28. In addition, Larimar’s open label extension (OLE) trial was also cleared for initiation by the FDA. Participants in the OLE will receive 25 mg of CTI-1601 daily. CTI-1601 is a novel protein replacement therapy designed to deliver frataxin to the mitochondria of patients with FA who have low levels of frataxin. 

Larimar received clearance to advance its Phase 2 trial to a 50 mg cohort and initiate its OLE trial following a review by the FDA of Larimar’s complete response to its partial clinical hold that included unblinded safety, pharmacokinetic (PK), and pharmacodynamic (PD) data from the Phase 2 trial’s completed 25 mg cohort. Data from the completed 25 mg cohort (n = 13) indicated that CTI-1601 was generally well tolerated and showed increases in frataxin (FXN) levels from baseline compared to placebo in all evaluated tissues (skin and buccal cells) at day 14 (the final day of daily dosing in the trial). Further dose escalation in the Phase 2 and OLE trials and the initiation of additional U.S. clinical trials evaluating CTI-1601 are contingent on FDA review of results from the Phase 2 trial’s 50 mg cohort in accordance with a partial clinical hold.

“Gaining clearance to advance to a 50 mg cohort in our Phase 2 trial and initiate the OLE trial are crucial steps in CTI-1601’s development as potentially the first therapy to increase frataxin levels in patients with FA,” said Carole Ben-Maimon, MD, President, and Chief Executive Officer of Larimar. “Given the inability of current treatments to address the frataxin deficiency underlying Friedreich's ataxia, we believe CTI-1601 has the potential to improve the treatment paradigm for this devastating disease. We now look forward to data from our Phase 2 trial’s 50 mg cohort in the first half of 2024, which will help us further characterize the safety and PK profiles of CTI-1601 and its ability to increase frataxin levels in a dose-dependent fashion as seen in our earlier Phase 1 studies.”

Leriglitazone

National Center for Biotechnology Information. PubChem Compound Summary for CID 4147757, Hydroxypioglitazone. https://pubchem.ncbi.nlm.nih.gov/compound/Hydroxypioglitazone. Accessed July 23, 2023.

Understanding the Impact of Entrada Therapeutics Inc. on NASDAQ:TRDA

JUL 22, 2023. CORP THESPYWHOBILLEDME. The company’s innovative approach to drug development has been a key factor in its success. Entrada Therapeutics Inc. uses its proprietary Endosomal Escape Vehicle (EEV) technology to develop drugs that can penetrate cells and deliver therapeutic agents directly to the site of disease. Investors have shown a keen interest in Entrada Therapeutics Inc., largely due to the company’s promising drug pipeline. 

The company’s lead candidate, ET-01, is currently in preclinical development for the treatment of Friedreich’s Ataxia, a debilitating genetic disease. The potential of ET-01, along with the company’s other drug candidates, has contributed to the positive performance of NASDAQ:TRDA

Patient Dosing Complete for Part 1 of Gene Therapy Trial in Friedreich Ataxia Cardiomyopathy

Neurologylive; Jul 20, 2023. According to a recent announcement, patient dosing in the first cohort of the SUNRISE-FA study (NCT05445323), a phase 1/2 trial assessing LX2006 (Lexeo Therapeutics), an adeno-associated virus (AAV) gene therapy, in patients with friedreich ataxia (FA) cardiomyopathy, has completed. 

The first patient in the second dose cohort of the trial has commenced as well. Thus far, preliminary data from the first dose cohort indicated that the therapy was well tolerated, with no unexpected events or toxicities.

 "We look forward to continuing to progress this program with data readouts expected in the first half of 2024."

Quantification of human mature frataxin protein expression in nonhuman primate hearts after gene therapy

Ian Blair, Teerapat Rojsajjakul, Juliette Hordeaux et al. Quantification of human mature frataxin protein expression in nonhuman primate hearts after gene therapy, 29 June 2023, PREPRINT (Version 1) available at Research Square doi:10.21203/rs.3.rs-3121549/v1 

Therefore, increasing expression of heart hFXN-M using gene therapy offers a way to prevent early mortality in FRDA. We used rhesus macaque monkeys to test the pharmacology of an adeno-associated virus (AAV)hu68.CB7.hFXN therapy. The advantage of using non-human primates for hFXN-M gene therapy studies is that hFXN-M and monkey FXN-M (mFXN-M) are 98.5% identical, which limits potential immunologic side-effects.

