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Martha Neuringer, Carol Hanna, Samuel Peterson, Betsy Ferguson, Norma Schroeder, Lauren Renner; Early Phenotype in a Nonhuman Primate Model of Bardet-Biedl Syndrome. Invest. Ophthalmol. Vis. Sci. 2021;62(8):2255.
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Bardet-Biedl syndrome (BBS), a syndromic form of retinitis pigmentosa, is a rare autosomal recessive ciliopathy linked to mutations in over 20 BBS genes. It is characterized by rod-cone degeneration in conjunction with renal dysfunction, polydactyly, obesity, hypogonadism and/or intellectual disability. We recently identified and characterized a pedigree of rhesus monkeys with a spontaneous mutation in BBS7. Three affected homozygotes showed severe degeneration of the macular retina by 3-4 years of age, and one developed kidney failure by 6 years of age (Peterson et al., Exp Eye Res 189, 2019, 1078252). We are now beginning to define the development of the retinal degeneration phenotype from birth.
Ova and sperm were collected from BBS7 carriers to produce embryos by intracytoplasmic sperm injection. Trophectoderm biopsies were sequenced to select BBS7-/- embryos, which were transferred to surrogate dams. A live infant was confirmed to be homozygous for the BBS7 mutation and was assessed by multimodal retinal imaging at 4, 8,16 and 24 weeks of age, by electroretinography (ERG) at 6, 12 and 24 weeks, and by preferential looking measures of visual acuity at 2, 4, 8, 12 and 16 weeks.
At the first retinal imaging session at 4 weeks of age, the EZ line was severely attenuated. Segmentation of OCT images from 4 - 24 weeks of age showed that thicknesses of the total retina and outer segment layers were well below the normal range as determined in 8 age-matched normal rhesus monkey infants, while the inner retinal layers were within or close to the normal range. At 6 - 24 weeks, photopic and scotopic electroretinograms were substantially reduced in amplitude and delayed. Visual acuity was half of normal values at all ages, compared with longitudinal values for 22 normal infants.
The first examination of an infant rhesus monkey with BBS7 showed evidence of retinal thinning and dysfunction as early as 4 weeks of age. The rapid onset of degenerative changes in this model will make it particularly valuable for preclinical studies of therapies for vision preservation or restoration. This is the first nonhuman primate model of retinitis pigmentosa with a known genetic cause, and its propagation will provide the foundation for future studies of cell replacement approaches to treatment for this family of blinding disorders.
This is a 2021 ARVO Annual Meeting abstract.
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