Molecular evolution of adeno-associated virus for enhanced glial gene delivery

James T. Koerber, Ryan Klimczak, Jae Hyung Jang, Deniz Dalkara, John G. Flannery, David V. Schaffer

Research output: Contribution to journalArticle

109 Citations (Scopus)

Abstract

The natural tropism of most viral vectors, including adeno-associated viral (AAV) vectors, leads to predominant transduction of neurons and epithelia within the central nervous system (CNS) and retina. Despite the clinical relevance of glia for homeostasis in neural tissue, and as causal contributors in genetic disorders such as Alzheimer's and amyotrophic lateral sclerosis, efforts to develop more efficient gene delivery vectors for glia have met with limited success. Recently, viral vector engineering involving high-throughput random diversification and selection has enabled the rapid creation of AAV vectors with valuable new gene delivery properties. We have engineered novel AAV variants capable of efficient glia transduction by employing directed evolution with a panel of four distinct AAV libraries, including a new semi-random peptide replacement strategy. These variants transduced both human and rat astrocytes in vitro up to 15-fold higher than their parent serotypes, and injection into the rat striatum yielded astrocyte transduction levels up to 16% of the total transduced cell population, despite the human astrocyte selection platform. Furthermore, one variant exhibited a substantial shift in tropism toward Müller glia within the retina, further highlighting the general utility of these variants for efficient glia transduction in multiple species within the CNS and retina.

Original languageEnglish
Pages (from-to)2088-2095
Number of pages8
JournalMolecular Therapy
Volume17
Issue number12
DOIs
Publication statusPublished - 2009 Dec 1

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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    Koerber, J. T., Klimczak, R., Jang, J. H., Dalkara, D., Flannery, J. G., & Schaffer, D. V. (2009). Molecular evolution of adeno-associated virus for enhanced glial gene delivery. Molecular Therapy, 17(12), 2088-2095. https://doi.org/10.1038/mt.2009.184