1. Serotype survey of AAV gene delivery via subconjunctival injection in mice
- Author
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Matthew L. Hirsch, Violeta Zaric, Brian C. Gilger, Laura Conatser, Telmo Llanga, and Liujiang Song
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Conjunctiva ,Eye Diseases ,viruses ,Transgene ,Genetic enhancement ,Genetic Vectors ,Green Fluorescent Proteins ,Gene delivery ,Biology ,Serogroup ,Cornea ,Mice ,03 medical and health sciences ,Transduction (genetics) ,0302 clinical medicine ,Transduction, Genetic ,Surveys and Questionnaires ,Genetics ,medicine ,Animals ,Humans ,Receptor ,Molecular Biology ,Gene Transfer Techniques ,Genetic Therapy ,Dependovirus ,eye diseases ,030104 developmental biology ,medicine.anatomical_structure ,030221 ophthalmology & optometry ,Molecular Medicine ,Tears ,sense organs - Abstract
AAV gene therapy approaches in the posterior eye resulted in the first FDA-approved gene therapy-based drug. However, application of AAV vectorology to the anterior eye has yet to enter even a Phase I trial. Furthermore, the simple and safe subconjunctival injection has been relatively unexplored in regard to AAV vector transduction. To determine the utility of this route for the treatment of various ocular disorders, a survey of gene delivery via natural AAV serotypes was performed and correlated to reported cellular attachment factors. AAV serotypes packaged with a self-complementary reporter were administered via subconjunctival injection to WT mice. Subconjunctival injection of AAV vectors was without incidence; however, vector shedding in tears was noted weeks following administration. AAV transduction was serotype dependent in anterior segment tissues including the eye lid, conjunctiva, and cornea, as well as the periocular tissues including muscle. Transgene product in the cornea was highest for AAV6 and AAV8, however, their corneal restriction was remarkably different; AAV6 appeared restricted to the endothelium layer while AAV8 efficiently transduced the stromal layer. Reported AAV cellular receptors were not well correlated to vector transduction; although, in some cases they were conserved among mouse and human ocular tissues. Subconjunctival administration of particular AAV serotypes may be a simple and safe targeted gene delivery route for ocular surface, muscular, corneal, and optic nerve diseases.
- Published
- 2018