{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T01:32:46Z","timestamp":1792373566196,"version":"4.4.0"},"reference-count":113,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T00:00:00Z","timestamp":1760659200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Kazan Federal University Strategic Academic Leadership Program","award":["PRIORITY-2030"],"award-info":[{"award-number":["PRIORITY-2030"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The development of gene therapies for rare hereditary disorders is hindered by small patient cohorts, incomplete characterization of natural disease history, and the impracticality of conducting long-term clinical trials. Surrogate biomarkers\u2014quantifiable indicators predictive of clinical outcomes\u2014represent a promising strategy to accelerate the evaluation of therapeutic efficacy. This review examines the role of surrogate endpoints in gene therapy, outlining essential validation criteria, including biological plausibility, analytical reproducibility, and clinical predictive value. Regulatory frameworks governing surrogate markers in the United States, European Union, Russia, Japan, China, and Canada are compared, with emphasis on mechanisms for expedited or conditional approval. Challenges associated with biomarker validation and extrapolation in the context of rare diseases are discussed, alongside future perspectives that integrate multi-omics technologies and artificial intelligence to enhance biomarker discovery and facilitate regulatory acceptance.<\/jats:p>","DOI":"10.3390\/ijms262010107","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T10:28:36Z","timestamp":1760696916000},"page":"10107","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Surrogate Biomarkers in Gene Therapy for Orphan Diseases: Validation, Application, and Regulatory Aspects"],"prefix":"10.3390","volume":"26","author":[{"given":"Aisylu I.","family":"Ayupova","sequence":"first","affiliation":[{"name":"Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8776-3662","authenticated-orcid":false,"given":"Valeriya V.","family":"Solovyeva","sequence":"additional","affiliation":[{"name":"Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1690-0199","authenticated-orcid":false,"given":"Shaza S.","family":"Issa","sequence":"additional","affiliation":[{"name":"Department of Genetics and Biotechnology, St. Petersburg State University, St. Petersburg 199034, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7543-2655","authenticated-orcid":false,"given":"Haidar J.","family":"Fayoud","sequence":"additional","affiliation":[{"name":"Department of Genetics and Biotechnology, St. Petersburg State University, St. Petersburg 199034, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9427-5739","authenticated-orcid":false,"given":"Albert A.","family":"Rizvanov","sequence":"additional","affiliation":[{"name":"Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia"},{"name":"Division of Medical and Biological Sciences, Academy of Sciences of the Republic of Tatarstan, Kazan 420111, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1889","DOI":"10.1016\/j.ymthe.2025.02.040","article-title":"Gene Therapy Then and Now: A Look Back at Changes in the Field over the Past 25 Years","volume":"33","author":"Wang","year":"2025","journal-title":"Mol. 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