{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:19:24Z","timestamp":1792790364886,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,29]]},"group-title":"Neuroscience","reference-count":51,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"National Institute of Neurological Disorders and Stroke","id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Apertura Gene Therapy"},{"name":"Merkin Foundation"},{"award":["UG3MH120096"],"award-info":[{"award-number":["UG3MH120096"]}],"id":[{"id":"https:\/\/ror.org\/04xeg9z08","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/01tm9b530","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Safe, efficient gene delivery throughout the CNS remains a central obstacle to treating genetic diseases of the brain and spinal cord. We describe BI-TfR1 CapX, a human transferrin receptor (TfR1)-binding AAV capsid that, after a low intravenous dose in adult humanized\n                  <jats:italic>TFRC<\/jats:italic>\n                  mice, transduced more than 80% of cortical and spinal neurons and \u223c60% of cortical astrocytes, with reduced distribution and expression in several peripheral tissues relative to AAV9. Unlike other engineered BBB-crossing capsids, CapX bound the CNS vasculature within minutes and a large fraction of its genomes reached parenchymal nuclei within 24 hours. Delivering a\n                  <jats:italic>Prnp<\/jats:italic>\n                  -targeted epigenetic silencer (\n                  <jats:italic>Prnp<\/jats:italic>\n                  -CHARM), CapX reduced brain\n                  <jats:italic>Prnp<\/jats:italic>\n                  mRNA by over 95% requiring 18-fold fewer vector genomes per brain cell than AAV-PHP.eB for 50% lowering. A CapX delivered dual-vector cytosine base editor installed a protein-truncating\n                  <jats:italic>PRNP<\/jats:italic>\n                  stop codon lowering brain prion protein by 80%. These properties make CapX an attractive vehicle for human CNS gene therapy.\n                <\/jats:p>","DOI":"10.64898\/2026.09.23.753669","type":"posted-content","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T18:30:18Z","timestamp":1790706618000},"source":"Crossref","is-referenced-by-count":0,"title":["BI-TfR1 CapX rapidly transits the blood-brain barrier for efficient, low-dose gene delivery throughout the CNS"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8853-5186","authenticated-orcid":false,"given":"Ken Y.","family":"Chan","sequence":"first","affiliation":[{"name":"Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA"},{"name":"Program in Brain Health, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chin-Yen","family":"Lin","sequence":"additional","affiliation":[{"name":"Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA"},{"name":"Program in Brain Health, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Huang","sequence":"additional","affiliation":[{"name":"Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA"},{"name":"Program in Brain Health, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Pacouret","sequence":"additional","affiliation":[{"name":"Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA"},{"name":"Program in Brain Health, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingxia","family":"Zheng","sequence":"additional","affiliation":[{"name":"Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA"},{"name":"Program in Brain Health, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John W.","family":"Harvey","sequence":"additional","affiliation":[{"name":"Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA"},{"name":"Program in Brain Health, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pam P.","family":"Brauer","sequence":"additional","affiliation":[{"name":"Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA"},{"name":"Program in Brain Health, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jencilin","family":"Johnston","sequence":"additional","affiliation":[{"name":"Stanley 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