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Genetically modifying BECs into protein factories that supply the CNS with recombinant proteins is a promising approach to overcome this hindrance, especially in genetic diseases, like Niemann Pick disease type C2 (NPC2), where both CNS and peripheral cells are affected. Here, we investigated the potential of the BEC\u2010specific adeno\u2010associated viral vector (AAV\u2010BR1) encoding NPC2 for expression and secretion from primary BECs cultured in an<jats:italic>in vitro<\/jats:italic>BBB model with mixed glial cells, and in healthy BALB\/c mice. Transduced primary BECs had significantly increased NPC2 gene expression and secreted NPC2 after viral transduction, which significantly reversed cholesterol deposition in NPC2 deficient fibroblasts. Mice receiving an intravenous injection with AAV\u2010BR1\u2010NCP2\u2010eGFP were sacrificed 8\u2009weeks later and examined for its biodistribution and transgene expression of eGFP and NPC2. AAV\u2010BR1\u2010NPC2\u2010eGFP was distributed mainly to the brain and lightly to the heart and lung, but did not label other organs including the liver. eGFP expression was primarily found in BECs throughout the brain but occasionally also in neurons suggesting transport of the vector across the BBB, a phenomenon also confirmed<jats:italic>in vitro<\/jats:italic>. NPC2 gene expression was up\u2010regulated in the brain, and recombinant NPC2 protein expression was observed in both transduced brain capillaries and neurons. Our findings show that AAV\u2010BR1 transduction of BECs is possible and that it may denote a promising strategy for future treatment of NPC2.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15621-fig-0008-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p>","DOI":"10.1111\/jnc.15621","type":"journal-article","created":{"date-parts":[[2022,5,12]],"date-time":"2022-05-12T14:55:00Z","timestamp":1652367300000},"page":"6-28","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["A novel strategy for delivering<scp>N<\/scp>iemann\u2010<scp>P<\/scp>ick type<scp>C2<\/scp>proteins across the blood\u2013brain barrier using the brain endothelial\u2010specific<scp>AAV\u2010BR1<\/scp>virus"],"prefix":"10.1111","volume":"164","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6535-3729","authenticated-orcid":false,"given":"Charlotte Laurfelt Munch","family":"Rasmussen","sequence":"first","affiliation":[{"name":"Neurobiology Research and Drug Delivery, Department of Health Science and Technology Aalborg University Aalborg Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6072-4970","authenticated-orcid":false,"given":"Eva","family":"Hede","sequence":"additional","affiliation":[{"name":"Neurobiology Research and Drug Delivery, Department of Health Science and Technology Aalborg University Aalborg Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3658-5859","authenticated-orcid":false,"given":"Lisa Juul","family":"Routhe","sequence":"additional","affiliation":[{"name":"Neurobiology Research and Drug Delivery, Department of Health Science and Technology Aalborg University Aalborg Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5435-7182","authenticated-orcid":false,"given":"Jakob","family":"K\u00f6rbelin","sequence":"additional","affiliation":[{"name":"Department of Oncology, Hematology and Bone Marrow Transplantation University Medical Center Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2452-7504","authenticated-orcid":false,"given":"Steinunn Sara","family":"Helgudottir","sequence":"additional","affiliation":[{"name":"Neurobiology Research and Drug Delivery, Department of Health Science and Technology Aalborg University Aalborg Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3144-7150","authenticated-orcid":false,"given":"Louiza Bohn","family":"Thomsen","sequence":"additional","affiliation":[{"name":"Neurobiology Research and Drug Delivery, Department of Health Science and Technology Aalborg University Aalborg Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4510-9718","authenticated-orcid":false,"given":"Markus","family":"Schwaninger","sequence":"additional","affiliation":[{"name":"Institute for Experimental and Clinical Pharmacology and Toxicology University of L\u00fcbeck L\u00fcbeck Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2086-4693","authenticated-orcid":false,"given":"Annette","family":"Burkhart","sequence":"additional","affiliation":[{"name":"Neurobiology Research and Drug Delivery, Department of Health Science and Technology Aalborg University Aalborg Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9989-0207","authenticated-orcid":false,"given":"Torben","family":"Moos","sequence":"additional","affiliation":[{"name":"Neurobiology Research and Drug Delivery, Department of Health Science and Technology Aalborg University Aalborg Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,5,25]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2009.07.030"},{"key":"e_1_2_10_3_1","first-page":"334","article-title":"The Hedgehog pathway promotes blood\u2010brain barrier integrity and CNS immune quiescence","volume":"80","author":"Alvarez J. 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