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To facilitate the development of such AAV therapies, here we have developed an AAV-transgene-target quantitative systems pharmacology (QSP) model that can simultaneously characterize the disposition of AAV, expressed antibody, therapeutic target, and the mAb-target complex in plasma, tissues, and the brain. The model was built by integrating previously published platform physiologically based pharmacokinetic (PBPK) models for AAV, protein therapeutics, and brain, with special emphasis on transport pathways and transduction mechanisms within the brain. The developed QSP model was able to capture the pharmacokinetics of AAV and the expressed mAb in the systemic circulation and brain tissues following AAV administration via diverse routes in the rats. The model suggested that intra-cisternal magna injection of medium AAV dose or intrastriatal injection of low AAV dose would provide better therapeutic options compared to intravenous administration of high AAV dose. Locally administered AAV was predicted to lead to sufficient antibody exposure and substantial target engagement in cerebrospinal fluid (CSF) and interstitial fluid (ISF), while minimizing systemic AAV and antibody exposure, leading to maximal efficacy and minimal toxicity. Overall, the present work not only supports cross-species and cross-serotypes translational potential of previously published AAV PBPK model, but also highlights application of QSP modeling to guide the development of AAV therapies for neurological disorders.<\/jats:p>","DOI":"10.1007\/s10928-026-10051-w","type":"journal-article","created":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T16:08:06Z","timestamp":1784390886000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["QSP model for AAV-mediated antibody delivery in rat brain"],"prefix":"10.1007","volume":"53","author":[{"given":"Shufang","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekram Ahmed","family":"Chowdhury","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengjia","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guy","family":"Meno-Tetang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dhaval K.","family":"Shah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,18]]},"reference":[{"issue":"2","key":"10051_CR1","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1016\/S0009-8981(01)00573-3","volume":"310","author":"H Reiber","year":"2001","unstructured":"Reiber H (2001) Dynamics of brain-derived proteins in cerebrospinal fluid. 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