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.

Patient-Derived iPSC-Neurons and Microglia for Modeling Friedreich’s Ataxia Disease

1694 Patient-Derived iPSC-Neurons and Microglia for Modeling Friedreich’s Ataxia Disease; Priyanka Mishra, Anusha Sivakumar, Avalon Johnson, Emily Hansen, Jacqueline Nguyen, Nicole Coufal, Stephanie Cherqui. May 01, 2023 Volume 31 Issue 4 Supplement 1 S1-794 26th Annual Meeting of the American Society of Gene & Cell Therapy.

Utilising these two models, to understand the role of microglia in the neurodegeneration in FRDA, and its rescue by the gene corrected microglia.

Safety of Ascending Doses of AAVrh.10hFXN to Treat the Cardiac Manifestations of Friedreich’s Ataxia

1656 Safety of Ascending Doses of AAVrh.10hFXN to Treat the Cardiac Manifestations of Friedreich’s Ataxia; Jonathan B. Rosenberg, Alessandria Greco, Carlos Munoz Zuluaga, Monica La Russa Gertz, Melissa Yost-Bido, Nicholas C. Gorman, Alvin Chen, Vikrum Kooner, Bishnu P. De, Stephen M. Kaminsky, Rodolfo J. Ricart Arbona, Heather R. Martin, Sebastien Monette, Richie Khanna, Ronald G. Crystal, Dolan Sondhi. 

 On average, the increase in cardiac FXN expression after AAVrh.10hFXN administration with 5.7x1011 and 1.8x1012 gc/kg doses was 6.5 and 37%, respectively, over the PBS-treated controls. Together, these data identify the safe doses of AAVrh.10hFXN relevant for the treatment of the cardiac manifestations of FA.

Novel AAV Capsid Identification and Characterization for Neuromuscular and Cardiac Indications

1549 Novel AAV Capsid Identification and Characterization for Neuromuscular and Cardiac Indications; Jennifer C. G. Green, Jessica F. Boehler, Meghan S. Soustek, Jamie L. Marshall, Tiffany Willacy, Prushti Bhavsar, Kristy J. Brown, Sharon McGonigle, Carl Morris (Solid Biosciences). May 01, 2023 Volume 31Issue 4Supplement 1S1-794 26th Annual Meeting of the American Society of Gene & Cell Therapy.

 Adeno-associated virus (AAV) mediated gene therapy continues to be a promising therapeutic path for various diseases, including monogenic neuromuscular and cardiac indications such as Duchenne muscular dystrophy (DMD) and Friedreich’s ataxia (FA). However, the high systemic doses currently required to achieve widespread therapeutic benefit can pose potential safety risks. These risks could be decreased or eliminated if therapeuticbenefit could be achieved using lower doses through a more targeted and efficacious vector.

Comparison of Cardiac Specific Promoters to Liver-Specific miRNA Targets to Maximize Cardiac vs Liver Expression Following Intravenous AAVrh.10-Mediated Cardiac Gene Therapy

1518 Comparison of Cardiac Specific Promoters to Liver-Specific miRNA Targets to Maximize Cardiac vs Liver Expression Following Intravenous AAVrh.10-Mediated Cardiac Gene Therapy; Abhishek Bose, Neil R. Hackett, Nadir Khan-Yusufzai, Katie M. Stiles, Ronald G. Crystal. May 01, 2023 Volume 31Issue 4Supplement 1S1-794 26th Annual Meeting of the American Society of Gene & Cell Therapy. 

 Intravenous (IV) administration of a cardiotropic AAV vector is the simplest and most effective strategy to deliver a gene to the myocardium for the treatment of hereditary cardiac disease. The challenge in using the IV route is that a substantial proportion of AAV vectors distribute to the liver, resulting in high liver expression with risks of liver toxicity.

CRISPR/Cas9 Edited Hematopoietic Stem and Progenitor Cells for Friedreich’s Ataxia

1354 CRISPR/Cas9 Edited Hematopoietic Stem and Progenitor Cells for Friedreich’s Ataxia; Anusha Sivakumar, Rafael Andres Badell-Grau, Rita Wan, Veenita Khare, Stephanie Cherqui. May 01, 2023 Volume 31Issue 4Supplement 1S1-794 26th Annual Meeting of the American Society of Gene & Cell Therapy.

Preliminary data suggest decreased pathological cardiac hypertrophy, improved mitochondrial biogenesis, reduced inflammation, and oxidativedamage in mice receiving gene-edited cells compared to mock. Altogether, the preliminary data from the in vivo studies demonstrate that single infusion of FXN gene corrected HSPCs engraft in the bone marrow niche to become a reservoir of healthy cells that can integrate into the injured organs for local and systemic delivery of frataxin protein.