PPAR-gamma agonist pioglitazone recovers mitochondrial quality controls in fibroblasts from PITRM1-deficient patients

DArio Brunetti, A. D., Donfrancesco, C., Berlingieri, C., Frascarelli, M., Giacomello, A. P., Magalhaes Rebelo, L., Bindoff, S., Reeval, P., Filippo, M., Santorelli, G., Massaro, C. F., Viscomi, M., & Zeviani, D. (s/f). PPAR-gamma agonist pioglitazone recovers mitochondrial quality controls in fibroblasts from PITRM1-deficient patients. Front. Pharmacol. Sec. Experimental Pharmacology and Drug Discovery, 14. doi:10.3389/fphar.2023.1220620 

 We found that the pharmacological stimulation of Peroxisome Proliferator-Activated Receptor Gamma (PPARG) by Pioglitazone upregulates IDE and also PITRM1 protein levels restoring the presequence processing machinery and improving Frataxin maturation and mitochondrial function. Our findings provide mechanistic insights and suggest a potential pharmacological strategy for this rare neurodegenerative mitochondrial disease.

Non-B DNA structures as a booster of genome instability

Renée C. Duardo, Federico Guerra, Simona Pepe, Giovanni Capranico, Non-B DNA structures as a booster of genome instability, Biochimie, 2023, ISSN 0300-9084, doi:10.1016/j.biochi.2023.07.002.

Transcription-dependent R-loops can also alter the expression levels of genes involved in various disorders. For example, it has been reported that R-loops cause gene silencing at expanded trinucleotide repeats at FXN and FMR1 genes consequently proving an R-loop role in Friedreich's ataxia and X fragile syndrome. Anyway, transcription-mediated R-loop harmful effects are mostly related to the replication process.

Targeting Ion Channels and Purkinje Neuron Intrinsic Membrane Excitability as a Therapeutic Strategy for Cerebellar Ataxia

Huang H, Shakkottai VG. Targeting Ion Channels and Purkinje Neuron Intrinsic Membrane Excitability as a Therapeutic Strategy for Cerebellar Ataxia. Life (Basel, Switzerland). 2023 Jun;13(6):1350. DOI: 10.3390/life13061350. PMID: 37374132; PMCID: PMC10302946. 

We further propose that treatments aimed at restoring Purkinje neuron intrinsic membrane excitability have the potential to be a shared therapy in cerebellar ataxia akin to levodopa for Parkinson's disease.

Novel Therapeutic Approaches in Inherited Neuropathies: A Systematic Review

Hustinx M, Shorrocks AM, Servais L. Novel Therapeutic Approaches in Inherited Neuropathies: A Systematic Review. Pharmaceutics. 2023 May;15(6):1626. DOI: 10.3390/pharmaceutics15061626. PMID: 37376074; PMCID: PMC10305260.

 Multiple trials have been conducted in subjects with FRDA in recent years, and our search yielded seven publications since 2018, assessing six different drugs. Most trials used the Friedreich Ataxia Rating Scale (FARS) or modified FARS (mFARS), 9-hole peg test (9HPT), and 25 or 8 min walk tests to assess the efficacies of the drugs. However, none of these tests are specific to neuropathy progression.

Direct Cysteine Desulfurase Activity Determination by NMR and the Study of the Functional Role of Key Structural Elements of Human NFS1

Sewell KE, Gola GF, Pignataro MF, et al. Direct Cysteine Desulfurase Activity Determination by NMR and the Study of the Functional Role of Key Structural Elements of Human NFS1. ACS Chemical Biology. 2023 Jul. DOI: 10.1021/acschembio.3c00147. PMID: 37410592.

We identified CTS as a key element that established interactions with ISCU2 and FXN concurrently; we found specific interactions that are established when FXN is present, reinforcing the idea that FXN not only forms part of the iron-sulfur cluster assembly site but also modulates the internal motions of ISCU2.

Alpha-tocopherylquinone differentially modulates claudins to enhance intestinal epithelial tight junction barrier via AhR and Nrf2 pathways

Ashwinkumar Subramenium Ganapathy, Kushal Saha, Alexandra Wang, Priya Arumugam, Viszwapriya Dharmaprakash, Gregory Yochum, Walter Koltun, Meghali Nighot, Gary Perdew, Todd A. Thompson, Thomas Ma, Prashant Nighot, Alpha-tocopherylquinone differentially modulates claudins to enhance intestinal epithelial tight junction barrier via AhR and Nrf2 pathways, Cell Reports, Volume 42, Issue 7,2023, 112705, doi:10.1016/j.celrep.2023.112705. 

 A clinical trial has examined the potential value of TQ in the treatment of Friedreich’s ataxia.

AI-based tools for the diagnosis and treatment of rare neurological disorders

Molnar, M.J., Molnar, V. AI-based tools for the diagnosis and treatment of rare neurological disorders. Nat Rev Neurol (2023). doi:10.1038/s41582-023-00841-y 

 AI-based methods have also been shown to accurately classify individuals with Friedreich ataxia and control individuals on the basis of kinematic biomarkers.

