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Molecular Therapy
Banin, E., Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Gootwine, E., Agricultural Research Organization, Volcani Center, Bet Dagan, Israel
Obolensky, A., Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Ezra-Elia, R., Koret School of Veterinary Medicine, Hebrew University of Jerusalem, Rehovot, Israel
Ejzenberg, A., Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Zelinger, L., Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Honig, H., Agricultural Research Organization, Volcani Center, Bet Dagan, Israel
Rosov, A., Agricultural Research Organization, Volcani Center, Bet Dagan, Israel
Yamin, E., Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Sharon, D., Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Averbukh, E., Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Hauswirth, W.W., Department of Ophthalmology, University of Florida, Gainesville, FL, United States
Ofri, R., Koret School of Veterinary Medicine, Hebrew University of Jerusalem, Rehovot, Israel
Achromatopsia is a hereditary form of day blindness caused by cone photoreceptor dysfunction. Affected patients suffer from congenital color blindness, photosensitivity, and low visual acuity. Mutations in the CNGA3 gene are a major cause of achromatopsia, and a sheep model of this disease was recently characterized by our group. Here, we report that unilateral subretinal delivery of an adeno-associated virus serotype 5 (AAV5) vector carrying either the mouse or the human intact CNGA3 gene under the control of the red/green opsin promoter results in long-term recovery of visual function in CNGA3-mutant sheep. Treated animals demonstrated shorter maze passage times and a reduced number of collisions with obstacles compared with their pretreatment status, with values close to those of unaffected sheep. This effect was abolished when the treated eye was patched. Electroretinography (ERG) showed marked improvement in cone function. Retinal expression of the transfected human and mouse CNGA3 genes at the mRNA level was shown by polymerase chain reaction (PCR), and cone-specific expression of CNGA3 protein was demonstrated by immunohistochemisrty. The rescue effect has so far been maintained for over 3 years in the first-treated animals, with no obvious ocular or systemic side effects. The results support future application of subretinal AAV5-mediated gene-augmentation therapy in CNGA3 achromatopsia patients. © The American Society of Gene & Cell Therapy.
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תנאי שימוש
Gene Augmentation Therapy Restores Retinal Function and Visual Behavior in a Sheep Model of CNGA3 Achromatopsia
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Banin, E., Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Gootwine, E., Agricultural Research Organization, Volcani Center, Bet Dagan, Israel
Obolensky, A., Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Ezra-Elia, R., Koret School of Veterinary Medicine, Hebrew University of Jerusalem, Rehovot, Israel
Ejzenberg, A., Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Zelinger, L., Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Honig, H., Agricultural Research Organization, Volcani Center, Bet Dagan, Israel
Rosov, A., Agricultural Research Organization, Volcani Center, Bet Dagan, Israel
Yamin, E., Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Sharon, D., Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Averbukh, E., Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Hauswirth, W.W., Department of Ophthalmology, University of Florida, Gainesville, FL, United States
Ofri, R., Koret School of Veterinary Medicine, Hebrew University of Jerusalem, Rehovot, Israel
Gene Augmentation Therapy Restores Retinal Function and Visual Behavior in a Sheep Model of CNGA3 Achromatopsia
Achromatopsia is a hereditary form of day blindness caused by cone photoreceptor dysfunction. Affected patients suffer from congenital color blindness, photosensitivity, and low visual acuity. Mutations in the CNGA3 gene are a major cause of achromatopsia, and a sheep model of this disease was recently characterized by our group. Here, we report that unilateral subretinal delivery of an adeno-associated virus serotype 5 (AAV5) vector carrying either the mouse or the human intact CNGA3 gene under the control of the red/green opsin promoter results in long-term recovery of visual function in CNGA3-mutant sheep. Treated animals demonstrated shorter maze passage times and a reduced number of collisions with obstacles compared with their pretreatment status, with values close to those of unaffected sheep. This effect was abolished when the treated eye was patched. Electroretinography (ERG) showed marked improvement in cone function. Retinal expression of the transfected human and mouse CNGA3 genes at the mRNA level was shown by polymerase chain reaction (PCR), and cone-specific expression of CNGA3 protein was demonstrated by immunohistochemisrty. The rescue effect has so far been maintained for over 3 years in the first-treated animals, with no obvious ocular or systemic side effects. The results support future application of subretinal AAV5-mediated gene-augmentation therapy in CNGA3 achromatopsia patients. © The American Society of Gene & Cell Therapy.
Scientific Publication
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