Safety and Efficacy of Gene Transfer for Leber's Congenital Amaurosis

Scheie Eye Institute, University of Pennsylvania, USA.
New England Journal of Medicine (Impact Factor: 55.87). 06/2008; 358(21):2240-8. DOI: 10.1056/NEJMoa0802315
Source: PubMed


Leber's congenital amaurosis (LCA) is a group of inherited blinding diseases with onset during childhood. One form of the disease, LCA2, is caused by mutations in the retinal pigment epithelium-specific 65-kDa protein gene (RPE65). We investigated the safety of subretinal delivery of a recombinant adeno-associated virus (AAV) carrying RPE65 complementary DNA (cDNA) ( number, NCT00516477 []). Three patients with LCA2 had an acceptable local and systemic adverse-event profile after delivery of AAV2.hRPE65v2. Each patient had a modest improvement in measures of retinal function on subjective tests of visual acuity. In one patient, an asymptomatic macular hole developed, and although the occurrence was considered to be an adverse event, the patient had some return of retinal function. Although the follow-up was very short and normal vision was not achieved, this study provides the basis for further gene therapy studies in patients with LCA.

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Available from: Francesco Testa
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    • "This has led to successful gene therapy in 2008. Restoration of vision in patients with Leber Congenital Amaurosis (LCA) caused by a mutation in a gene coding for the retinal pigment epithelium protein (RPE65), essential for photoreceptor physiological activity (Fig. 1), constitutes the first example of gene therapy in the CNS (Bainbridge et al., 2008; Maguire et al., 2008). Since the first treatment, vision has been restored in one eye of (now approximately) 50 patients by means of a single subretinal injections of adeno-associated viral vectors (AAV), effectively transducing cells of the outer retina and RPE and delivering copies of the normal RPE65 gene (Thompson et al., 2015). "
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    ABSTRACT: Retinal photoreceptors are highly specialized and performing neurons. Their cellular architecture is exquisitely designed to host a high concentration of molecules involved in light capture, phototransduction, electric and chemical signaling, membrane and molecular turnover, light and dark adaption, network activities etc. Such high efficiency and molecular complexity require a great metabolic demand, altogether conferring to photoreceptors particular susceptibility to external and internal insults, whose occurrence usually precipitate into degeneration of these cells and blindness. In Retinitis Pigmentosa, an impressive number of mutations in genes expressed in the retina and coding for a large varieties of proteins leads to the progressive death of photoreceptors and blindness. Recent advances in molecular tools have greatly facilitated the identification of the underlying genetics and molecular bases of RP leading to the successful implementation of gene therapy for some types of mutations, with visual restoration in human patients. Yet, genetic heterogeneity of RP makes mutation-independent approaches highly desirable, although many obstacles pave the way to general strategies for treating this complex disease, which remains orphan. The review will focus on treatments for RP based on pharmacological tools, choosing, among the many ongoing studies, approaches which rely on strong experimental evidence or rationale. For perspective treatments, new concepts are foreseen to emerge from basic studies elucidating the pathways connecting the primary mutations to photoreceptor death, possibly revealing common molecular targets for drug intervention. Copyright © 2015. Published by Elsevier Ltd.
    Full-text · Article · Jun 2015 · Progress in Retinal and Eye Research
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    • "TABLE 1. Registered Clinical Trials of Gene Therapy for Retinal Diseases Disease (Gene) Identifier Vector Name Locations Key Publications LCA2 (RPE65) NCT00481546 rAAV2-CBSB-hRPE65 University of Pennsylvania University of Florida Health Shands Hospital Bainbridge et al., 2008 6 Maguire et al., 2008 7 Cideciyan et al., 2008 8 Hauswirth et al., 2008 9 Simonelli et al., 2010 10 Cideciyan et al., 2013 11 NCT00516477 NCT00999609 NCT01208389 AAV2-hRPE65v2 AAV2-hRPE65v2 AAV2-hRPE65v2 Children's Hospital of Philadelphia, University of Iowa NCT00643747 rAAV 2/2.hRPE65p.hRPE65 Moorfields Eye Hospital NCT00749957 rAAV2-CB-hRPE65 Oregon Health and Science University University of Massachusetts-Worcester NCT00821340 rAAV2-hRPE65 Haddasah Medical Organization NCT01496040 rAAV2/4.hRPE65 "