Decreased filamentous actin and tight junction protein expression, and paracellular permeability in Frataxin-deficient human brain microvascular endothelial cells – implications for blood-brain barrier integrity in Friedreich's Ataxia

Smith FM, Kosman DJ. Decreased filamentous actin and tight junction protein expression, and paracellular permeability in Frataxin-deficient human brain microvascular endothelial cells – implications for blood-brain barrier integrity in Friedreich's Ataxia. Research Square; 2023. DOI: 10.21203/rs.3.rs-3025871/v1. 

 We identified that insufficient FXN levels in the hBMVEC BBB model causes changes in cytoskeletal architecture and tight junction protein abundance, co-incident with increased barrier permeability. Changes in the integrity of the BBB may be related to patient brain iron accumulation, neuroinflammation, neurodegeneration, and stroke. Furthermore, our findings implicate other barrier cells, e.g. , the cardiac microvasculature, likely contributory also to disease pathology in FRDA.

Frataxin inhibits the sensitivity of the myocardium to ferroptosis by regulating iron homeostasis

Zhang Z, Jiang W, Zhang C, Yin Y, Mu N, Wang Y, Yu L, Ma H. Frataxin inhibits the sensitivity of the myocardium to ferroptosis by regulating iron homeostasis. Free Radic Biol Med. 2023 Jun 19;205:305-317. doi: 10.1016/j.freeradbiomed.2023.06.016. Epub ahead of print. PMID: 37343689. 

 We showed that regulators of iron metabolism, especially iron regulatory protein activity, were increased in the ischemic myocardium or hypoxia cardiomyocytes. In addition, we found that frataxin, which is involved in iron metabolism, is differentially expressed in the ischemic and reperfused myocardium and involved in the regulation of cardiomyocytes ferroptosis.

Multiway sparse distance weighted discrimination

Guo B, Eberly LE, Henry PG, Lenglet C, Lock EF. Multiway sparse distance weighted discrimination. J Comput Graph Stat. 2023;32(2):730-743. doi: 10.1080/10618600.2022.2099404. Epub 2022 Aug 30. PMID: 37377729; PMCID: PMC10292743. 

 Magnetic resonance spectroscopy (MRS) was used to measure the abundance of several metabolites across multiple neurological regions and across multiple time points in a mouse model of Friedreich’s ataxia, yielding a four-way data array.

Adult-Onset Neuroepidemiology in Finland: Lessons to Learn and Work to Do

Sipilä JOT. Adult-Onset Neuroepidemiology in Finland: Lessons to Learn and Work to Do. Journal of Clinical Medicine. 2023 Jun;12(12):3972. DOI: 10.3390/jcm12123972. PMID: 37373667. 

Some disorders, such as Friedreich's ataxia (FRDA) and Wilson's disease (WD), are almost absent or completely absent in the population. 

Reata Pharmaceuticals Announces Approval of Prior Approval Supplement for SKYCLARYS® (Omaveloxolone) and Commercial Availability of SKYCLARYS for Patients with Friedreich’s Ataxia

June 27, 2023. PLANO, Texas--(BUSINESS WIRE)-- Reata Pharmaceuticals, Inc. (Nasdaq: RETA) (“Reata,” the “Company,” “our,” “us,” or “we”), a global, biopharmaceutical company focused on developing and commercializing novel therapies for patients with severe diseases, announced that the United States Food and Drug Administration (FDA) has approved the Prior Approval Supplement (PAS) to update the drug substance specification for SKYCLARYS® (omaveloxolone), the first and only FDA approved drug for the treatment of Friedreich’s ataxia in adults and adolescents aged 16 years and older. With the approval of the PAS, SKYCLARYS is now available to patients with Friedreich’s ataxia in the United States.

Retinal hypoplasia and degeneration result in vision loss in Friedreich ataxia

Rodden, L.N., McIntyre, K., Keita, M., Wells, M., Park, C., Profeta, V., Waldman, A., Rummey, C., Balcer, L.J. and Lynch, D.R. (2023), Retinal hypoplasia and degeneration result in vision loss in Friedreich ataxia. Ann Clin Transl Neurol. doi:10.1002/acn3.51830 

 These data suggest that both hypoplasia and subsequent degeneration of the RNFL may be responsible for the optic nerve dysfunction in FRDA and support the development of a vision-directed treatment for selected patients early in the disease to prevent RNFL loss from reaching the critical threshold

Anodal Cerebellar Transcranial Direct Current Stimulation Reduces Motor and Cognitive Symptoms in Friedreich's Ataxia: A Randomized, Sham-Controlled Trial

