Human immunodeficiency virus type 2 (HIV-2) vector-mediated in vivo gene transfer into adult rabbit retina

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...

Section: Tools For Gene Delivery To Injured Rgcsmentioning

confidence: 99%

Gene therapy for retinal ganglion cell neuroprotection in glaucoma

Wilson

Polo

2011

“…Additional transduction of neuroretinal neuronal and glial cells, albeit of variable efficiencies and distributions, is reported using HIV-1, (refs 16-18) HIV-2, (ref. 25) EIAV, (refs 30,33,35) BIV 35 and FIV 36,39,40,42 vectors in rodents, rabbits or NHPs, and by some groups delivering HIV-1 vectors in young rodents 7,10 (Figure 2). Lentiviral Typical transduction profiles of VSV-G-pseudotyped lentiviral vectors harbouring ubiquitous promoters after intraocular delivery in C57Bl/6J mice.…”

Section: Sub-retinal Deliverymentioning

confidence: 99%

“…5,6 OCULAR TRANSDUCTION PROFILES OF LENTIVIRAL VECTORS The transduction properties of HIV-1, (refs 7-24) HIV-2, (ref. 25) SIV, [26][27][28][29] EIAV, 21,[30][31][32][33][34][35] FIV, 24,[36][37][38][39][40][41][42][43] and BIV 44 vectors incorporating a diverse array of envelope pseudotypes and transgene promoters have been evaluated after in vivo and ex vivo delivery in a variety of animal species (Supplementary Tables 1 and 2). Most ocular studies have used vesicular stomatitis virus-G (VSV-G)-pseudotyped vectors incorporating ubiquitous promoters and these are described below unless otherwise stated.…”

Section: Introductionmentioning

confidence: 99%

Ocular gene delivery using lentiviral vectors

Balaggan

Ali²

2011

Substantial advances in our understanding of lentivirus lifecycles and their various constituent proteins have permitted the bioengineering of lentiviral vectors now considered safe enough for clinical trials for both lethal and non-lethal diseases. They possess distinct properties that make them particularly suitable for gene delivery in ophthalmic diseases, including high expression, consistent targeting of various post-mitotic ocular cells in vivo and a paucity of associated intraocular inflammation, all contributing to their ability to mediate efficient and stable intraocular gene transfer. In this review, the intraocular tropisms and therapeutic applications of both primate and non-primate lentiviral vectors, and how the unique features of the eye influence these, are discussed. The feasibility of therapeutic targeting using these vectors in animal models of both anterior and posterior ophthalmic disorders has been established, and has, in combination with substantial progress in enhancing lentiviral vector bio-safety over the past two decades, paved the way for the first human ophthalmic clinical trials using lentivirus-based gene transfer vectors.

“…Photoreceptor cell transduction or transfection by early adenovirus, 11 HIV-based lentiviruses 12,13 or various non-viral methods 3 is relatively inefficient, and the duration of transgene expression limited either by silencing of the transgene promoter 14 or through clearance of transduced cells after immune responses to vector proteins. 15 Further development of these vector systems, for example, by the removal of immunogenic viral genes from the vector genome of adenovirus 16 or the removal of bacterial plasmid sequences in DNA mini-circles in non-viral gene transfer 17 has resulted in significant improvements in longevity of expression.…”

Section: Gene Transfer To Photoreceptor Cellsmentioning

confidence: 99%

Gene supplementation therapy for recessive forms of inherited retinal dystrophies

Smith¹,

Bainbridge²,

Ali³

2011

Over the last decade, gene supplementation therapy for inherited retinal degeneration has come of age. Early proof-of-concept studies in animal models of disease showed modest, but genuine improvements in retinal function and/or survival. Further development of the vectors used for gene transfer to the retina has led to better treatment efficacy in a wide variety of animal models, leading in 2008 to the initiation of three clinical trials for Leber congenital amaurosis caused by retinal pigment epithelium 65 deficiency. The results from these trials suggest that the treatment of inherited retinal dystrophy by gene therapy can be safe and effective. Here, we examine the progress of gene supplementation therapy in the retina, and discuss the potential for using gene therapy to treat different forms of inherited retinal degeneration.