Gene Therapy Targeting Glaucoma: Where Are We?

Abstract

In a chronic disease such as glaucoma, a therapy that provides a long lasting local effect, with minimal systemic side effects, while circumventing the issue of patient compliance, is very attractive. The field of gene therapy is growing rapidly and ocular applications are expanding. Our understanding of the molecular pathogenesis of glaucoma is leading to greater specificity in ocular tissue targeting. Improvements in gene delivery techniques, refinement of vector construction methods, and development of better animal models combine to bring this potential therapy closer to reality.

Ocular gene delivery using lentiviral vectors

“…Strategies (reviewed in detail by Liu et al 67 ) could be developed to increase aqueous outflow through the various implicated pathways, inhibit aqueous production and inhibit scarring after filtration surgery, or be developed to augment neuroprotection mechanisms promoting retinal ganglion cell survival, for example, by the inhibition of retinal ganglion cell apoptosis. However, knowledge of the pathogenic mechanisms in this group of diseases is limited compared with those involved in retinal degeneration, and a greater understanding is required before rational, targeted, clinically effective molecular therapies are developed.…”

Application of Canaloplasty in Glaucoma Gene Therapy: Where Are We?

“…[4][5][6][7][8] For glaucoma, various genes have been investigated (dominant negative Rho or Rho kinase, caldesmon, C3 transferase, matrixmetalloproteinases, and specific siRNAs) for efficacy in decreasing outflow resistance. [9][10][11][12] These genes are thought to modify the structure of the TM that is responsible for the outflow resistance. Prostaglandin pathway gene therapy has also been investigated and found to produce sustained reduction of IOP in domestic cat and nonhuman primate models.…”

“…13,14 Gene delivery techniques include nonviral (naked DNA injection, physical, and chemical approaches) and viral (herpes simplex viruses, lentiviruses, adenovirus, and adeno-associated virus) systems. 9 Viral methods have induced transgene expression in cultured TM cells and/or the TM of live animal eyes. 9 Viral vectors (FIV and scAAV) encoding genes for green fluorescent protein (GFP) show long-term (2 + years) expression in the outflow pathways of nonhuman primate eyes following transcorneal intracameral injection.…”

“…9 Viral methods have induced transgene expression in cultured TM cells and/or the TM of live animal eyes. 9 Viral vectors (FIV and scAAV) encoding genes for green fluorescent protein (GFP) show long-term (2 + years) expression in the outflow pathways of nonhuman primate eyes following transcorneal intracameral injection. 15,16 Transcorneal intracameral injection has been the method of choice for transferring transgenes/vectors into the anterior chamber (AC) of the eye.…”

“…3 In recent years, the possibility of decreasing this outflow resistance via gene therapy using TM/SC-targeted transgene delivery systems has generated considerable interest. [4][5][6][7][8][9][10][11][12][13][14][15][16] We hypothesized that a canaloplasty approach might also be used for localized transgene delivery into this region. In this article, we have briefly reviewed canaloplasty surgery and discuss its possible role in transgene delivery into the SC.…”