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Patrick Benoit, Kelly Tenneson, Terence Appelqvist; Nonclinical safety of SAR422459 following subretinal injection in both eyes of monkeys. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4095.
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© ARVO (1962-2015); The Authors (2016-present)
Stargardt Disease (SD) is a bilateral blinding disease. In an ongoing clinical trial of SAR422459, an ABCA4 gene replacement therapy, treatment is given to only the more severely affected eye. We investigated the toxicology and immunogenicity of SAR422459 following subretinal injection in both eyes of rhesus monkeys to support a clinical development involving both eyes of patients for improved benefit.
Two groups of 3 monkeys/sex were given a 100 µL subretinal injection of SAR422459 at 4.7x105 or 1.8x106 TU in the first eye, followed by a similar injection in the second eye, 4-weeks later. A control group received vehicle under the same conditions. Animals were euthanized 4-weeks after the second injection. They were assessed for toxicity based on clinical signs, body weight, food consumption, electrocardiography, complete ophthalmology exams, and histopathology. Serum was taken for immunology throughout the study.
Subretinal administration of SAR422459 to both eyes of monkeys was well tolerated. Specifically, there were no adverse clinical findings and body weight and food consumption were unaffected. Compared to first injected eyes, there was a slight increase in perioperative anterior chamber inflammation of second eyes but the levels recorded were similar to those in control eyes. ERG was unaffected in treated eyes. At histopathology, changes in the second eye included dose-related minimal to moderate mononuclear cell infiltrates in vitreous, retina, anterior uvea, choroid and sclera, and moderate mixed cell infiltrates in vitreous, whereas findings were limited to minimal/mild mononuclear cell infiltrates in vitreous body and retina for the high dose group only in first injected eyes. The differences between eyes were considered likely to be due to the longer recovery time between injection and necropsy for the first eye (8 vs 4 weeks for second eye), rather than an immune response in the second eye. There were no signs of overt toxicity or other changes to the retina, and no relevant histopathological changes in systemic tissues. At immunology, no antibodies to SAR422459 or components were detected.
There was no evidence of an immunogenic reaction following treatment of the second eye with SAR422459 and no increased toxicity at the injection site or elsewhere. These results support the subretinal administration of SAR422459 in both eyes of patients with SD.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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