Naeije, G., Rovai, A., Destrebecq, V., Trotta, N. and De Tiège, X. (2023), Anodal Cerebellar Transcranial Direct Current Stimulation Reduces Motor and Cognitive Symptoms in Friedreich's Ataxia: A Randomized, Sham-Controlled Trial. Mov Disord. doi:10.1002/mds.29453 

 One week of treatment with anodal ctDCS reduces motor and cognitive symptoms in individuals with FRDA, likely by restoring the neocortical inhibition normally exerted by cerebellar structures. This study provides class I evidence that ctDCS stimulation is effective and safe in FRDA

LEXEO Therapeutics Announces Completion of First Cohort and Dosing in Second Cohort in SUNRISE-FA, a Phase 1/2 Clinical Trial of LX2006 for the Treatment of Friedreich’s Ataxia Cardiomyopathy

NEW YORK, June 13, 2023 (GLOBE NEWSWIRE) -- LEXEO Therapeutics (LEXEO), a clinical-stage gene therapy company advancing adeno-associated virus (AAV)-based gene therapy candidates for genetically defined cardiovascular diseases and a genetically defined sub-group of Alzheimer’s disease, announced today the completion of the first dose cohort and the dosing of the first patient in the second dose cohort in SUNRISE-FA, a Phase 1/2 clinical trial of LX2006 in patients with Friedreich’s ataxia (FA) cardiomyopathy. In the first dose cohort, LX2006 has been well tolerated with no unexpected events or toxicities observed. Following the Data Safety Monitoring Board recommendation to proceed, investigators have initiated dosing in the second cohort.

A Retrospective Claims Analysis Characterizing Health Care Resource Use Among Patients with Friedreich Ataxia in the United States,

C. Qian, D. Lynch, L. Powell, A. Salvucci, G. Vasco, K.M Johnston, I. Tomazos, A Retrospective Claims Analysis Characterizing Health Care Resource Use Among Patients with Friedreich Ataxia in the United States, Value in Health, Volume 26, Issue 6, Supplement, 2023, Page S385, doi:10.1016/j.jval.2023.03.2157.

Patients with FA have significantly higher rates of HCRU, when compared to non-FA. This study demonstrates the multidisciplinary care required for this complex disease. Currently there are no disease modifying treatments for FA – these findings can help better estimate the impact of new interventions on the healthcare system.

The Clinical Burden of Friedreich Ataxia: A Retrospective Claims Analysis in the United States

L. Powell, D. Lynch, C. Qian, A. Salvucci, G. Vasco, K.M Johnston, I. Tomazos, The Clinical Burden of Friedreich Ataxia: A Retrospective Claims Analysis in the United States, Value in Health, Volume 26, Issue 6, Supplement, 2023, Page S379, doi:10.1016/j.jval.2023.03.2128. 

 Patients with FA in comparison to non-FA, experience significant clinical manifestations and comorbidities. This study provides real-world estimates of this disease burden, for commercially insured patients with FA in the US, underlying the unmet medical need in this population.

Adult-Onset Neuroepidemiology in Finland: Lessons to Learn and Work to Do

Sipilä, J.O.T. Adult-Onset Neuroepidemiology in Finland: Lessons to Learn and Work to Do. J. Clin. Med. 2023, 12, 3972. doi:10.3390/jcm12123972 

 Jokela type (SMAJ) and adult-onset dystonia. On the other hand, some disorders, such as Friedreich’s ataxia (FRDA) and Wilson’s disease (WD), are almost absent or completely absent in the population.

Jackson Laboratory receives $22.8 million grant for gene-editing based work

Published: Jun. 10, 2023​. BAR HARBOR, Maine (WABI) - Researchers aiming to develop and validate new gene-editing based therapeutic approaches have gotten a substantial financial investment.

The work being done revolves around four different neurological conditions including Spinal Muscular Atrophy, Friedreich’s Ataxia, Huntington’s Disease and Rett Syndrome.

Pharmacists are initiators in palliative care for patients with rare diseases

Dooms, M. Pharmacists are initiators in palliative care for patients with rare diseases. Orphanet J Rare Dis 18, 141 (2023). doi:10.1186/s13023-023-02765-8 

 A community pharmacist can play a key role in advocating timely access to palliative care. Medication reconciliation must alert them to start communicating with the patient and/or his relatives about refocusing treatment and care as part of palliative and terminal care. Pharmaceutical activities for these patients include dispensing of devices and medicinal products, compounding personalized medication and participating as a member of the Palliative Support Team. Most of the several thousands of rare diseases are caused by genetic defects and up to now have no cure and a late diagnosis.

