Genetic modification of human trabecular meshwork with lentiviral vectors

Nils Loewen, Michael P. Fautsch, Mary Peretz, Cindy K. Bahler, J. Douglas Cameron, Douglas H. Johnson, Eric M. Poeschla

Research output: Contribution to journalArticle

70 Scopus citations

Abstract

Glaucoma, a group of optic neuropathies, is the leading cause of irreversible blindness. Neuronal apoptosis in glaucoma is primarily associated with high intraocular pressure caused by chronically impaired outflow of aqueous humor through the trabecular meshwork, a reticulum of mitotically inactive endothelial-like cells located in the angle of the anterior chamber. Anatomic, genetic, and expression profiling data suggest the possibility of using gene transfer to treat glaucomatous intraocular pressure dysregulation, but this approach will require stable genetic modification of the differentiated aqueous outflow tract. We injected transducing unit-normalized preparations of either of two lentiviral vectors or an oncoretroviral vector as a single bolus into the aqueous circulation of cultured human donor eyes, under perfusion conditions that mimicked natural anterior chamber flow and maintained viability ex vivo. Reporter gene expression was assessed in trabecular meshwork from 3 to 16 days after infusion of 1.0 × 108 transducing units of each vector. The oncoretroviral vector failed to transduce the trabecular meshwork. In contrast, feline immunodeficiency virus and human immunodeficiency virus vectors produced efficient, localized transduction of the trabecular meshwork in situ. The results demonstrate that lentiviral vectors permit efficient genetic modification of the human trabecular meshwork when delivered via the afferent aqueous circulation, a clinically accessible route. In addition, controlled comparisons in this study establish that feline and human immunodeficiency virus vectors are equivalently efficacious in delivering genes to this terminally differentiated human tissue.

Original languageEnglish (US)
Pages (from-to)2109-2119
Number of pages11
JournalHuman gene therapy
Volume12
Issue number17
DOIs
StatePublished - 2001

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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    Loewen, N., Fautsch, M. P., Peretz, M., Bahler, C. K., Cameron, J. D., Johnson, D. H., & Poeschla, E. M. (2001). Genetic modification of human trabecular meshwork with lentiviral vectors. Human gene therapy, 12(17), 2109-2119. https://doi.org/10.1089/10430340152677449