Research ArticleGene Therapy

Dosage Thresholds for AAV2 and AAV8 Photoreceptor Gene Therapy in Monkey

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Science Translational Medicine  22 Jun 2011:
Vol. 3, Issue 88, pp. 88ra54
DOI: 10.1126/scitranslmed.3002103

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Gene Therapy Shines Light on Darkness

Using gene therapy to treat diseases of retinal degeneration is feasible because the human eye is compact, easy to access, and is an immune-privileged site. Phase I and II clinical trials using an adeno-associated virus serotype 2 (AAV2) viral vector to deliver a gene encoding RPE65 to retinal pigment epithelium (RPE) in children with congenital blindness due to Leber congenital amaurosis disease have shown the feasibility of using gene therapy to restore retinal function and partial vision. Other diseases of retinal degeneration are caused primarily by loss of the rod and cone photoreceptor cells rather than degeneration of RPE. Photoreceptor cells are more difficult to target with a vector carrying a therapeutic gene. As a first step toward using gene therapy to treat diseases caused by degeneration of photoreceptors, Vandenberghe et al. experiment with the dose of two AAV vectors (AAV2 and AAV8) in a nonhuman primate model.

The researchers injected either AAV2 or AAV8 vectors subretinally in cynomolgus macaques across a range of doses (from 108 to 1011 genome copies). The vectors carried a transgene encoding green fluorescent protein (GFP), and the researchers used this marker to discern at which dose both RPE and photoreceptor cells could be transduced with the vector and express GFP. After injection, the monkeys were examined for any retinal damage due to surgery and for any immune response to the vector or to GFP. Both vector serotypes were efficient at transducing RPE, but AAV8 was also able to transduce photoreceptor cells (primarily rods but also some cones); AAV2 could only transduce photoreceptor cells at the highest dose. With respect to an immune response, anti–vector-neutralizing antibodies and a T cell response directed at GFP were detected at the highest doses of AAV2 and AAV8 leading to retinal inflammation and thinning. Thus, the authors conclude that using AAV8 at intermediate doses will be the best approach for using gene therapy to transduce photoreceptor cells with a therapeutic gene. These preclinical studies pave the way toward using gene therapy to treat a variety of retinal degeneration diseases caused by loss of photoreceptor cells.


  • * Present address: F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.

  • Present address: Princeton University, Princeton, NJ 08155, USA.

  • Citation: L. H. Vandenberghe, P. Bell, A. M. Maguire, C. N. Cearley, R. Xiao, R. Calcedo, L. Wang, M. J. Castle, A. C. Maguire, R. Grant, J. H. Wolfe, J. M. Wilson, J. Bennett, Dosage Thresholds for AAV2 and AAV8 Photoreceptor Gene Therapy in Monkey. Sci. Transl. Med. 3, 88ra54 (2011).

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