Targeting Ion Channels and Purkinje Neuron Intrinsic Membrane Excitability as a Therapeutic Strategy for Cerebellar Ataxia

Huang H, Shakkottai VG. Targeting Ion Channels and Purkinje Neuron Intrinsic Membrane Excitability as a Therapeutic Strategy for Cerebellar Ataxia. Life. 2023; 13(6):1350. doi:10.3390/life13061350 

 In degenerative neurological disorders such as Parkinson’s disease, a convergence of widely varying insults results in a loss of dopaminergic neurons and, thus, the motor symptoms of the disease. Dopamine replacement therapy with agents such as levodopa is a mainstay of therapy. Cerebellar ataxias, a heterogeneous group of currently untreatable conditions, have not been identified to have a shared physiology that is a target of therapy. In this review, we propose that perturbations in cerebellar Purkinje neuron intrinsic membrane excitability, a result of ion channel dysregulation, is a common pathophysiologic mechanism that drives motor impairment and vulnerability to degeneration in cerebellar ataxias of widely differing genetic etiologies. We further propose that treatments aimed at restoring Purkinje neuron intrinsic membrane excitability have the potential to be a shared therapy in cerebellar ataxia akin to levodopa for Parkinson’s disease.

Randomized controlled trial data for successful new drug application for rare diseases in the United States

Kubota, Y., Narukawa, M. Randomized controlled trial data for successful new drug application for rare diseases in the United States. Orphanet J Rare Dis 18, 89 (2023). doi:10.1186/s13023-023-02702-9 

 This study focused on 233 drugs with orphan drug designations approved in the US between April 2001 and March 2021. Univariable and multivariable logistic regression analyses were conducted to investigate the association between the presence or absence of RCTs in the clinical data package for new drug applications.

Ataxia de Friedreich, revisión y actualización de la literatura con búsqueda sistemática de casos en Latinoamérica

Alfaro-Olivera M, Calle-Nuñez A, Uribe-León A, Aguirre-Quispe W, Sarapura-Castro E, Cornejo-Olivas M. Ataxia de Friedreich, revisión y actualización de la literatura con búsqueda sistemática de casos en Latinoamérica. Revista de Neuro-Psiquiatría [Internet]. 27abr.2023 [citado 7jun.2023];86(1):45-1. Available from: https://revistas.upch.edu.pe/index.php/RNP/article/view/4466 

 La prevalencia de AF en poblaciones caucásicas es estimada entre 2 y 5 casos por 100 000 habitantes. En Latinoamérica se han publicado 35 estudios que reúnen 1481 casos en 6 países.

XC-103 by Ixchel Pharma for Friedreich Ataxia: Likelihood of Approval

June 5, 2023. XC-103 is under clinical development by Ixchel Pharma and currently in Phase I for Friedreich Ataxia. According to GlobalData, Phase I drugs for Friedreich Ataxia does not have sufficient historical data to build an indication benchmark PTSR for Phase I. GlobalData uses proprietary data and analytics to create drugs-specific PTSR and LoA in the IXC-103 LoA Report.

Amplifying gene expression with RNA-targeted therapeutics

Khorkova O, Stahl J, Joji A, Volmar CH, Wahlestedt C. Amplifying gene expression with RNA-targeted therapeutics. Nature reviews. Drug Discovery. 2023 May. DOI: 10.1038/s41573-023-00704-7. PMID: 37253858; PMCID: PMC10227815. 

This Review highlights emerging RNA-targeted therapeutics for gene activation, focusing on opportunities and challenges for translation to the clinic.

Anaesthetic management of thyroid storm in a patient with Friederich’s ataxia. A case report

M. Sneyers Closa, A. Pérez Requena, S. Sánchez García, J. Sistac Ballarín, Anaesthetic management of thyroid storm in a patient with Friederich’s ataxia. A case report, Revista Española de Anestesiología y Reanimación (English Edition), 2023, doi:10.1016/j.redare.2023.06.002.

 A 26-year-old patient with Friederich's ataxia with hypertrophic obstructive cardiomyopathy undergoing total thyroidectomy due to persistent amiodarone-induced thyrotoxicosis (despite high doses of antithyroid drugs and corticosteroids), presented an intraoperative episode suggestive of thyroid storm. Thyroid storm is an endocrine emergency that is associated with high morbidity and mortality. Early diagnosis and treatment, which is of vital importance to improve survival, includes symptomatic treatment, treatment of cardiovascular, neurological, and/or hepatic manifestations and thyrotoxicosis, measures to suppress or avoid triggering stimuli, and definitive treatment. 

