{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T09:05:20Z","timestamp":1784624720168,"version":"3.55.0"},"reference-count":22,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Friedreich\u2019s ataxia (FRDA) is a neurodegenerative disorder driven by frataxin deficiency, resulting in mitochondrial dysfunction and reduced nuclear factor erythroid 2-related factor 2 (Nrf2) signaling. Pharmacologic trials have yielded inconsistent results, prompting an updated synthesis of evidence. Methods: We searched MEDLINE\/PubMed, Google Scholar, Cochrane CENTRAL, ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) from database inception to 29 June 2025. Embase, Scopus and Web of Science were not searched due to institutional access limitations. Two reviewers independently screened studies, extracted data, and assessed risk of bias. Random-effects meta-analyses were conducted, and Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) was used. Primary outcomes were modified Friedreich Ataxia Rating Scale (mFARS)\/Friedreich Ataxia Rating Scale (FARS); safety outcomes included adverse events (AEs) and serious AEs. Secondary outcomes were Scale for the Assessment and Rating of Ataxia (SARA), International Cooperative Ataxia Rating Scale (ICARS), Nine-Hole Peg Test, and the Timed 25-Foot Walk. Results: Sixteen studies (17 reports, n = 351) met inclusion criteria. Omaveloxolone was the only agent showing a statistically significant improvement in mFARS (mean difference (MD) \u22122.40; 95% confidence interval (CI) \u22124.24 to \u22120.56; p = 0.014), supported by low-certainty evidence. Other therapies showed no consistent benefit. Overall AE risk was comparable to control (risk ratio (RR) 1.00; 95% CI 0.98\u20131.03). Apparent subgroup differences by therapeutic class or age likely reflected drug-specific effects and small samples. Conclusions: Omaveloxolone was the only agent to reach statistical significance for mFARS and is the most promising and best-supported therapy among those reviewed; however, this rests on low-certainty evidence and needs confirmation in larger trials. No clear difference in overall adverse events was observed between intervention and control groups; however, available safety evidence remains limited by imprecision, small sample sizes, and short follow-up durations. Longer, standardized, and age-stratified randomized controlled trials (RCTs) are needed.<\/jats:p>","DOI":"10.3390\/jcm15145707","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T08:14:27Z","timestamp":1784621667000},"page":"5707","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Evolution of Friedreich\u2019s Ataxia Management Across Established and Emerging Therapies\u2014Systematic Review and Meta-Analysis"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2263-5114","authenticated-orcid":false,"given":"Basel","family":"Garah","sequence":"first","affiliation":[{"name":"College of Medicine, Taibah University, Madinah 42353, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisham","family":"Aljabri","sequence":"additional","affiliation":[{"name":"College of Medicine, Taibah University, Madinah 42353, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdullah","family":"Aljohani","sequence":"additional","affiliation":[{"name":"College of Medicine, Taibah University, Madinah 42353, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ethar","family":"Alnuzha","sequence":"additional","affiliation":[{"name":"College of Medicine, Taibah University, Madinah 42353, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arwa","family":"Maihoub","sequence":"additional","affiliation":[{"name":"College of Medicine, Taibah University, Madinah 42353, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4756-6617","authenticated-orcid":false,"given":"Reenad","family":"Almuzaini","sequence":"additional","affiliation":[{"name":"College of Medicine, Taibah University, Madinah 42353, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Layan","family":"Aljohani","sequence":"additional","affiliation":[{"name":"College of Medicine, Taibah University, Madinah 42353, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0080-1982","authenticated-orcid":false,"given":"Layan","family":"Alshamani","sequence":"additional","affiliation":[{"name":"College of Medicine, Taibah University, Madinah 42353, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5416-6247","authenticated-orcid":false,"given":"Majed","family":"Alluqmani","sequence":"additional","affiliation":[{"name":"College of Medicine, Taibah University, Madinah 42353, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1093\/bmb\/ldx034","article-title":"Friedreich\u2019s ataxia: Clinical features, pathogenesis and management","volume":"124","author":"Cook","year":"2017","journal-title":"Br. 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