Surgical approaches to gene and stem cell therapy for retinal disease.


As pointed out in the papers in this special issue of Human Gene Therapy, the eye presents a unique opportunity to study the delivery of therapeutic genetic material. There are many factors that make ocular gene therapy attractive and successful: (1) Almost all of the structures of the eye are visible and can be examined in the clinic by the slit lamp, and treatment response and potential complications can be visualized in real time; (2) a wide variety of objective, noninvasive imaging, and functional assessment modalities have been developed to evaluate visual function; (3) almost all the structures of the eye are surgically approachable via minimally invasive procedures that are performed in the outpatient setting under local anesthesia; (4) the eye is relatively immunoprivileged, with a robust blood–retinal barrier and essentially no lymphatic system; (5) the eye is a compact organ that requires relatively small volumes and doses of therapeutic agents; and, finally, (6) the vision loss associated with many ophthalmic diseases is symptomatic at stages that are amenable to intervention. Given these advantages and the increasing number of gene and stem cell-based ocular therapies, what is important to know about the eye and its abilities? The retina is a multilayered neural structure that forms the inner lining of the posterior segment of the eye. Light entering the eye is focused onto the retina, where photons activate photopigments in the outer segments of the photoreceptors. The resultant electrical signals are relayed via bipolar cells and processed by a variety of intermediate neuronal cell types before relay by retinal ganglion cells to the central visual system. The photoreceptors lie in intimate association with the retinal pigment epithelium (RPE), a single layer of cells that serve numerous metabolic, nutritional, and immunological functions. Blood and nutrients are supplied to the human retina from two sources: the retinal arterioles and the choroid, which lies external to the RPE. A large number of retinal degenerative disorders are recognized, principally affecting the photoreceptors and RPE in the outer retina. These include age-related macular degeneration (AMD) and the inherited retinal degenerations (IRDs). In both types of disease, vision loss occurs primarily because of progressive retinal photoreceptor death involving many common molecular processes. The need for new treatment strategies is compelling. AMD is the leading cause of blindness in the developed world, affecting more than 10 million individuals in the United States alone (Friedman et al., 2004). Both genetic and environmental factors contribute to its development. Although the precise etiology of the condition remains to be elucidated, a major role for inflammation has been implicated (Bird et al., 1995; Klein et al., 2004; Haddad et al., 2006). One phenotypic hallmark of AMD is the accumulation of drusen (subretinal yellow deposits) at the macula. The number of drusen, or area that they occupy, correlates with risk of progression to the advanced form of the disease (Klein et al., 2002; Umeda et al., 2005). Advanced AMD is characterized by poor central vision following the development of (1) choroidal neovascularization (CNV), which leads to hemorrhage and scarring in the retina, also known as ‘‘wet AMD,’’ or (2) patches of retinal pigment epithelial and photoreceptor atrophy, ‘‘geographic atrophy’’ (GA), also known as ‘‘advanced dry AMD.’’ Strategies to treat ‘‘wet’’ AMD are aimed at destroying or encouraging regression of neovascularization (Stone, 2006). Even with the latest intraocular antiangiogenic treatment, most patients cannot expect visual improvement (Kaiser, 2006; Rosenfeld et al., 2006a). Although antioxidant vitamin and mineral supplements may retard progression in patients with AMD who have the ‘‘dry’’ phenotype, there are no effective treatment options for most patients (Seddon and Hennekens, 1994; Bone et al., 2003; Blodi, 2004). The inherited retinal degenerations (IRDs) are a diverse group of genetically determined disorders. Common examples include retinitis pigmentosa, Usher syndrome, and Stargardt macular dystrophy. Rarer degenerations of note include Leber congenital amaurosis (in particular those caused by mutations in the gene RPE65) and X-linked retinoschisis. The underlying genetic mutations are diverse, and although known in many cases, they are undefined in the majority of cases. In IRDs, a variety of patterns of visual failure may occur, including peripheral visual field loss progressing to complete blindness. There is no treatment for these conditions.

DOI: 10.1089/hum.2011.060

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@article{Stout2011SurgicalAT, title={Surgical approaches to gene and stem cell therapy for retinal disease.}, author={Julie C. Stout and Peter James Francis}, journal={Human gene therapy}, year={2011}, volume={22 5}, pages={531-5} }