 Paciente de 26 años afecto de ataxia de Friederich con una miocardiopatía hipertrófica obstructiva sometido a una tiroidectomía total por tirotoxicosis secundaria a amiodarona persistente (a pesar de elevadas dosis de antitiroideos y corticoides) que intraoperatoriamente presentó un episodio sugestivo de tormenta tiroidea. La tormenta tiroidea es una emergencia endocrinológica que asocia una elevada morbimortalidad. Para mejorar la supervivencia es de vital importancia un diagnóstico y tratamiento precoz que incluya: un tratamiento sintomático; el tratamiento de las manifestaciones cardiovasculares, neurológicas y/o hepáticas y de la tirotoxicosis; y así como suprimir o evitar estímulos desencadenantes y practicar un tratamiento definitivo.

Continuous, but not intermittent, regimens of hypoxia prevent and reverse ataxia in a murine model of Friedreich’s ataxia

Tslil Ast, Hong Wang, Eizo Marutani, Fumiaki Nagashima, Rajeev Malhotra, Fumito Ichinose, Vamsi K Mootha, Continuous, but not intermittent, regimens of hypoxia prevent and reverse ataxia in a murine model of Friedreich’s ataxia, Human Molecular Genetics, 2023;, ddad091, doi:10.1093/hmg/ddad091 

 The detrimental effect of this regimen is likely due to transient tissue hyperoxia that results when daily exposure to 21% O2 combines with chronic polycythemia, as we could blunt this toxicity by pharmacologically inhibiting polycythemia. Second, we report that more mild regimens of chronic hypoxia (17% O2) confer a modest benefit by delaying the onset of ataxia. Third, excitingly, we show that initiating chronic, continuous 11% O2 breathing once advanced neurological disease has already started can rapidly reverse ataxia. Our studies showcase both the promise and limitations of candidate hypoxia-inspired regimens for FA and underscore the need for additional pre-clinical optimization before future translation into humans.

SEXUAL DIMORPHISM AND CARDIAC ARRHYTHMIAS IN A MOUSE MODEL OF FRIEDREICH'S ATAXIA: WHAT DO WE KNOW?

Francisco Figueroa, Lili Salinas, Claire Montgomery, Phung N. Thai, Nipavan Chiamvimonvat, Gino Cortopassi, Elena Dedkova, PO-01-126 SEXUAL DIMORPHISM AND CARDIAC ARRHYTHMIAS IN A MOUSE MODEL OF FRIEDREICH'S ATAXIA: WHAT DO WE KNOW?, Heart Rhythm, Volume 20, Issue 5, Supplement, 2023, Page S141, doi.:10.1016/j.hrthm.2023.03.489. 

Our study revealed sexual dimorphism and significant impairment in electrical and contractile function in FXN cKO males compared to females. A detailed characterization of impaired electrical signals in FA hearts will build a platform for drug testing to treat lethal cardiomyopathy in FA.

THE CALCIUM HANDLING MACHINERY IS REMODELED IN FRIEDREICH’S ATAXIA

Bojjibabu Chidipi, Roman Czornobil, Elizabeth Remily-Wood, David R. Lynch, Sami F. Noujaim, PO-01-124 THE CALCIUM HANDLING MACHINERY IS REMODELED IN FRIEDREICH’S ATAXIA, Heart Rhythm, Volume 20, Issue 5, Supplement, 2023, Page S140, doi:10.1016/j.hrthm.2023.03.487. 

The development of left ventricular contractile dysfunction in FA is associated with reduced expression of calcium handling proteins, abnormal calcium cycling, and mitochondrial dysfunction.

Recent Advances on Therapeutic Approaches for Friedreich’s Ataxia: New Pharmacological Targets, Protein, and Gene Therapy

Chellapandi, D.M., Mosbach, V., Paschaki, M., Puccio, H. (2023). Recent Advances on Therapeutic Approaches for Friedreich’s Ataxia: New Pharmacological Targets, Protein, and Gene Therapy. In: Soong, Bw., Manto, M., Brice, A., Pulst, S.M. (eds) Trials for Cerebellar Ataxias. Contemporary Clinical Neuroscience. Springer, Cham. doi:10.1007/978-3-031-24345-5_23 

 In this chapter, we discuss recent therapeutic approaches, including a proof-of-concept study for gene therapy, drug development targeting the affected downstream pathways, paving the way for the first disease-modifying therapeutic approaches.

Therapeutic Use of Interferon Gamma in Friedreich Ataxia

Martinuzzi, A., Paparella, G., Vavla, M., D’Angelo, M.G., Arrigoni, F., Testi, R. (2023). Therapeutic Use of Interferon Gamma in Friedreich Ataxia. In: Soong, Bw., Manto, M., Brice, A., Pulst, S.M. (eds) Trials for Cerebellar Ataxias. Contemporary Clinical Neuroscience. Springer, Cham. doi:10.1007/978-3-031-24345-5_24 

In patients with FRDA, IFN-γ upregulated frataxin levels in cells from FRDA patients and increased frataxin expression in dorsal root ganglia neurons. In this chapter we review the basic science behind the proposal of IFN-γ as a potential treatment for FRDA and summarize the clinical studies related to the use of IFN-γ in FRDA, outlining critical lessons that have been learned in terms of drug efficacy and tolerability.

