Article

Adeno-associated virus-vectored gene therapy for retinal disease

Department of Ophthalmology, Powell Gene Therapy Center, University of Florida, Gainesville, FL 32610, USA.
Human Gene Therapy (Impact Factor: 3.62). 07/2005; 16(6):649-63. DOI: 10.1089/hum.2005.16.649
Source: PubMed

ABSTRACT Recombinant adeno-associated viral (AAV) vectors have become powerful gene delivery tools for the treatment of retinal degeneration in a variety of animal models that mimic corresponding human diseases. AAV vectors possess a number of features that render them ideally suited for retinal gene therapy, including a lack of pathogenicity, minimal immunogenicity, and the ability to transduce postmitotic cells in a stable and efficient manner. In the sheltered environment of the retina, AAV vectors are able to maintain high levels of transgene expression in the retinal pigmented epithelium (RPE), photoreceptors, or ganglion cells for long periods of time after a single treatment. Each cell type can be specifically targeted by choosing the appropriate combination of AAV serotype, promoter, and intraocular injection site. The focus of this review is on examples of AAV-mediated gene therapy in those animal models of inherited retinal degeneration caused by mutations directly affecting the interacting unit formed by photoreceptors and the RPE. In each case discussed, expression of the therapeutic gene resulted in significant recovery of retinal structure and/or visual function. Because of the key role of the vasculature in maintaining a healthy retina, a summary of AAV gene therapy applications in animal models of retinal neovascular diseases is also included.

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    • "Here we show for the first time that p300 can promote neurite outgrowth in retinal ganglion cells, supporting the neuronal intrinsic effect of p300 in axonal regeneration. We used adenoviral infection to achieve p300 overexpression due to the large size of p300 ($8 kb), which is too large for other viral vectors such as adeno-associated virus (maximum insert size 55 kb) that have become the gold standard for retinal ganglion cell infection in vivo in recent years (Dinculescu et al., 2005). However, adenoviruses have been extensively used to infect both non-neuronal and neuronal cells in the eye, both via intravitreal (Jomary et al., 1994; Li et al., 1994; Weise et al., 2000; Zhang et al., 2008) or axonal retrograde injection (Cayouette and Gravel, 1996; Isenmann et al., 2001), and our findings suggest that our adenovirus is able to infect primary neurons at very high efficiency in culture and at a lower efficiency in vivo. "
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    ABSTRACT: Axonal regeneration and related functional recovery following axonal injury in the adult central nervous system are extremely limited, due to a lack of neuronal intrinsic competence and the presence of extrinsic inhibitory signals. As opposed to what occurs during nervous system development, a weak proregenerative gene expression programme contributes to the limited intrinsic capacity of adult injured central nervous system axons to regenerate. Here we show, in an optic nerve crush model of axonal injury, that adenoviral (cytomegalovirus promoter) overexpression of the acetyltransferase p300, which is regulated during retinal ganglion cell maturation and repressed in the adult, can promote axonal regeneration of the optic nerve beyond 0.5 mm. p300 acetylates histone H3 and the proregenerative transcription factors p53 and CCAAT-enhancer binding proteins in retinal ganglia cells. In addition, it directly occupies and acetylates the promoters of the growth-associated protein-43, coronin 1 b and Sprr1a and drives the gene expression programme of several regeneration-associated genes. On the contrary, overall increase in cellular acetylation using the histone deacetylase inhibitor trichostatin A, enhances retinal ganglion cell survival but not axonal regeneration after optic nerve crush. Therefore, p300 targets both the epigenome and transcription to unlock a post-injury silent gene expression programme that would support axonal regeneration.
    Brain 07/2011; 134(Pt 7):2134-48. DOI:10.1093/brain/awr142 · 10.23 Impact Factor
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    • "AAV1 through 9 vectors have been tested for their transduction properties in the retinas of rodents and primates (Auricchio et al., 2001; Lebherz et al., 2008; Rabinowitz et al., 2002; Yang et al., 2002). AAV2 and AAV5 have been used extensively in the retina and have proven effective for gene delivery to photoreceptors, retinal pigment epithelium cells (RPE) and ganglion cells (Allocca et al., 2006; Dinculescu et al., 2005). AAVrh8 and AAVrh10 are two additional AAV capsids isolated from rhesus monkey (Gao et al., 2003), and recombinant vectors using these capsids have yet to be tested in retina. "
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    Experimental Eye Research 11/2010; 91(5):652-9. DOI:10.1016/j.exer.2010.08.011 · 3.02 Impact Factor
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    • "This has greatly added in the development of gene therapies for different kinds of inherited human diseases. Gene therapy for retinal diseases is particularly attractive due to intrinsic features of the retina that lend themselves to gene mediated therapies; specifically, isolated anatomical structure and immunological privilege (Bainbridge et al., 2006; Dinculescu et al., 2005). Though there are several ways to transfect the target ocular tissues and cells with genes, viral vectors, especially the utilizing recombinant adenoassociate virus (rAAV), have become widely used. "
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    Experimental Eye Research 02/2010; 90(5):546-54. DOI:10.1016/j.exer.2010.01.011 · 3.02 Impact Factor
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