Reversal of Cardiac Phenotype in a Mouse Model of Friedreich’s Ataxia Following Administration of AAV Gene Therapy

1184 Reversal of Cardiac Phenotype in a Mouse Model of Friedreich’s Ataxia Following Administration of AAV Gene Therapy; Joshua C. Chang, Whitney Blankenberger, Su Liu, Marie Stark, Jacqueline A. Brassard, Tianbi Zhang, Fria Bolan, Samuel D. Sutton, Mario Guerrero, José A. Corleto, Nakyo Heo, Dwaipayan Sen, Mark A. Champe, Fabrizia Urbinati, Bala Medicherla, Carlos Fonck (Astellas Gene Therapies); May 01, 2023 Volume 31Issue 4Supplement 1S1-794 26th Annual Meeting of the American Society of Gene & Cell Therapy 

The livers of KO mice treated with AAV-PGK-hFXN displayed Kupffer cell hypertrophy and minimal hepatocyte necrosis. These liver changes are commonly associated with AAV gene therapies, are likely related to gene expression, and are considered non-adverse given the low incidence of observations. Overall, dose-dependent efficacy was observed in AAV-PGK-hFXN-treated KO mice compared with vehicle-treated mice based on survival, cardiac function, cardiac injury biomarkers, and histology. These data support the use AAV-based gene transfer as a promising approach to treat patients with FA cardiomyopathy.

Dose-Dependent Cardiac Responses to Intravenous AAVrh.10hFXN Treatment of the MCK Murine Model of Friedreich’s Ataxia

363 Dose-Dependent Cardiac Responses to Intravenous AAVrh.10hFXN Treatment of the MCK Murine Model of Friedreich’s Ataxia; Dolan Sondhi, Alessandria Greco, Nicholas C. Gorman, Bishnu P. De, Isabelle Wilson, Melissa Yost-Bido, Rachel Spokony, Neil R. Hackett, Stephen M. Kaminsky, Richie Khanna, Ronald G. Crystal;(LEXEO Therapeutics, Inc). May 01, 2023 Volume 31Issue 4Supplement 1S1-794 26th Annual Meeting of the American Society of Gene & Cell Therapy 

 At the 33X dose, there was a decrease in ejection fraction, consistent with cardiac toxicity. In summary, there is a substantial survival and cardiac benefit in AAV-mediated expression of frataxin above the normal physiological level achieved at the 10X reference dose in the MCK mouse model of Friedrich’s ataxia, but toxicity at high doses. This provides a rationale for ascending the dose in human clinical studies, but with caution regarding toxicity.

Efficacy and Safety of a Novel FXN Gene Therapy (AVB-202) for the Treatment of Friedreich’s Ataxia

169 Efficacy and Safety of a Novel FXN Gene Therapy (AVB-202) for the Treatment of Friedreich’s Ataxia; Grace K. Pavlath, Jennifer Wheeler, Arden Bond, Jennifer L. Marlowe.(Solid Biosciences); May 01, 2023 Volume 31Issue 4Supplement 1S1-794 26th Annual Meeting of the American Society of Gene & Cell Therapy 

 AVB-202, a novel AAV9 gene therapy product expressing FXN under the control of a CBA promoter, is intended to restore functional levels of frataxin across disease-relevant tissues using a dual route of administration (intravenous and intrathecal) with the goal of preventing progression or reversing cardiac and CNS manifestations of FA.

Larimar Therapeutics Reports Preliminary Top-line Data from Phase 2 Trial’s 25 mg Cohort Showing Increases in Frataxin Levels in Patients with Friedreich’s Ataxia

BALA CYNWYD, Pa., May 15, 2023 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (“Larimar”) (Nasdaq: LRMR), a clinical-stage biotechnology company focused on developing treatments for complex rare diseases, today announced preliminary top-line data from the 25 mg cohort of its Phase 2, four-week, placebo-controlled, dose exploration trial of CTI-1601 in participants with Friedreich’s ataxia (FA). Participants in the trial’s 25 mg cohort (n=13) were randomized to receive subcutaneous injections of 25 mg CTI-1601 (n=9) or placebo (n=4) daily for 14 days and then every-other-day thereafter until day 28. Data from the cohort indicate 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.

New Drug Evaluation: Omaveloxolone Oral Capsules

Drug Use Research & Management Program. Oregon State University. Date of Review: June 2023. Brand Name (Manufacturer): Skyclarys™ (Reata Pharmaceuticals, Inc.). 

Recommendation: Maintain omaveloxolone as non-preferred on the Practitioner-Managed Prescription Drug Plan (PMPDP) with clinical prior authorization (PA) criteria to ensure medically appropriate use.