Apparent Opportunities and Hidden Pitfalls: The Conflicting Results of Restoring NRF2-Regulated Redox Metabolism in Friedreich’s Ataxia Pre-Clinical Models and Clinical Trials

Tiberi J, Segatto M, Fiorenza MT, La Rosa P. Apparent Opportunities and Hidden Pitfalls: The Conflicting Results of Restoring NRF2-Regulated Redox Metabolism in Friedreich's Ataxia Pre-Clinical Models and Clinical Trials. Biomedicines. 2023 Apr;11(5):1293. DOI: 10.3390/biomedicines11051293. PMID: 37238963.

 The issues discussed here indicate that there are still many dark spots that require elucidation in order for FRDA patients to benefit from effective antioxidant therapy. However, although the relationship between the lack of FXN in FRDA and the benefits of NRF2–ARE axis activation have not yet been fully elucidated, it is important to highlight the significant correlation found between FXN expression and NRF2 activity, which is associated with the presence of three highly conserved ARE sequences on the FXN gene promoter, which are crucial for the binding of the NRF2–sMaf complex to promote the transcription of detoxification and antioxidant genes [105,106]. In light of this, by addressing the limitations that currently separate pre-clinical models from patient trials and improving early diagnostic systems, it is auspicial that new treatments or molecules, especially in conjunction with other therapeutic approaches (i.e., lentivirus-mediated FXN gene delivery [228] or human embryonic stem cell (hESC) therapy [229]), may pave the way for effective treatments of this pathology.

A Milestone in the Treatment of Ataxias: Approval of Omaveloxolone for Friedreich Ataxia

Subramony SH, Lynch DL. A Milestone in the Treatment of Ataxias: Approval of Omaveloxolone for Friedreich Ataxia. Cerebellum (London, England). 2023 May. DOI: 10.1007/s12311-023-01568-8. PMID: 37219716. 

The exciting news about the US FDA approval of omaveloxolone as the first-ever drug to be approved for an inherited ataxia is welcome news for patients and families that deal with this devastating disease as well as for health care providers and investigators with an interest in this and other rare diseases. This event is the culmination of long and fruitful collaboration between patients, their families, clinicians, laboratory researchers, patient advocacy organizations, industry, and regulatory agencies. The process has generated intense discussion about outcome measures, biomarkers, trial design, and the nature of approval process for such diseases. It also has brought hope and enthusiasm for increasingly better therapies for genetic diseases in general.

Characterisation of the Cognitive Profile of Patients Suffering From Friedreich's Ataxia (CPCAF)

ClinicalTrials.gov Identifier: NCT05874388. First Posted: May 24, 2023. Sponsors and Collaborators: Institut National de la Santé Et de la Recherche Médicale, France

The role of behavioural and cognitive assessment in the clinical trial The effectiveness of a treatment is ultimately determined by the elimination of the physiological cause of the disease and the alleviation of the symptoms that patients suffer. However, new treatments rarely eliminate all causes and symptoms of the disease. As long as the effectiveness of a treatment is unknown, it is subtle changes in parameters that decide whether the approach taken is worth pursuing. For a clinical trial which is supposed to evaluate the effectiveness of a treatment for Friedreich's Ataxia, it is therefore necessary to evaluate subtle changes in the functioning of the motor and cognitive system induced by the treatment. For this reason, the project is assembling a battery of tests that quantify the most important aspects of motor, cognitive and speech function in patients with FA. These tests are designed with the specific needs of FA patients in mind, i.e. on the one hand, the tests assess functions that are particularly important in view of the symptoms of Friedreich's disease indicated in the scientific literature, and on the other hand, the psychometric characteristics of the tests are adapted to the general abilities of FA patients. In this respect, it is important to point out that the expansion of the GAA repetition in people with Friedreich's disease varies from 150 to 1,000 triples (compared to 7 to 25 in the rest of the population), and that this large variation in the genotype of FA patients could potentially influence the cognitive profile of the participants. Previous studies have suggested the relationship between the number of repeats of the GAA triplet of the FXN gene and performance in cognitive assessment tests. Specifically, while in FA patients both alleles of the FXN gene contain an unusually high number of GAA repeats, performance in cognitive tests would correlate with the number of GAA repeats in the allele that contains fewer such repeats. Using this test battery, we are therefore able to achieve our main objective, i.e. to characterise the cognitive profile of FA patients as a function of the number of GAA triplet repeats of the FXN gene. Specifically, the test battery will establish whether motor, executive and speech symptoms affect patients differently according to their particular genetic characteristics.

