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.

43 Reads
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    Progress in Retinal and Eye Research 06/2015; 48. DOI:10.1016/j.preteyeres.2015.06.005 · 8.73 Impact Factor
  • Source
    • "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 "
    [Show abstract] [Hide abstract]
    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.
    Investigative Ophthalmology &amp Visual Science 02/2015; 56(2):918-31. DOI:10.1167/iovs.14-16049 · 3.40 Impact Factor
  • Source
    • "The great advances in ocular gene therapy in the past decade can be attributed to the use of AAV vectors. As such AAV vectors have been prominently used in the most recent gene therapy clinical trials, especially in retinal disease, that have shown overwhelming safety and in some trials, efficacy [3] [4] [6]. The main limitation of this virus considering ocular applications is its limited packaging capacity (less than "
    [Show abstract] [Hide abstract]
    ABSTRACT: Gene transfer efficiency and expression stability are key factors to a successful gene therapy approach. In the present work we have developed a combined system for gene transfer that integrates well established non-viral polymeric vectors based on chitosan particles with the properties of phiC31-integrase that promotes a relatively non-immunogenic, site-specific integration, with sustained gene expression. Simultaneously, to overcome one of the major limitations in adeno-associated virus mediated gene transfer – the delivery of large genes – we have tested the capacity of our non-viral vectors to incorporate a large (8 Kb) transgene. Polyplexes were extensively characterized for their size, surface charge, morphology, pDNA complexation, transfection efficiency and transgene expression in vitro using HEK293 cells. Co-transfection with integrase was done by complexation in a single polyplex preparation or the use of two separate polyplex preparations. Transgene expression, GFP and CEP290 (1 Kb and 8 Kb, respectively), was evaluated by fluorescence microscopy, flow cytometry and Western blot analysis. DNA complexation efficiency, particle size and morphology were consistent with gene delivery for all formulations. In contrast, transfection efficiency and transgene expression varied with polymer and polyplex size. Following delivery by chitosan polyplexes, high levels of GFP expression were still visible 16 weeks post-transfection and over-expression of the large transgene was detected at least 6 weeks post-transfection. Polyplexes incorporating phiC1 integrase demonstrate prolonged gene expression of both small (GFP, 1 Kb) and large genes (CEP290, 8 Kb). This approach, using a combined strategy of polymers and integrase may overcome the size limitation found in commonly used adeno-associated virus mediated gene transfer techniques, while maintaining a high safety profile and prolonged, sustained gene expression, thus constituting an alternative for gene delivery.
    Acta Biomaterialia 01/2015; 17. DOI:10.1016/j.actbio.2015.01.013 · 6.03 Impact Factor
Show more

Similar Publications

Full-text (3 Sources)

43 Reads
Available from
Jun 6, 2014