Ocular gene delivery using lentiviral vectors

Abstract

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.

Gene therapy for retinal ganglion cell neuroprotection in glaucoma

“…For example, introduction of Ad-5 to the superior colliculus or to the transected optic nerve stump results in retrograde transport of viral particles and subsequent gene expression in some RGCs. 28 Subretinal injection of lentiviral vectors results in transgene expression primarily by RPE cells, although other cells, including some photoreceptors, bipolar cells and Müller glia, may occasionally be transduced (see review by Balaggan et al 29 ). Some studies have observed limited transduction of the inner retina when HIV-1 vectors are delivered intravitreally, 8 whereas others have reported some transduction of RGCs following intravitreal injection of HIV-2 vectors.…”

La conception de vecteurs adaptés à la thérapie génique oculaire

“…Les lentivirus (Lv) sont des rétrovirus à ARN ayant une capacité de chargement d'ADN d'environ 8 à 10 kb ; ils s'intègrent dans le génome de l'hôte [14]. Bien qu'aucune transformation maligne n'ait été rapportée dans les yeux de souris en utilisant des titres élevés de lentivirus [14], la question de la mutagenèse insertionnelle continue d'être étudiée par la génération de lentivirus dits « non intégrants » et l'utilisation de lentivirus issus de primates non humains [14].…”

“…Bien qu'aucune transformation maligne n'ait été rapportée dans les yeux de souris en utilisant des titres élevés de lentivirus [14], la question de la mutagenèse insertionnelle continue d'être étudiée par la génération de lentivirus dits « non intégrants » et l'utilisation de lentivirus issus de primates non humains [14]. De nombreuses études montrent que, lorsqu'ils sont injectés par voie sous-rétinienne, les lentivirus transduisent efficacement l'épithélium rétinien pigmentaire chez les rongeurs [15,16], mais la transduction des photorécepteurs reste variable [17,18].…”

Gene Therapy of Inherited Retinopathies: A Long and Successful Road from Viral Vectors to Patients

“…Many studies over the past years have provided evidence of the higher efficiency of viral versus nonviral vehicles (Andrieu-Soler et al, 2006) for retinal gene delivery; however, recent reports on nanoparticle-mediated retinal gene therapy showed an improvement compared with previous studies with nonviral agents (Cai et al, 2008). The vectors most studied and used for retinal gene transfer are those derived from adenoviruses (Kumar-Singh, 2008), lentiviruses (Balaggan and Ali, 2012), and adeno-associated viruses (Vandenberghe and Auricchio, 2012) which are capable of infecting and transducing nondividing cells such as PRs and RPE.…”

“…LVs are integrating RNA retroviruses with a cargo capacity of about 8-10 kb (Balaggan and Ali, 2012). LVs are deleted of all viral genes and, thus, do not activate the immune system (Bennett, The PR OS is formed by an elaborate system of stacked membranous discs that contain the photosensitive opsin proteins.…”