Frataxin deficiency disrupts mitochondrial respiration and pulmonary endothelial cell function

Culley MK, Rao RJ, Mehta M, Zhao J, El Khoury W, Harvey LD, Perk D, Tai YY, Tang Y, Shiva S, Rabinovitch M, Gu M, Bertero T, Chan SY. Frataxin deficiency disrupts mitochondrial respiration and pulmonary endothelial cell function. Vascul Pharmacol. 2023 May 8:107181. doi: 10.1016/j.vph.2023.107181. Epub ahead of print. PMID: 37164245. 

These data were observed in primary pulmonary endothelial cells after pharmacologic inhibition of FXN, mice carrying a genetic endothelial deletion of FXN, and inducible pluripotent stem cell-derived endothelial cells from patients with FXN mutations. Altogether, this study indicates FXN is an upstream driver of pathologic aberrations in metabolism and genomic stability. Moreover, our study highlights FXN-specific vasoconstriction in vivo, prompting future studies to investigate available and novel PH therapies in contexts of FXN deficiency.

AIDE À LA PRISE EN CHARGE DU PATIENT ATTEINT D'UNE MALADIE RARE : l'ataxie de Friedreich

Iris Marolleau. Kinésithér Scient 2023,0653:15-20 - 10/05/2023

L'ataxie de Friedreich est une maladie rare du système nerveux central. C'est une maladie génétique évolutive qui touche le sujet jeune. La rééducation fonctionnelle est primordiale pour améliorer la qualité de vie et l'autonomie de ces patients. Peu d'études et de recommandations existent pour aider les kinésithérapeutes à adopter les bonnes pratiques dans la prise en charge de ces patients. Des fiches d'aide d'évaluation et de rééducation ont été réalisées pour guider le thérapeute.

Identification of Safe and Effective Intravenous Dose of AAVrh.10hFXN to Treat the Cardiac Manifestations of Friedreich's Ataxia

Dr. Carlos Munoz-Zuluaga, Dr. Monica Gertz, Ms. Melissa Yost-Bido, Ms. Alessandria Greco, Mr. Nicholas Gorman, Mr. Alvin Chen, Mr. Vikrum Kooner, Dr. Jonathan B Rosenberg, Dr. Bishnu P De, Dr. Stephen M. Kaminsky, Dr. Alain Bborczuk, Dr. Rodolfo Ricart Arbona, Dr. Heather R Martin, Dr. Sebastien Monette, Dr. Richie Khanna, Dr. Jay A Barth, Dr. Ronald G Crystal, and Dr. Dolan Sondhi. Identification of Safe and Effective Intravenous Dose of AAVrh.10hFXN to Treat the Cardiac Manifestations of Friedreich's Ataxia. Human Gene Therapy. ahead of print doi:10.1089/hum.2023.020 Online Ahead of Editing: May 11, 2023

 These data identify both minimally and significantly effective therapeutic doses that are clinically relevant for the treatment of the cardiac manifestations of FA.

Design Therapeutics Provides Pipeline Updates and Reports First Quarter 2023 Financial Results

CARLSBAD, Calif., May 09, 2023 (GLOBE NEWSWIRE) -- Design Therapeutics, Inc. 

Initial Data from Ongoing Phase 1 MAD Trial of DT-216 for FA Expected in the Third Quarter of 2023: Design is evaluating its lead GeneTAC™ small molecule, DT-216, in an ongoing Phase 1 MAD clinical trial designed to evaluate the safety, tolerability, pharmacokinetic, biodistribution, and pharmacodynamic effects of three weekly doses of DT-216 in adults with FA. FA is a multisystem degenerative disease caused by a GAA nucleotide repeat expansion in the frataxin (FXN) gene that impairs transcription and reduces FXN mRNA. DT-216 is designed to specifically target the GAA repeat expansion mutation and restore FXN gene expression. An unanticipated vendor issue related to the study drug vial stopper caused a short delay in product supply, which has been resolved. Design now anticipates presenting initial results from the MAD trial in the third quarter of 2023. The company plans to initiate a Phase 2 trial in the second half of 2023.

Omaveloxolone: First Approval

Lee A. Omaveloxolone: First Approval. Drugs. 2023 May 8. doi: 10.1007/s40265-023-01874-9. Epub ahead of print. PMID: 37155124. 

Omaveloxolone (SKYCLARYS™) is an orally active, small molecule semi-synthetic triterpenoid drug that increases antioxidant activity, which is being developed by Reata Pharmaceuticals, Inc. for the treatment of Friedreich's ataxia. In patients with Friedreich's ataxia, the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway is suppressed, which is associated with oxidative stress, mitochondrial dysfunction and damage to cells, including central and peripheral neurones. The Nrf2 pathway may be activated by omaveloxolone as it blocks the ubiquitination and degradation of Nrf2. Omaveloxolone was approved in February 2023 in the USA for the treatment of Friedreich's ataxia. This article summarizes the milestones in the development of omaveloxolone leading to this first approval for the treatment of Friedreich's ataxia in adults and adolescents aged 16 years and older.

