AAV and compacted DNA nanoparticles for the treatment of retinal disorders: challenges and future prospects

Abstract

Gene therapy based on delivery of viral and nonviral vectors has shown great promise for the treatment of human ocular diseases; however, limitations have consistently prevented its widespread clinical application. Viral vectors have generally been better in terms of efficiency but have safety concerns. Nonviral vectors, on the other hand, offer safety but have often been disappointing in terms of efficiency of nuclear delivery and gene expression. Extensive animal studies have reported significant progress using both systems, but thus far only a few studies have shown promise in human clinical trials. This article reviews both viral and nonviral work with focus on two candidates for clinical ocular application--AAV and nanoparticles. Of particular interest are various requirements for successful clinical application of these technologies including vector trafficking, delivery, specific gene expression, and treatment safety, and tolerance.

Figure 1.

Results of a PubMed search (number of “hits”) with the key words “viral and AAV” and “nonviral and NPs” from 2000 to 2009. The AAV and NPs hits are part of the total “viral” and “nonviral” hits, respectively.

Figure 2.

Diagram of AAV versus CK30PEG NP trafficking. (A) First trafficking steps involve AAV and CK30PEG NP binding to cognate receptors such as HSPG for AAV and nucleolin for NPs. (B) AAV undergoes endocytosis, usually by a clathrin-mediated pathway and is processed through the endosomal system before being released. CK30PEG NPs are internalized via raft-mediated endocytosis and traffic to the nucleus, using the cellular microtubule system. (C) The mechanisms for AAV and CK30PEG NP entry in the nucleus are not clear but may rely on diffusion through the nuclear pore complex (NPC) or processing by nuclear receptors.