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      Ly6a Differential Expression in Blood-Brain Barrier Is Responsible for Strain Specific Central Nervous System Transduction Profile of AAV-PHP.B.

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          Abstract

          Adeno-associated virus (AAV) gene therapy for neurological diseases was revolutionized by the discovery that AAV9 crosses the blood-brain barrier (BBB) after systemic administration. Transformative results have been documented in various inherited diseases, but overall neuronal transduction efficiency is relatively low. The recent development of AAV-PHP.B with ∼60-fold higher efficiency than AAV9 in transducing the adult mouse brain was the major first step toward acquiring the ability to deliver genes to the majority of cells in the central nervous system (CNS). However, little is known about the mechanism utilized by AAV to cross the BBB, and how it may diverge across species. In this study, we show that AAV-PHP.B is ineffective for systemic CNS gene transfer in the inbred strains BALB/cJ, BALB/cByJ, A/J, NOD/ShiLtJ, NZO/HILtJ, C3H/HeJ, and CBA/J mice, but it is highly potent in C57BL/6J, FVB/NJ, DBA/2J, 129S1/SvImJ, and AKR/J mice and also the outbred strain CD-1. We used the power of classical genetics to uncover the molecular mechanisms AAV-PHP.B engages to transduce CNS at high efficiency, and by quantitative trait locus mapping we identify a 6 Mb region in chromosome 15 with an logarithm of the odds (LOD) score ∼20, including single nucleotide polymorphisms in the coding region of 9 different genes. Comparison of the publicly available data on the genome sequence of 16 different mouse strains, combined with RNA-seq data analysis of brain microcapillary endothelia, led us to conclude that the expression level of Ly6a is likely the determining factor for differential efficacy of AAV-PHP.B in transducing the CNS across different mouse strains.

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          Author and article information

          Journal
          Hum. Gene Ther.
          Human gene therapy
          Mary Ann Liebert Inc
          1557-7422
          1043-0342
          Jan 2020
          : 31
          : 1-2
          Affiliations
          [1 ] Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts.
          [2 ] Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts.
          [3 ] Rare and Orphan Disease Center, The Jackson Laboratory, Bar Harbor, Maine.
          [4 ] Department of Radiology, University of Massachusetts Medical School, Worcester, Massachusetts.
          [5 ] RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts.
          Article
          10.1089/hum.2019.186
          31696742
          739641a3-920d-485c-884b-1e0a263fd542
          History

          mouse genetics,blood–brain barrier,Ly6a,CNS transduction,AAV-PHP.B

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