Jacobson, SG, Aleman, TS, Cideciyan, AV, Sumaroka, A, Schwartz, SB, Windsor, EA et al.. Identifying photoreceptors in blind eyes caused by RPE65 mutations: Prerequisite for human gene therapy success. Proc Natl Acad Sci USA 102: 6177-6182

Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 05/2005; 102(17):6177-82. DOI: 10.1073/pnas.0500646102
Source: PubMed


Mutations in RPE65, a gene essential to normal operation of the visual (retinoid) cycle, cause the childhood blindness known as Leber congenital amaurosis (LCA). Retinal gene therapy restores vision to blind canine and murine models of LCA. Gene therapy in blind humans with LCA from RPE65 mutations may also have potential for success but only if the retinal photoreceptor layer is intact, as in the early-disease stage-treated animals. Here, we use high-resolution in vivo microscopy to quantify photoreceptor layer thickness in the human disease to define the relationship of retinal structure to vision and determine the potential for gene therapy success. The normally cone photoreceptor-rich central retina and rod-rich regions were studied. Despite severely reduced cone vision, many RPE65-mutant retinas had near-normal central microstructure. Absent rod vision was associated with a detectable but thinned photoreceptor layer. We asked whether abnormally thinned RPE65-mutant retina with photoreceptor loss would respond to treatment. Gene therapy in Rpe65(-/-) mice at advanced-disease stages, a more faithful mimic of the humans we studied, showed success but only in animals with better-preserved photoreceptor structure. The results indicate that identifying and then targeting retinal locations with retained photoreceptors will be a prerequisite for successful gene therapy in humans with RPE65 mutations and in other retinal degenerative disorders now moving from proof-of-concept studies toward clinical trials.

