Gene therapy for retinal ganglion cell neuroprotection in glaucoma

Abstract

Glaucoma is the leading cause of irreversible blindness worldwide. The primary cause of glaucoma is not known, but several risk factors have been identified, including elevated intraocular pressure and age. Loss of vision in glaucoma is caused by the death of retinal ganglion cells (RGCs), the neurons that convey visual information from the retina to the brain. Therapeutic strategies aimed at delaying or halting RGC loss, known as neuroprotection, would be valuable to save vision in glaucoma. In this review, we discuss the significant progress that has been made in the use of gene therapy to understand mechanisms underlying RGC degeneration and to promote the survival of these neurons in experimental models of optic nerve injury. Gene Therapy (2012) 19, 127-136; doi:10.1038/gt.2011; published online 6 October 2011Keywords: retinal ganglion cell; neuroprotection; glaucoma NEUROPROTECTION IN GLAUCOMA: RATIONALE AND CURRENT LIMITATIONS Adult-onset glaucoma is an optic neuropathy that affects more than 50 million people around the world, with 47 million having bilateral (both eyes) blindness due to this disease. As more effective diagnostic tools become available, the number of cases is expected to rise, and a recent study predicts that there will be 70 million people with glaucoma in 2020. 1 Glaucoma is considered to be a group of diseases characterized by progressive optic nerve degeneration that results in visual field loss and irreversible blindness. The cause of glaucoma is unknown, but several risk factors have been identified, including high intraocular pressure, age and genetic predisposition. Open angle and angle-closure glaucoma, the most common forms of the disease, are often associated with high intraocular pressure. A crucial element in the pathophysiology of all forms of glaucoma is the death of retinal ganglion cells (RGCs; Figure 1) and, as these are central nervous system neurons, their loss is irreversible. At present, there is no cure for glaucoma, and the standard treatment is to lower intraocular pressure by medication or surgery. However, a significant proportion of patients continue to experience visual loss even when pharmacological treatments effectively reduce eye pressure. Therefore, novel therapeutic approaches are needed for its treatment and management.Early-onset glaucoma, comprising primary congenital glaucoma and juvenile open-angle glaucoma, has a clear genetic basis. Between 10 and 30% of individuals with juvenile open-angle glaucoma have mutations in the gene encoding myocilin, 2,3 and, on average, B40% of people with primary congenital glaucoma have mutations in the gene encoding cytochrome P450 protein. 4 Both genes are expressed in the trabecular meshwork and ciliary body, and defects in these genes may cause ocular hypertension. The elucidation of the genetic basis underlying adult-onset glaucoma is difficult because the late onset of disease limits the number of individuals available for linkage analysis. However, at least 29 genetic loci for various forms of glaucoma and 12...

Retinal neurodegeneration in experimental glaucoma

“…The numbers of Brn3a + RGCs in the vehicle-treated retinas examined at 12 or 15 days represented 56% (n ¼ 4) or 45% (n ¼ 4), respectively, of the control values, whereas for the BDNF-treated retinas these proportions were 83% (n ¼ 4) or 72% (n ¼ 4) at 12 or 15 days, respectively (Valiente-Soriano et al, 2015b). These findings are consistent with previous studies (Fu et al, 2009;Ko et al, 2001;Martin et al, 2003;Quigley et al, 2000;Wilson and Di Polo, 2012) that have found BDNF, NT4-5, insulin-like growth factor, or glialderived neurotrophic factor to afford transient neuroprotection against injuryinduced RGC death (Di Polo et al, 1998;Galindo-Romero et al, 2013b;Lindqvist et al, 2004;Parrilla-Reverter et al, 2009a;Sánchez-Migallón et al, 2011).…”

“…Partial and transient rescue of RGCs against a variety of retinal injuries has been shown with several neuroprotective agents ( Jehle et al, 2008;Vidal-Sanz et al, 2000, 2001, including brain-derived neurotrophic factor (BDNF), which has been shown to be one of the most potent RGC neuroprotectants (Di Polo et al, 1998;Galindo-Romero et al, 2013b;Mansour-Robaey et al, 1994;Peinado-Ramón et al, 1996;Sánchez-Migallón et al, 2011). Indeed, the administration of BDNF has been shown to prevent OHT-induced RGC loss (Almasieh et al, 2012;Di Polo et al, 1998;Fu et al, 2009;Ko et al, 2001;Lebrun-Julien et al, 2008;Martin et al, 2003;Quigley et al, 2000;Wilson and Di Polo, 2012). Here, we review some recent studies on the neuroprotective effects of BDNF on the population of injured RGCs, including melanopsin-expressing (m + RGCs) and nonmelanopsin-expressing RGCs (ValienteSoriano et al, 2015b).…”

Neuroprotection for glaucoma: Requirements for clinical translation

“…First, further work understanding the genetics of glaucoma should help identify novel pathways or target genes that can be approached via overexpression or knockdown (Wilson and Di Polo, 2012). Second, the continued development of novel pharmacological agents for neuroprotection, or the adaptation of pre-existing drugs towards glaucoma neuroprotection, will be useful in targeting both new and known pathways of RGC degeneration and glial activation.…”

Reduced retinal transduction and enhanced transgene-directed immunogenicity with intravitreal delivery of rAAV following posterior vitrectomy in dogs

“…Since AAV vectors can stably transduce post-mitotic inner retinal cells, long-term transgene expression resulting in a lifetime therapeutic effect becomes a theoretical possibility. 7 Evaluation of IVT-delivered AAV vectors in small animal models has demonstrated rescue of RGCs following axonal insult; however, this effect appears to be variable by retinal region. 8 AAV delivered via IVT in large animal models also produces variable RGC transduction between retinal regions.…”