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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    • "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.
    BMC Medical Ethics 07/2014; 15(1):58. DOI:10.1186/1472-6939-15-58 · 1.50 Impact Factor
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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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    ABSTRACT: Here, we briefly review the state of knowledge of human cancer genetics to elaborate on the need for different types of mammalian models, highlighting the strengths of the dog. Mouse models are unparalleled for their experimental tractability and rapid genetic manipulation but have some key limitations in the area of human relevance. Companion dog models are attractive, because they are genetically more similar to humans, share environmental exposures with their owners, suffer from the same diseases as humans, and receive a high level of health care. They are ideal for the study of chronic diseases, because they age five to eight times faster than humans and generally live to old age. In addition, each dog breed is on the order of 100-fold genetically simpler than the whole human or dog population. These traits make the dog ideal for the study of complex genetics of naturally occurring cancers. Here, we contrast the relative strengths of cancer genetics in humans and dogs. We propose that humans are most ideal for the study of somatic cancer genetics, whereas dogs are most ideal for germline genetics. That proposition is supported by comparison of genome-wide association studies (GWASs) in human and canine cancer. One of the advantages of dog cancer GWASs is the ability to rapidly map complex traits, conduct fine mapping and identification of causative variation, and thus be in a position to move on to functional studies. We mention how these strengths of dog models will lead to rapid advances in translational medicine.
    ILAR journal / National Research Council, Institute of Laboratory Animal Resources 06/2014; 55(1):16-45. DOI:10.1093/ilar/ilu010 · 2.39 Impact Factor
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    • "A sobering aspect of this otherwise exciting progress is the extremely slow pace of moving these therapies from a ‘proof of concept’ stage in animals to a fully approved treatment that is available to anyone who needs it. For example, convincing efficacy of RPE65 gene replacement was demonstrated in dogs in 2001 (52), and 13 years later, fewer than 100 patients have been treated world-wide and the phase 3 clinical trial is still underway. This raises the possibility that some diseases might be so rare in the population that it is not economically possible to bring a treatment through the regulatory gauntlet and into clinical availability. "
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    ABSTRACT: Vision is the most important human sense. It facilitates every major activity of daily living ranging from basic communication, mobility and independence to an appreciation of art and nature. Heritable diseases of the retina, such as age-related macular degeneration and retinitis pigmentosa, are the leading cause of blindness in the developed world, collectively affecting as many as one-third of all people over the age of 75, to some degree. For decades, scientists have dreamed of preventing vision loss or of restoring the vision of patients affected with retinal degeneration through some type of drug, gene or cell-based transplantation approach. In this review, we will discuss the current literature pertaining to retinal transplantation. We will focus on the use of induced pluripotent stem cells for interrogation of disease pathophysiology, analysis of drug and gene therapeutics and as a source of autologous cells for cell replacement.
    Human Molecular Genetics 03/2014; 23(R1). DOI:10.1093/hmg/ddu124 · 6.39 Impact Factor
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