Light Reduction, Neuroprotection, And Subretinal Gene Therapy In A Mouse Model Of Bardet Biedl Syndrome

Abstract

Purpose: : To evaluate diverse treatment modalities in mouse models of cilia-related retinal degeneration.

Methods: : Mouse models of Bardet Biedl syndrome (BBS) types 1, 2, 3, 4 and 6 were generated using homologous recombination. Rd10 mice were used as a control non-cilia related retinopathy. Pupillometry, electroretinography, indirect ophthalmoscopy, fundus photography, and histology were performed to evaluate whether treatment modalities altered the course of the retinopathy. Treatment modalities included dark rearing, delivery of neuroprotective molecules, and subretinal injection of AAV-WTBbs1.

Results: : Mice homozygous for the most common human BBS mutation, M390R, demonstrated improved pupillary responses after being reared in the dark (F-test comparison of curves P < 0.0001). Bbs1 mice reared in the dark have some preservation of ERG amplitudes at 6 mos. Bbs1 M390R homozygous mice (N=14) that received unilateral subretinal injection of AAV-WTBbs1 demonstrated expression of Bbs1 protein in photoreceptors. After initial small decrease in ERG amplitudes, ERG appeared to stabilize in treated eyes relative to control, uninjected eyes. Ongoing studies include evaluation of treatment with the neuroprotective agent , TUDCA. Rd10 mice demonstrate less attenuation of ERG amplitudes when systemic TUDCA is administered every 3 days. This protocol is currently being applied to Bbs1 M390R/M390R mice.

Conclusions: : Ciliopathies such as BBS cause severe early onset retinal degeneration in humans. In a mouse model of BBS, light reduction and subretinal gene therapy show potential as treatment modalities, however longer follow up is required in this slowly evolving model. Neuroprotective molecules may also have a role.

Keywords: retinal degenerations: hereditary • gene transfer/gene therapy