05:08pm Wednesday 01 April 2020

Shining a Light with Gene Therapy: Repeat Gene Therapy Proved Safe and Resulted in Improved Vision in Small Study

BOSTON   – Gene therapy has great potential for treating certain diseases, such as Leber congenital amaurosis, by providing therapeutic genes to target cells. Administration of a gene therapy vector carrying the RPE65 gene to one eye in each of 12 patients with congenital blindness due to RPE65 mutations led to improvements in retinal and visual function and proved to be a safe and stable procedure. In this follow-up study, published in the Feb. 8 issue of Science Translational Medicine, the same group of  researchers, including Eric A. Pierce, M.D., Ph.D., director of the Ocular Genomics Institute at Mass. Eye and Ear, set out to discover if it was possible to safely administer the vector and therapeutic transgene to the other eye of these patients. 
The lead authors of this new paper are Jean Bennett, M.D., Ph.D., and Albert Maguire, M.D.,  both of the F.M. Kirby Center of Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania and the Center for Cellular and Molecular Therapeutics at the Children’s Hospital of Philadelphia; Kathy High, M.D., Center for Cellular and Molecular Therapeutics at the Children’s Hospital of Philadelphia; and Manzar Ashtari, Ph.D., Department of Radiology, The Children’s Hospital of Philadelphia.
The authors described the study in the summary abstract:  
A big concern was whether the first gene therapy injection might have primed the patients’ immune system to respond to the adeno-associated virus (AVV) vector or the product of the transgene that it had delivered.
To test the safety and efficacy of a second administration of gene therapy to the second eye, the authors demonstrated that readmission was both safe and effective in animal models. Then they selected three of the original 12 patients and readmininstered the AVV vector and its RPE65 transgene to the contralateral eye. They assessed safety by  evaluating  inflammatory responses, immune reactions and extraocular exposure to the AVV vector. Efficacy was assessed through qualitative and quantitative measures of retinal and visual function including the ability to read letters, the extent of side vision, light sensitivity, the pupillary light reflex, the ability to navigate in dim light and evidenced from neuroimaging studies of cortical activation, which demonstrated that signals from the retina were recognized by the brain.
The researchers did not discover any safety concerns and did not identify immune responses to the vector or transgene product. Before and after comparisons of psychophysical data and cortical responses provided the authors with evidence that gene therapy readministration was effective and mediated improvements in retinal and visual function in the three patients. The researchers report that the lack of immune response and the robust safety profile in this readministration gene therapy study may be due in part to the immune-privileged nature of the eye, and the low dose and very pure preparation of the AVV vector.
Funding sources: Center for Cellular and Melecular Therapeutics at CHOP, Foundation Fighting Blindness-sponsored CHOP-PENN Pediatric Center for Retinal Degenerations; Clinical Translation Science Award NIH/National Center for Research Resources UL1-RR-02134, 1R21EY020662, and 1RO1EY019014-01A2; Transdisciplinary Award Program in Translational Medicine and Therapeutics (TAPITMAT) from University of Pennsylvania; Research to Prevent Blindness; Hope for Vision; Howard Hughes Medical Institute; Paul and Evanina Mackall Foundation for Trust at Scheie Eye Institute; anonymous donors; Italian Telethon Foundation; and F.M. Kirby Foundation.
About Mass. Eye and Ear: Founded in 1824, Massachusetts Eye and Ear Infirmary is an independent specialty hospital providing patient care for disorders of the eye, ear, nose, throat, head and neck. Mass. Eye and Ear is an international leader in Ophthalmology and Otolaryngology research and a teaching partner of Harvard Medical School. In June 2010, the Massachusetts Eye and Ear Infirmary and Schepens Eye Research Institute united to form the world’s largest and most robust private basic and clinical ophthalmology research enterprise. For more information about Mass. Eye and Ear, call 617-523-7900 or visit www.MassEyeAndEar.org
Contact:  Mary Leach, 617-573-4170

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