Published at www.nejm.org April 27, 2008 (10.1056/NEJMoa0802315)
Safety and Efficacy of Gene Transfer for Leber's Congenital Amaurosis
Albert M. Maguire, M.D., Francesca Simonelli, M.D., Eric A. Pierce, M.D., Ph.D., Edward N. Pugh, Jr., Ph.D., Federico Mingozzi, Ph.D., Jeannette Bennicelli, Ph.D., Sandro Banfi, M.D., Kathleen A. Marshall, C.O.T., Francesco Testa, M.D., Enrico M. Surace, D.V.M., Settimio Rossi, M.D., Arkady Lyubarsky, Ph.D., Valder R. Arruda, M.D., Barbara Konkle, M.D., Edwin Stone, M.D., Ph.D., Junwei Sun, M.S., Jonathan Jacobs, Ph.D., Lou Dell'Osso, Ph.D., Richard Hertle, M.D., Jian-xing Ma, M.D., Ph.D., T. Michael Redmond, Ph.D., Xiaosong Zhu, M.D., Bernd Hauck, Ph.D., Olga Zelenaia, Ph.D., Kenneth S. Shindler, M.D., Ph.D., Maureen G. Maguire, Ph.D., J. Fraser Wright, Ph.D., Nicholas J. Volpe, M.D., Jennifer Wellman McDonnell, M.S., Alberto Auricchio, M.D., Katherine A. High, M.D., and Jean Bennett, M.D., Ph.D.
Leber's congenital amaurosis (LCA) is a group of inherited blindingdiseases with onset during childhood. One form of the disease,LCA2, is caused by mutations in the retinal pigment epithelium–specific65-kDa protein gene (RPE65). We investigated the safety of subretinaldelivery of a recombinant adeno-associated virus (AAV) carryingRPE65 complementary DNA (cDNA) (ClinicalTrials.gov number, NCT00516477
[ClinicalTrials.gov]
).Three patients with LCA2 had an acceptable local and systemicadverse-event profile after delivery of AAV2.hRPE65v2. Eachpatient had a modest improvement in measures of retinal functionon subjective tests of visual acuity. In one patient, an asymptomaticmacular hole developed, and although the occurrence was consideredto be an adverse event, the patient had some return of retinalfunction. Although the follow-up was very short and normal visionwas not achieved, this study provides the basis for furthergene therapy studies in patients with LCA.
Source Information
From the Scheie Eye Institute, University of Pennsylvania (A.M.M., E.A.P., E.N.P., J. Bennicelli, A.L., K.S.S., M.G.M., N.J.V., J. Bennett), Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia (A.M.M., F.M., K.A.M., V.R.A., J.S., X.Z., B.H., O.Z., J.F.W., J.W.M., K.A.H., J. Bennett), and the University of Pennsylvania School of Medicine (A.M.M., E.A.P., J. Bennicelli, A.L., V.R.A., B.K., K.S.S., M.G.M., J.F.W., N.J.V., K.A.H.) — all in Philadelphia; Seconda Universita degli Studi di Napoli (F.S., F.T., S.R.), Telethon Institute of Genetics and Medicine (F.S., S.B., E.M.S., A.A.), and Federico II University (A.A.) — all in Naples; the University of Iowa Carver Center, College of Medicine, Iowa City (E.S.); Veterans Affairs Medical Center, Cleveland (J.J., L.D.); Children's Hospital of Pittsburgh, Pittsburgh (R.H.); the University of Oklahoma, Oklahoma City (J.M.); the National Eye Institute, Bethesda, MD (T.M.R.); and the Howard Hughes Medical Institute (K.A.H., E.S.). Drs. Maguire, Simonelli, Auricchio, High, and Bennett contributed equally to this article. This article (10.1056/NEJMoa0802315) was published at www.nejm.org on April 27, 2008. It will appear in the May 22 issue of the Journal.
Address reprint requests to Dr. Bennett at the F.M. Kirby Center for Molecular Ophthalmology, 309C Stellar-Chance Labs, 422 Curie Blvd., Philadelphia, PA 19104, or at jebennet{at}mail.med.upenn.edu.
Tan, M. H., Smith, A. J., Pawlyk, B., Xu, X., Liu, X., Bainbridge, J. B., Basche, M., McIntosh, J., Tran, H. V., Nathwani, A., Li, T., Ali, R. R.
