Spontaneous Polygenetic AMD Preclinical Models Selected from the BXD Family of Mice

Abstract

Purpose : Modeling of complex, polygenetic and environmentally-modulated diseases such as age-related macular degeneration (AMD) presents the need for a nuanced approach to accurately mimic the disease that is found in humans. To tackle this problem, we mined the BXD family of recombinant inbred lines of mice for polygenetic models of AMD using a systems genetics approach. Our goal is to provide the vision community with one or more spontaneous polygenetic pre-clinical models of AMD.

Methods : Based on the literature, we identified 27 genes associated with human AMD, 11 of which have polymorphisms in the BXD family of mice that are predicted to change the function of the gene product in a similar manner to that predicted in humans. We chose 6 strains of mice with various combinations of the 11 genes with the goal of selecting mice with various presentations of AMD. BXD strains and C57B/6J controls are being aged from 6 to 18 months and are evaluated clinically every three months. Optical coherence tomography (OCT), full field electroretinogram (ERG), funduscopy/fluorescein angiography (FA) and optokinetic nystagmus (OKN) measurements are used to document any pathophysiology. Histological and ultrastructural analyses are being performed upon euthanasia at 18 months.

Results : Here we present preliminary data from our two most promising polygenetic AMD mouse strains. BXD34 presents with functional deficits documented as lessened ERG amplitudes along with reductions in visual acuity and contrast senstitivity by 9 months of age. Subretinal deposits are evident by OCT analyses and ultrastructural analyses reveals marked basal linear and basal laminar deposits. Moreover, there are numerous vesicles filled with debris present in the cytoplasm of the retinal pigment epithelium (RPE). In contrast, BXD38 presents with no functional deficits up to 9 months of age despite the presence of subretinal deposits that were detected using OCT. These strains are continuing to be aged and phenotyped.

Conclusions : Currently, BXD34 exhibits the most similarities to an atrophic AMD-like phenotype by exhibiting drusen-like deposits and both anatomical and physiological declines in retinal health. BXD38 presents with more mild functional deficits coupled with the presence of subretinal deposits. These strains are continuing to be evaluated up to 18 months of age at which time ultrastructural and immunohistochemical analyses will performed.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.