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Available from: Artur Cideciyan, Oct 04, 2015
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    • "With respect to ocular gene transfer, however, the hope for a cure may be misplaced. Jacobson et al. [64] demonstrated that while vision loss can be halted and even improved by restoring function of dormant but otherwise viable photoreceptors, a cure is not theoretically afforded by gene transfer. This is because gene transfer is non-regenerative, and therefore cannot revive degenerated photoreceptors [64]. "
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    ABSTRACT: Background Ocular gene transfer clinical trials are raising hopes for blindness treatments and attracting media attention. News media provide an accessible health information source for patients and the public, but are often criticized for overemphasizing benefits and underplaying risks of novel biomedical interventions. Overly optimistic portrayals of unproven interventions may influence public and patient expectations; the latter may cause patients to downplay risks and over-emphasize benefits, with implications for informed consent for clinical trials. We analyze the news media communications landscape about ocular gene transfer and make recommendations for improving communications between clinicians and potential trial participants in light of media coverage. Methods We analyzed leading newspaper articles about ocular gene transfer (1990-2012) from United States (n = 55), Canada (n = 26), and United Kingdom (n = 77) from Factiva and Canadian Newsstand databases using pre-defined coding categories. We evaluated the content of newspaper articles about ocular gene transfer for hereditary retinopathies, exploring representations of framing techniques, research design, risks/benefits, and translational timelines. Results The dominant frame in 61% of stories was a celebration of progress, followed by human-interest in 30% of stories. Missing from the positive frames were explanations of research design; articles conflated clinical research with treatment. Conflicts-of-interest and funding sources were similarly omitted. Attention was directed to the benefits of gene transfer, while risks were only reported in 43% of articles. A range of visual outcomes was described from slowing vision loss to cure, but the latter was the most frequently represented even though it is clinically infeasible. Despite the prominence of visual benefit portrayals, 87% of the articles failed to provide timelines for the commencement of clinical trials or for clinical implementation. Conclusions Our analysis confirms that despite many initiatives to improve media communications about experimental biotechnologies, media coverage remains overly optimistic and omits important information. In light of these findings, our recommendations focus on the need for clinicians account for media coverage in their communications with patients, especially in the context of clinical trial enrolment. The development of evidence-based communication strategies will facilitate informed consent and promote the ethical translation of this biotechnology.
    BMC Medical Ethics 07/2014; 15(1):58. DOI:10.1186/1472-6939-15-58 · 1.50 Impact Factor
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    • "The structural integrity of the patient’s retina and locus of existing vision must be considered. Evidence suggests GUCY2D-LCA1 is unlike any form of LCA studied in detail to date (Jacobson et al., 1998, 2003, 2005, 2007a,b, 2009b, 2011; Cideciyan et al., 2007). Their hallmark retinal preservation suggests that LCA1 patients may be good candidates for subretinal injection of AAV-GUCY2D (Simonelli et al., 2007; Pasadhika et al., 2010; Jacobson et al., 2013). "
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    ABSTRACT: Vertebrate species possess two retinal guanylate cyclases (retGC1 and retGC2) and at least two guanylate cyclase activating proteins (GCAPs), GCAP1 and GCAP2. GCAPs function as Ca(2+) sensors that regulate the activity of guanylate cyclases. Together, these proteins regulate cGMP and Ca(2+) levels within the outer segments of rod and cone photoreceptors. Mutations in GUCY2D, the gene that encodes retGC1, are a leading cause of the most severe form of early onset retinal dystrophy, Leber congenital amaurosis (LCA1). These mutations, which reduce or abolish the ability of retGC1 to replenish cGMP in photoreceptors, are thought to lead to the biochemical equivalent of chronic light exposure in these cells. In spite of this, the majority of LCA1 patients retain normal photoreceptor laminar architecture aside from foveal cone outer segment abnormalities, suggesting they may be good candidates for gene replacement therapy. Work began in the 1980s to characterize multiple animal models of retGC1 deficiency. 34 years later, all models have been used in proof of concept gene replacement studies toward the goal of developing a therapy to treat GUCY2D-LCA1. Here we use the results of these studies as well as those of recent clinical studies to address specific questions relating to clinical application of a gene therapy for treatment of LCA1.
    Frontiers in Molecular Neuroscience 05/2014; 7:43. DOI:10.3389/fnmol.2014.00043 · 4.08 Impact Factor
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    • "A few molecular forms of LCA, however, have unexpectedly shown retained outer retinal structure, indicating structure-function dissociation. For example, the form of LCA associated with RPE65 (retinal pigment epithelium-specific-65-kDa) gene mutations can have retained photoreceptors [4] and treating regions with residual retinal pigment epithelium (and photoreceptors) with viral-mediated gene augmentation has led to remarkable increases in vision. The road to clinical trials of RPE65-LCA was paved by critical proof-of-concept research with large and small animal models of the human disease [5]. "
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    ABSTRACT: Mutations in the CEP290 (cilia-centrosomal protein 290 kDa) gene in Leber congenital amaurosis (LCA) cause early onset visual loss but retained cone photoreceptors in the fovea, which is the potential therapeutic target. A cone-only mouse model carrying a Cep290 gene mutation, rd16;Nrl-/-, was engineered to mimic the human disease. In the current study, we determined the natural history of retinal structure and function in this murine model to permit design of pre-clinical proof-of-concept studies and allow progress to be made toward human therapy. Analyses of retinal structure and visual function in CEP290-LCA patients were also performed for comparison with the results in the model. Rd16;Nrl-/- mice were studied in the first 90 days of life with optical coherence tomography (OCT), electroretinography (ERG), retinal histopathology and immunocytochemistry. Structure and function data from a cohort of patients with CEP290-LCA (n = 15; ages 7-48) were compared with those of the model. CEP290-LCA patients retain a central island of photoreceptors with normal thickness at the fovea (despite severe visual loss); the extent of this island declined slowly with age. The rd16;Nrl-/- model also showed a relatively slow photoreceptor layer decline in thickness with ∼80% remaining at 3 months. The number of pseudorosettes also became reduced. By comparison to single mutant Nrl-/- mice, UV- and M-cone ERGs of rd16;Nrl-/- were at least 1 log unit reduced at 1 month of age and declined further over the 3 months of monitoring. Expression of GNAT2 and S-opsin also decreased with age. The natural history of early loss of photoreceptor function with retained cone cell nuclei is common to both CEP290-LCA patients and the rd16;Nrl-/- murine model. Pre-clinical proof-of-concept studies for uniocular therapies would seem most appropriate to begin with intervention at P35-40 and re-study after one month by assaying interocular difference in the UV-cone ERG.
    PLoS ONE 03/2014; 9(3):e92928. DOI:10.1371/journal.pone.0092928 · 3.23 Impact Factor
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