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Personalized genetic therapy represents one promising approach for their treatment. We present a road map for individualized treatment of an ultra-rare disease by establishing a gene replacement therapy developed for a single patient with hereditary spastic paraplegia type 50 (SPG50). Through a multicenter collaboration, an adeno-associated virus-based gene therapy product carrying the <jats:italic>AP4M1<\/jats:italic> gene was created and successfully administered intrathecally to a 4-year-old patient within 3 years of diagnosis as part of a single-patient phase 1 trial. Primary endpoints were safety and tolerability, and secondary endpoints evaluated efficacy. At 12 months after dosing, the therapy was well tolerated. No serious adverse events were observed, with minor events, including transient neutropenia and <jats:italic>Clostridioides difficile<\/jats:italic> gastroenteritis, experienced but resolved. Preliminary efficacy measures suggest a stabilization of the disease course. Longer follow-up is needed to confirm the safety and provide additional insights on the efficacy of the therapy. Overall, this report supports the safety of gene therapy for SPG50 and provides insights into precision therapy development for rare diseases. Clinical trial registration: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT06069687?term=NCT06069687\">NCT06069687<\/jats:ext-link>.<\/jats:p>","DOI":"10.1038\/s41591-024-03078-4","type":"journal-article","created":{"date-parts":[[2024,6,28]],"date-time":"2024-06-28T10:02:44Z","timestamp":1719568964000},"page":"1882-1887","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["AAV gene therapy for hereditary spastic paraplegia type 50: a phase 1 trial in a single patient"],"prefix":"10.1038","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3984-4169","authenticated-orcid":false,"given":"James J.","family":"Dowling","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terry","family":"Pirovolakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keshini","family":"Devakandan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Stosic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mia","family":"Pidsadny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Nigro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7044-2953","authenticated-orcid":false,"given":"Mustafa","family":"Sahin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darius","family":"Ebrahimi-Fakhari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Souad","family":"Messahel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ganapathy","family":"Varadarajan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2091-8201","authenticated-orcid":false,"given":"Benjamin M.","family":"Greenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Berge A.","family":"Minassian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6775-1496","authenticated-orcid":false,"given":"Ronald","family":"Cohn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5930-2324","authenticated-orcid":false,"given":"Carsten G.","family":"Bonnemann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6240-8621","authenticated-orcid":false,"given":"Steven J.","family":"Gray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,28]]},"reference":[{"key":"3078_CR1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06277-0","author":"J Kim","year":"2023","unstructured":"Kim, J. et al. 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Of note, T.P. is a parent of the study patient. Also, subsequent to the completion of this study, T.P. formed Elpida Therapeutics, and MELPIDA (AAV-AP4M1) represents one of the clinical programs in its developmental pipeline. S.J.G. is a nonpaid member of the Elpida board of directors, and S.M. is head of clinical operations. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}