PTC Therapeutics Discontinues Some Programs In Gene Therapy

May 23, 2023. (RTTNews) - PTC Therapeutics Inc. (PTCT) said that it has discontinued pre-clinical and early research programs in gene therapy as part of a strategic portfolio prioritization. The discontinued gene therapy programs include preclinical stage programs in Friedreich ataxia and Angelman syndrome as well as several other programs targeting rare CNS and ophthalmological disorders of high unmet medical need at various stages of preclinical development. 

 In a separate press release, PTC Therapeutics said that phase 3 trial of vatiquinone in patients with Friedreich ataxia did not meet its primary endpoint of statistically significant change in mFARS score at 72 weeks in the primary analysis population.

 However, vatiquinone treatment did demonstrate significant benefit on key disease subscales and secondary endpoints. In addition, in the population of subjects that completed the study protocol, significance was reached in the mFARS endpoint and several secondary endpoints.

PTC Therapeutics Announces Topline Results from Vatiquinone MOVE-FA Registration-Directed Trial Twitter Facebook LinkedIn GooglePlus Pinterest

SOUTH PLAINFIELD, N.J. , May 23, 2023 /PRNewswire/ -- PTC Therapeutics, Inc. (NASDAQ: PTCT) today reported topline results from the MOVE-FA trial of vatiquinone in patients with Friedreich ataxia. The study did not meet its primary endpoint of statistically significant change in mFARS score at 72 weeks in the primary analysis population. However, vatiquinone treatment did demonstrate significant benefit on key disease subscales and secondary endpoints. In addition, in the population of subjects that completed the study protocol, significance was reached in the mFARS endpoint and several secondary endpoints.

Large-scale expansions of Friedreich's ataxia GAA•TTC repeats in an experimental human system: role of DNA replication and prevention by LNA-DNA oligonucleotides and PNA oligomers

Anastasia Rastokina, Jorge Cebrián, Negin Mozafari, Nicholas H Mandel, C I Edvard Smith, Massimo Lopes, Rula Zain, Sergei M Mirkin, Large-scale expansions of Friedreich's ataxia GAA•TTC repeats in an experimental human system: role of DNA replication and prevention by LNA-DNA oligonucleotides and PNA oligomers, Nucleic Acids Research, 2023;, gkad441, doi:10.1093/nar/gkad441 

 In summary, we developed a first of a kind, genetically tractable experimental system to study large-scale expansions of FRDA GAA•TTC repeats in cultured human cells. Our candidate gene analysis implicates fork reversal and restoration in the process. We believe that this system could be a valuable tool for elucidating the mechanisms of large-scale expansions in humans and for evaluating the efficiency of perspective FRDA drugs targeting the instability of GAA•TTC repeats. Finally, we have showed that LNA-modified oligonucleotides and PNA oligomers targeting the GAA•TTC repeats prevent their expansion holding a promise to be developed as future therapeutics for the treatment of FRDA.

The Loss of Frataxin Impairs Microglia Homeostatic Functions in Friedreich’s Ataxia

Ferrara G. Abstracts of the Fifth Brainstorming Research Assembly for Young Neuroscientists (BraYn), Italy, 28-30 September 2022. Neurology International. 2023 Mar;15(1):415-496. DOI: 10.3390/neurolint15010028. PMID: 36976671; PMCID: PMC10056600. 

Martina Milani, Ilaria Della Valle, Riccardo Turchi, Flavia Tortolici, Daniele Lettieri Barbato, Katia Aquilano, Savina Apolloni and Nadia D’Ambrosi. These data suggest that microglia targeting could play a valuable role in ameliorating neuronal circuits in FRDA-affected CNS regions, consistent with other neurodegenerative conditions, where the modulation of microglia represents one of the most promising therapeutic strategies.

Neuropsychiatric symptoms in spinocerebellar ataxias and Friedreich ataxia

Karamazovova S, Matuskova V, Ismail Z, Vyhnalek M. Neuropsychiatric symptoms in spinocerebellar ataxias and Friedreich ataxia. Neuroscience and Biobehavioral Reviews. 2023 May;150:105205. DOI: 10.1016/j.neubiorev.2023.105205. PMID: 37137435. 

 Apart from its role in motor coordination, the importance of the cerebellum in cognitive and affective processes has been recognized in the past few decades. Spinocerebellar ataxias (SCA) and Friedreich ataxia (FRDA) are rare neurodegenerative diseases of the cerebellum presenting mainly with a progressive loss of gait and limb coordination, dysarthria, and other motor disturbances, but also a range of cognitive and neuropsychiatric symptoms.