Immunology of AAV-Mediated Gene Transfer in the Eye

Abstract

The eye has been at the forefront of translational gene therapy largely owing to suitable disease targets, anatomic accessibility, and well-studied immunologic privilege. These advantages have fostered research culminating in several clinical trials and adeno-associated virus (AAV) has emerged as the vector of choice for many ocular therapies. Pre-clinical and clinical investigations have assessed the humoral and cellular immune responses to a variety of naturally occurring and engineered AAV serotypes as well as their delivered transgenes and these data have been correlated to potential clinical sequelae. Encouragingly, AAV appears safe and effective with clinical follow-up surpassing 5 years in some studies. As disease targets continue to expand for AAV in the eye, thorough and deliberate assessment of immunologic safety is critical. With careful study, the development of these technologies should concurrently inform the biology of the ocular immune response.

Keywords: RPE65; adeno-associated virus; gene therapy for rare diseases; immune privilege; sub-retinal injection; translational medical research.

Figure 1

Trends in vectors studied for gene therapy in the eye. (A) Number of results returned when the MEDLINE database was queried via PubMed for “aav eye 2001” etc. (B) Newly registered clinical trials by year from the database Gene Therapy Clinical Trials Online from the Journal of Gene Medicine. Results restricted to “ocular diseases” and sorted by date approved.

Figure 2

Clinical trials of ocular AAV registered on www.clinicaltrials.gov. Searched as search term = eye and interventions = adeno-associated virus OR AAV OR rAAV. Number of patients reported as actual or planned numbers for enrollment.

Figure 3

Schematic of anatomic approach to administration of gene therapy vectors in the eye. Counterclockwise from upper left – LG, lacrimal gland; T, topical eye drop; IS, intra-stromal of cornea; IC, intra-cameral, i.e., anterior chamber; IVI, intravitreal; SR, sub-retinal; Sys, systemic.