{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T11:24:06Z","timestamp":1787397846902,"version":"build-2736575974"},"reference-count":67,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Therapeutic Advances in Rare Disease"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:p>\n                    Primary mitochondrial diseases (PMD) are ultra-rare, genetically diverse disorders that impair cellular energy metabolism and typically present with multisystemic symptoms. Over the past decades, the therapeutic landscape of PMD has evolved substantially. Early trials of non-specific antioxidant and metabolic therapies produced largely negative or mixed results, providing important methodological lessons for the field. More recent studies have adopted improved outcome measures, natural history-informed designs, and precision therapeutic approaches, including gene therapy and nucleoside therapy, which have shown encouraging clinical and regulatory progress. Regulatory agencies have only recently begun approving disease-modifying therapies for selected mitochondrial disorders. The European Medicines Agency (EMA) approved idebenone for Leber Hereditary Optic Neuropathy (LHON) in 2015 but only recently, in 2025 did the Food and Drug Administration (FDA) in the US approve a treatment for Barth syndrome and thymidine kinase 2 deficiency (TK2d). Friedreich\u2019s ataxia received regulatory approval in 2023 from both the EMA and FDA, marking another milestone in mitochondria-related disorders. To comprehensively review clinical and regulatory developments in PMD over the past two decades, we conducted a structured scoping review and horizon scan of published clinical trials and regulatory approvals in PMD from January 2000 to November 2025. Data sources included PubMed, Embase,\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/ClinicalTrials.gov\">https:\/\/ClinicalTrials.gov<\/jats:ext-link>\n                    , and regulatory agency websites. Recent accelerated and full FDA approvals validate the feasibility of tailored evidence packages, but sustaining this momentum will require more rigorous alignment of trial design with molecular biology, strengthening of natural history infrastructure, deployment of sensitive biomarkers, and adoption of innovative statistical approaches. Early regulatory engagement and robust patient-community partnerships will be key.\n                  <\/jats:p>","DOI":"10.1177\/26330040261473291","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T09:20:21Z","timestamp":1787217621000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["2000\u20132025: Emerging therapies in primary mitochondrial disease: A structured review, horizon scan, and roadmap for the future"],"prefix":"10.1177","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5781-9824","authenticated-orcid":false,"given":"Amel","family":"Karaa","sequence":"first","affiliation":[{"name":"Massachusetts General Hospital, Harvard Medical School"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Isabel G.","family":"Lopez Sanchez","sequence":"additional","affiliation":[{"name":"Centre for Eye Research Australia"},{"name":"Mito Foundation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1991-6495","authenticated-orcid":false,"given":"Clare","family":"Stuart","sequence":"additional","affiliation":[{"name":"Mito Foundation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Bolliger","sequence":"additional","affiliation":[{"name":"The POLG Foundation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate","family":"Murray","sequence":"additional","affiliation":[{"name":"Mito Canada Foundation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8524-4781","authenticated-orcid":false,"given":"Maria E.","family":"O\u2019Hanlon","sequence":"additional","affiliation":[{"name":"The Lily Foundation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Tseng","sequence":"additional","affiliation":[{"name":"The POLG Foundation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Yeske","sequence":"additional","affiliation":[{"name":"United Mitochondrial Disease Foundation (UMDF)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean","family":"Murray","sequence":"additional","affiliation":[{"name":"Mito Foundation"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"e_1_3_9_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24362"},{"key":"e_1_3_9_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2016.80"},{"key":"e_1_3_9_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.02.051"},{"key":"e_1_3_9_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-821751-1.00002-6"},{"key":"e_1_3_9_6_2","volume-title":"FDA Grants Accelerated Approval to First Treatment for Barth Syndrome","author":"Research C for DE and. 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