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.