{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T17:03:26Z","timestamp":1785171806741,"version":"3.55.0"},"reference-count":67,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Rettco Inc."},{"name":"Republic of T\u00fcrkiye Minister of National Education"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: PTEN Hamartoma Tumour Syndrome (PHTS) is a rare inherited disorder caused by germline PTEN mutations, presenting with cancer predisposition and neurodevelopmental abnormalities, including macrocephaly. PTEN functions as a tumour suppressor by regulating the PI3K\/AKT\/mTOR pathway and contributes to cellular adhesion, migration, and genomic stability. As no curative therapy exists, gene therapy represents a promising avenue to correct the underlying genetic defect. Methods: In this study we evaluated the therapeutic potential of AAV9-mediated PTEN gene delivery in a Pten\u03945\/+ mouse model, which is predominantly characterized by progressive lymphoid hyperplasia leading to lymph node tumour development, as well as hepatic focal lesions and macrocephaly. Results: Systemic vector delivery did not improve lymph node enlargement which represents the predominant disease phenotype in the Pten\u03945\/+ mice at the doses tested, due to restricted vector biodistribution, but it did effectively rescue the hepatic lesions, including steatosis and steatohepatitis-like changes. Mechanistically, AAV-mediated PTEN expression significantly reduced elevated p-AKT levels, indicating attenuated hyperactivation of the PI3K\/AKT\/mTOR pathway. Additionally, intracranial delivery of the same vector in Pten\u03945\/+ mouse neonates ameliorated macrocephaly without apparent adverse effects. Conclusions: These findings highlight the therapeutic potential of AAV9-mediated PTEN gene therapy in PHTS, particularly for hepatic and neuroanatomical manifestations. Optimization of vector biodistribution and transduction efficiency will be critical for clinical translation.<\/jats:p>","DOI":"10.3390\/pharmaceutics18080922","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T16:11:56Z","timestamp":1785168716000},"page":"922","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["AAV9-Mediated PTEN Gene Therapy Rescues Hepatic Pathology and Neuroanatomical Abnormalities in a Murine Model of PTEN Hamartoma Tumour Syndrome"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6894-2542","authenticated-orcid":false,"given":"Ceren","family":"Erdem","sequence":"first","affiliation":[{"name":"Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH8 9XD, UK"},{"name":"Department of Medical Biology, Faculty of Medicine, Pamukkale University, Denizli 20070, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Thomson","sequence":"additional","affiliation":[{"name":"Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH8 9XD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3819-0108","authenticated-orcid":false,"given":"Noha","family":"Bahey","sequence":"additional","affiliation":[{"name":"Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH8 9XD, UK"},{"name":"Department of Histology, Faculty of Medicine, Tanta University, Tanta 31527, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2473-4386","authenticated-orcid":false,"given":"Jim","family":"Selfridge","sequence":"additional","affiliation":[{"name":"Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH8 9XD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4174-2786","authenticated-orcid":false,"given":"Timothy","family":"Kendall","sequence":"additional","affiliation":[{"name":"Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh EH16 4UU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart","family":"Cobb","sequence":"additional","affiliation":[{"name":"Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH8 9XD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamal","family":"Gadalla","sequence":"additional","affiliation":[{"name":"Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH8 9XD, UK"},{"name":"Centre for Systems Health and Integrated Metabolic Research (SHiMR), Department of Biosciences, School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,27]]},"reference":[{"key":"ref_1","first-page":"399","article-title":"Germline PTEN Mutation in a Family with Cowden Syndrome and Bannayan-Riley-Ruvalcaba Syndrome","volume":"80","author":"Zori","year":"1998","journal-title":"J. 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