(2009). Gene therapy for retinitis pigmentosa and Leber congenital amaurosis caused by defects in AIPL1: effective rescue of mouse models of partial and complete Aipl1 deficiency using AAV2/2 and AAV2/8 vectors. Hum Mol Genet
18: 2099-2114
[Abstract][Full Text]
Maeda, T., Cideciyan, A. V., Maeda, A., Golczak, M., Aleman, T. S., Jacobson, S. G., Palczewski, K.
(2009). Loss of cone photoreceptors caused by chromophore depletion is partially prevented by the artificial chromophore pro-drug, 9-cis-retinyl acetate. Hum Mol Genet
18: 2277-2287
[Abstract][Full Text]
Wilson, J. M.
(2009). A History Lesson for Stem Cells. Science
324: 727-728
[Abstract][Full Text]
Jacobson, S. G., Aleman, T. S., Cideciyan, A. V., Roman, A. J., Sumaroka, A., Windsor, E. A. M., Schwartz, S. B., Heon, E., Stone, E. M.
(2009). Defining the Residual Vision in Leber Congenital Amaurosis Caused by RPE65 Mutations. IOVS
50: 2368-2375
[Abstract][Full Text]
Samardzija, M., Tanimoto, N., Kostic, C., Beck, S., Oberhauser, V., Joly, S., Thiersch, M., Fahl, E., Arsenijevic, Y., von Lintig, J., Wenzel, A., Seeliger, M. W., Grimm, C.
(2009). In conditions of limited chromophore supply rods entrap 11-cis-retinal leading to loss of cone function and cell death. Hum Mol Genet
18: 1266-1275
[Abstract][Full Text]
Jacobson, S. G., Aleman, T. S., Sumaroka, A., Cideciyan, A. V., Roman, A. J., Windsor, E. A. M., Schwartz, S. B., Rehm, H. L., Kimberling, W. J.
(2009). Disease Boundaries in the Retina of Patients with Usher Syndrome Caused by MYO7A Gene Mutations. IOVS
50: 1886-1894
[Abstract][Full Text]
Cideciyan, A. V., Swider, M., Aleman, T. S., Tsybovsky, Y., Schwartz, S. B., Windsor, E. A.M., Roman, A. J., Sumaroka, A., Steinberg, J. D., Jacobson, S. G., Stone, E. M., Palczewski, K.
(2009). ABCA4 disease progression and a proposed strategy for gene therapy. Hum Mol Genet
18: 931-941
[Abstract][Full Text]
Morgan, J. I. W., Dubra, A., Wolfe, R., Merigan, W. H., Williams, D. R.
(2009). In Vivo Autofluorescence Imaging of the Human and Macaque Retinal Pigment Epithelial Cell Mosaic. IOVS
50: 1350-1359
[Abstract][Full Text]
Lorenz, B., Poliakov, E., Schambeck, M., Friedburg, C., Preising, M. N., Redmond, T. M.
(2008). A Comprehensive Clinical and Biochemical Functional Study of a Novel RPE65 Hypomorphic Mutation. IOVS
49: 5235-5242
[Abstract][Full Text]
Jacobson, S. G., Cideciyan, A. V., Aleman, T. S., Sumaroka, A., Windsor, E. A. M., Schwartz, S. B., Heon, E., Stone, E. M.
(2008). Photoreceptor Layer Topography in Children with Leber Congenital Amaurosis Caused by RPE65 Mutations. IOVS
49: 4573-4577
[Abstract][Full Text]
Cideciyan, A. V., Aleman, T. S., Boye, S. L., Schwartz, S. B., Kaushal, S., Roman, A. J., Pang, J.-j., Sumaroka, A., Windsor, E. A. M., Wilson, J. M., Flotte, T. R., Fishman, G. A., Heon, E., Stone, E. M., Byrne, B. J., Jacobson, S. G., Hauswirth, W. W.
(2008). Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics. Proc. Natl. Acad. Sci. USA
105: 15112-15117
[Abstract][Full Text]
Rattner, A., Toulabi, L., Williams, J., Yu, H., Nathans, J.
(2008). The Genomic Response of the Retinal Pigment Epithelium to Light Damage and Retinal Detachment. J. Neurosci.
28: 9880-9889
[Abstract][Full Text]
