Recombinant adeno-associated viral (AAV) vectors can transduce cells of the CNS, resulting in long-term expression. AAV vector transduction varies depending on the serotype used and the region of the brain injected. AAV serotypes 7, 8, 9, and Rh10 have recently become available, but the transduction capabilities of these serotypes within the CNS have not been determined. We show that AAV 7, 8, 9, and Rh10 vectors expressing cDNA for a lysosomal enzyme transduce neurons, but not astrocytes or oligodendrocytes, in the cortex, striatum, hippocampus, and thalamus. Although all of the vectors contained the same genome, there were markedly different transduction patterns that could be due only to the differences in capsid proteins. The AAV 9 vector was found to undergo vector genome transport to distal neuronal cell bodies via known axonal pathways. This facilitated the distribution of enzyme, resulting in correction of lysosomal storage lesions in regions of a diseased brain that would not be corrected if the genome were not transported.

Gene therapy is emerging as a therapeutic modality for treating disorders of the retina. Photoreceptor cells are the primary cell type affected in many inherited diseases of retinal degeneration. Successfully treating these diseases with gene therapy requires the identification of efficient and safe targeting vectors that can transduce photoreceptor cells. One serotype of adeno-associated virus, AAV2, has been used successfully in clinical trials to treat a form of congenital blindness that requires transduction of the supporting cells of the retina in the retinal pigment epithelium (RPE). Here, we determined the dose required to achieve targeting of AAV2 and AAV8 vectors to photoreceptors in nonhuman primates. Transgene expression in animals injected subretinally with various doses of AAV2 or AAV8 vectors carrying a green fluorescent protein transgene was correlated with surgical, clinical, and immunological observations. Both AAV2 and AAV8 demonstrated efficient transduction of RPE, but AAV8 was markedly better at targeting photoreceptor cells. These preclinical results provide guidance for optimal vector and dose selection in future human gene therapy trials to treat retinal diseases caused by loss of photoreceptors.

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