Omaveloxolone (SkyclarysTM) for patients with Friedreich’s ataxia

Sharadha Dayalan Naidu, Albena T. Dinkova-Kostova, Omaveloxolone (SkyclarysTM) for patients with Friedreich’s ataxia, Trends in Pharmacological Sciences, 2023, doi:10.1016/j.tips.2023.03.005.

Omaveloxolone is the first and only FDA-approved drug for patients with Friedreich’s ataxia. Omaveloxolone has received Orphan Drug, Fast Track, and Rare Pediatric Disease Designations from the FDA, and Orphan Drug Designation for the treatment of Friedreich’s ataxia from the European Commission. It is currently not approved outside of the USA.

A systematic overview of rare disease patient registries: challenges in design, quality management, and maintenance

Hageman, I.C., van Rooij, I.A., de Blaauw, I. et al. A systematic overview of rare disease patient registries: challenges in design, quality management, and maintenance. Orphanet J Rare Dis 18, 106 (2023). doi:10.1186/s13023-023-02719-0 

Rare disease patient registries are valuable for research and evaluation of clinical care, and an increasing number have emerged. However, registries need to be continuously evaluated for data quality and long-term sustainability to remain relevant for future use.

Ketolysis is required for the proper development and function of the somatosensory nervous system

Enders J, Jack J, Thomas S, Lynch P, Lasnier S, Cao X, Swanson MT, Ryals JM, Thyfault JP, Puchalska P, Crawford PA, Wright DE. Ketolysis is required for the proper development and function of the somatosensory nervous system. Exp Neurol. 2023 Apr 24:114428. doi: 10.1016/j.expneurol.2023.114428. Epub ahead of print. PMID: 37100111. 

We conclude that ketone metabolism is essential for the development of the somatosensory nervous system. These findings also suggest that decreased ketone oxidation in the somatosensory nervous system may explain the neurological symptoms of Friedreich's ataxia.

Natural History Studies Drive Data Sharing, Drug Approval

Heidt, A. (2023, May 1). Natural history studies drive data sharing, drug approval. Retrieved May 1, 2023, from BioSpace website: https://www.biospace.com/article/natural-history-studies-drive-data-sharing-drug-approval/ 

Two recent announcements—the world’s first treatment for Friedreich's ataxia (FA), whose approval was based in part on a natural history database, and a new data-sharing agreement between industry and nonprofit partners to investigate myopathy—underpin just how helpful these studies can be in establishing new collaborations to tackle rare diseases.

Mapa epidemiológico transversal de las ataxias y paraparesias espásticas hereditarias en España

G. Ortega Suero, M.J. Abenza Abildúa, C. Serrano Munuera, I. Rouco Axpe, F.J. Arpa Gutiérrez, A.D. Adarmes Gómez, F.J. Rodríguez de Rivera, B. Quintans Castro, I. Posada Rodríguez, A. Vadillo Bermejo, Á. Domingo Santos, E. Blanco Vicente, I. Infante Ceberio, J. Pardo Fernández, E. Costa Arpín, C. Painous Martí, J.E. Muñoz, P. Mir Rivera, F. Montón Álvarez, L. Bataller Alberola, J. Gascón Bayarri, C. Casasnovas Pons, V. Vélez Santamaría, A. López de Munain, G. Fernández-Eulate, J. Gazulla Abío, I. Sanz Gallego, L. Rojas Bartolomé, Ó. Ayo Martín, T. Segura Martín, C. González Mingot, M. Baraldés Rovira, R. Sivera Mascaró, E. Cubo Delgado, A. Echavarría Íñiguez, F. Vázquez Sánchez, M. Bártulos Iglesias, M.T. Casadevall Codina, E.M. Martínez Fernández, C. Labandeira Guerra, B. Alemany Perna, A. Carvajal Hernández, C. Fernández Moreno, M. Palacín Larroy, N. Caballol Pons, A. Ávila Rivera, F.J. Navacerrada Barrero, R. Lobato Rodríguez, M.J. Sobrido Gómez, Mapa epidemiológico transversal de las ataxias y paraparesias espásticas hereditarias en España (Epidemiology of ataxia and hereditary spastic paraplegia in Spain: a cross-sectional study), Neurología (English Edition), 2023, doi.org/:10.1016/j.nrleng.2023.04.003. 

 In our sample, the estimated prevalence of ataxia and hereditary spastic paraplegia was 7.73 cases per 100 000 population. This rate is similar to those reported for other countries. Genetic diagnosis was not available in 47.6% of cases. Despite these limitations, our study provides useful data for estimating the necessary healthcare resources for these patients, raising awareness of these diseases, determining the most frequent causal mutations for local screening programmes, and promoting the development of clinical trials.