Acland, G.M. et al. Gene therapy restores vision in a canine model of childhood blindness. Nat. Genet. 28, 92-95

James A. Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.
Nature Genetics (Impact Factor: 29.35). 06/2001; 28(1):92-5. DOI: 10.1038/88327
Source: PubMed


The relationship between the neurosensory photoreceptors and the adjacent retinal pigment epithelium (RPE) controls not only normal retinal function, but also the pathogenesis of hereditary retinal degenerations. The molecular bases for both primary photoreceptor and RPE diseases that cause blindness have been identified. Gene therapy has been used successfully to slow degeneration in rodent models of primary photoreceptor diseases, but efficacy of gene therapy directed at photoreceptors and RPE in a large-animal model of human disease has not been reported. Here we study one of the most clinically severe retinal degenerations, Leber congenital amaurosis (LCA). LCA causes near total blindness in infancy and can result from mutations in RPE65 (LCA, type II; MIM 180069 and 204100). A naturally occurring animal model, the RPE65-/- dog, suffers from early and severe visual impairment similar to that seen in human LCA. We used a recombinant adeno-associated virus (AAV) carrying wild-type RPE65 (AAV-RPE65) to test the efficacy of gene therapy in this model. Our results indicate that visual function was restored in this large animal model of childhood blindness.

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    • "Recent methods, including cell transplantation (Tropepe et al., 2000; MacLaren et al., 2006), gene therapy (Acland et al., 2001), and electronic (Weiland et al., 2005) or biological (Bi et al., 2006; Lagali et al., 2008; Lin et al., 2008; Busskamp et al., 2010) implants , have demonstrated a remarkable potential for sight restoration during retinal degenerations (RD) associated with a loss of photoreceptors. Because all these strategies aim to stimulate remnant retinal circuits in the degenerate retina, it has become imperative to understand how neural circuits remodel in response to photoreceptor death (Marc et al., 2007). "
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    ABSTRACT: Sensory deafferentation resulting from the loss of photoreceptors during retinal degeneration (rd) is often accompanied by a paradoxical increase in spontaneous activity throughout the visual system. Oscillatory discharges are apparent in retinal ganglion cells in several rodent models of rd, indicating that spontaneous activity can originate in the retina. Understanding the biophysical mechanisms underlying spontaneous retinal activity is interesting for two main reasons. First, it could lead to strategies that reduce spontaneous retinal activity, which could improve the performance of vision restoration strategies that aim to stimulate remnant retinal circuits in blind patients. Second, studying emergent network activity could offer general insights into how sensory systems remodel upon deafferentation. Here we provide an overview of the work describing spontaneous activity in the degenerating retina, and outline the current state of knowledge regarding the cellular and biophysical properties underlying spontaneous neural activity.
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    • "Oncogenic risks arise from insertional mutagenesis and a severe immune response to the viral vector has resulted in death [1]. Risks specific to ocular gene transfer include surgical complications, loss of an eye due to inflammation, loss of remaining vision, as well as the very low risk of brain toxicity due to viral vector integration into the optic nerve [6-8,33,60]. A discussion of risks emphasizes the early-stage, experimental nature of the technology, which has historically been associated with risk and uncertainty. "
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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.
    Full-text · Article · Jul 2014 · BMC Medical Ethics
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    • "Natural Mendelian dog mutants have been bred to study diseases such as muscular dystrophy and an early-onset childhood retinal dystrophy that can result from mutation in one of several genes (Leber congenital amaurosis). Both those models have shown significant clinical improvement, with gene therapy addressing the pathological mutations of Dystrophin and RPE65, respectively (Acland et al. 2001; Bainbridge et al. 2008 "
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    Full-text · Article · Jun 2014 · ILAR journal / National Research Council, Institute of Laboratory Animal Resources
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