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.