AI Article Synopsis
- * Researchers designed AAV9 variants with cell-penetrating peptides, specifically AAV.CPP.16 and AAV.CPP.21, which showed significantly improved ability to enter central nervous system cells in both mice and macaques.
- * AAV.CPP.16 not only retains its effectiveness in different age groups of macaques but also enhances transport across the BBB and successfully delivers antitumor treatments in glioblastoma mouse models, paving the way for better gene therapy options.
Article Abstract
The development of gene therapies for the treatment of diseases of the central nervous system has been hindered by the limited availability of adeno-associated viruses (AAVs) that efficiently traverse the blood-brain barrier (BBB). Here, we report the rational design of AAV9 variants displaying cell-penetrating peptides on the viral capsid and the identification of two variants, AAV.CPP.16 and AAV.CPP.21, with improved transduction efficiencies of cells of the central nervous system on systemic delivery (6- to 249-fold across 4 mouse strains and 5-fold in cynomolgus macaques, with respect to the AAV9 parent vector). We also show that the neurotropism of AAV.CPP.16 is retained in young and adult macaques, that this variant displays enhanced transcytosis at the BBB as well as increased efficiency of cellular transduction relative to AAV9, and that it can be used to deliver antitumour payloads in a mouse model of glioblastoma. AAV capsids that can efficiently penetrate the BBB will facilitate the clinical translation of gene therapies aimed at the central nervous system.
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| http://dx.doi.org/10.1038/s41551-022-00938-7 | DOI Listing |
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