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    ABSTRACT: Although rare in the general population, retinal dystrophies occupy a central position in current efforts to develop innovative therapies for blinding diseases. This status derives, in part, from the unique biology, accessibility, and function of the retina, as well as from the synergy between molecular discoveries and transformative advances in functional assessment and retinal imaging. The combination of these factors has fueled remarkable progress in the field, while at the same time creating complex challenges for organizing collective efforts aimed at advancing translational research. The present position paper outlines recent progress in gene therapy and cell therapy for this group of disorders, and presents a set of recommendations for addressing the challenges remaining for the coming decade. It is hoped that the formulation of these recommendations will stimulate discussions among researchers, funding agencies, industry, and policy makers that will accelerate the development of safe and effective treatments for retinal dystrophies and related diseases. Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.
    Full-text · Article · Feb 2015 · Investigative Ophthalmology & Visual Science
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    • "Furthermore, in recent years several blinding dystrophies have been linked to genetic aberrations in the retina, such as RPE65-Leber congenital amaurosis (RPE65-LCA), Leber Hereditary Optic Neuropathy (LHON) and X-linked juvenile retinoschisis. The promise of gene therapy was substantiated in different clinical studies in patients suffering from RPE65-LCA [1] [2] [3] [4], which further spurred research on retinal gene therapy. "
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    ABSTRACT: Retinal gene therapy could potentially affect the lives of millions of people suffering from blinding disorders. Yet, one of the major hurdles remains the delivery of therapeutic nucleic acids to the retinal target cells. Due to the different barriers that need to be overcome in case of topical or systemic administration, intravitreal injection is an attractive alternative administration route for large macromolecular therapeutics. Here it is essential that the therapeutics do not aggregate and remain mobile in the vitreous humor in order to reach the retina. In this study, we have evaluated the use of hyaluronic acid (HA) as an electrostatic coating for nonviral polymeric gene nanomedicines, p(CBA-ABOL)/pDNA complexes, to provide them with an anionic hydrophilic surface for improved intravitreal mobility. Uncoated polyplexes had a Z-averaged diameter of 108 nm and a zeta potential of + 29 mV. We evaluated polyplexes coated with HA of different molecular weights (22 kDa, 137 kDa and 2700 kDa) in terms of size, surface charge and complexation efficiency and noticed their zeta potentials became anionic at 4-fold molar excess of HA-monomers compared to cationic monomers, resulting in submicron ternary polyplexes. Next, we used a previously optimized ex vivo model based on excised bovine eyes and fluorescence single particle tracking (fSPT) microscopy to evaluate mobility in intact vitreous humor. It was confirmed that HA-coated polyplexes had good mobility in bovine vitreous humor, similar to polyplexes functionalized with polyethylene glycol (PEG), except for those coated with high molecular weight HA (2700 kDa). However, contrary to PEGylated polyplexes, HA-coated polyplexes were efficiently taken up in vitro in ARPE-19 cells, despite their negative charge, indicating uptake via CD44-receptor mediated endocytosis. Furthermore, the HA-polyplexes were able to induce GFP expression in this in vitro cell line without apparent cytotoxicity, where coating with low molecular weight HA (22 kDa) was shown to induce the highest expression. Taken together our experiments show that HA-coating of nonviral gene complexes is an interesting approach towards retinal gene therapy by intravitreal administration. To our knowledge, this is the first time electrostatic HA-coating of polyplexes with different molecular weights has been evaluated in terms of their suitability for intravitreal delivery of therapeutic nucleic acids towards the retina.
    Full-text · Article · Jan 2015 · Journal of Controlled Release
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