Research ArticlesRetinal Disease

Safety and Efficacy of Subretinal Readministration of a Viral Vector in Large Animals to Treat Congenital Blindness

Science Translational Medicine  03 Mar 2010:
Vol. 2, Issue 21, pp. 21ra16
DOI: 10.1126/scitranslmed.3000659

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Both Sides Now

Blind and deaf from birth, Helen Keller—whose life is the subject of the drama The Miracle Worker—once remarked that “the world is full of suffering; it is also full of overcoming.” Ms. Keller knew something about rising above one’s circumstances—despite her dual disability, she became a renowned author, activist, and lecturer. Last year, through a ground-breaking clinical trial, a research team from The Children’s Hospital of Philadelphia (CHOP) and the University of Pennsylvania helped a group of children to overcome their near-complete blindness by a different route—a gene therapy regimen that replaced a mutated gene and partially restored visual function in one eye of all 12 patients. Now, this same team of researchers has taken an essential step toward the ability to offer these patients the same sight-restoring treatment for their second eyes.

These trial participants had all inherited a specific type of Leber’s congenital amaurosis (LCA), a class of progressive retinal degenerative conditions that can be detected in infancy and results in complete blindness by the age of 40. The loss of photosensitive retinal cells characteristic of this class of diseases stems from mutations in one of 14 genes. The LCA-RPE65 patients in the CHOP trial all had aberrant copies of the RPE65 gene, which encodes an enzyme in the retinal pigment epithelium whose function is a crucial component of the visual cycle. Therefore, surgeons delivered a wild-type copy of RPE65 housed in an adeno-associated virus vector (AAV2-hRPE65v2) into one of the eyes of each of these trial subjects. As one might imagine, the sight-restoring success of this gene therapy trial has patients clamoring for more—more treatment, that is, of their second eyes. But first, researchers needed to assess whether a second treatment would be safe and effective. Specifically, scientists investigated whether subjects who developed neutralizing antibodies (NAbs) directed against the AAV vector used in the first round of gene therapy would benefit from a second round or whether the anti-AAV NAbs would impede gene transfer.

This week’s issue of Science Translational Medicine reports the results of Amado et al. on the immunological and functional consequences of serial subretinal readministration of the RPE65-carrying AAV vector. The authors performed their studies in two large animal models—a canine model of LCA-RPE65 and nonhuman primates without eye disease. Both animals sport eyes similar in size to those of humans, and all primates have macula, a specialized region of the retina responsible for central vision. Also, because nonhuman primates can be infected with wild-type AAV and develop antibodies to viral components, these animals likely give researchers a window into the human immune response that manifests upon vector injection. The authors show that the readministration treatment is safe and effective in both models, even in animals that display preexisting immunity to the vector. These results suggest that a patient who has undergone AAV2-hRPE65v2—mediated gene therapy in one eye may indeed enjoy success from a second surgery. Furthermore, scientists had routinely excluded from clinical trials patients who already carried NAbs to AAVs in their sera. And, as Amado et al. also show, this crowd encompasses a substantial portion of the human population, a number that increases with age. Now, LCA-RPE65 patients with antibodies to AAV may be eligible for gene therapy. This study thus represents an essential step in the further translation of gene therapy for LCA—and a reason for celebration in the gene therapy research community.


  • * These authors contributed equally to this work.

  • Citation: D. Amado, F. Mingozzi, D. Hui, J. L. Bennicelli, Z. Wei, Y. Chen, E. Bote, R. L. Grant, J. A. Golden, K. Narfstrom, N. A. Syed, S. E. Orlin, K. A. High, A. M. Maguire, J. Bennett, Safety and efficacy of subretinal readministration of a viral vector in large animals to treat congenital blindness. Sci. Transl. Med. 2, 21ra16 (2010).