Advancing research on Retinitis Pigmentosa: An investigation of natural history, visual system plasticity, and mutation-independent treatment.

Retinitis Pigmentosa (RP) is an inherited retinal disease characterized by rod and then cone photoreceptor degeneration. ~25% of cases are caused by a genetic mutation that results in autosomal dominant RP (adRP). There has been a lack of exploration of the progression of degeneration in adRP models. In Chapter Two, I examined visual acuity (VA) changes, retinal structure, and function from early to late-stage disease in a murine P23H Rho ‘knock-in’ mouse model (RhoP23H/+), the most common form of adRP in North America. To establish a natural history, I evaluated behavioral VA, using the visual water task, and retinal function using full field electroretinograms (ffERG) at the same scotopic and photopic levels. I quantified the thickness of the outer nuclear layer (ONL) in the retina. I constructed a natural history for each measurement. Compared to C57Bl6/J (WT), I find a significant decline in RhoP23H/+ scotopic VA at early-stage disease and in photopic VA at late-stage disease. RhoP23H/+ scotopic VA decline is significantly slower than ERG decline and VA is retained even when the scotopic b-wave is absent. In Chapter Three, to determine if additional plasticity of the visual system is beneficial during vision loss, I assessed the same measures in RhoP23H/+ mice lacking nogo receptor 1 (NgR1), a gene that restricts visual plasticity. NgR1-/- mice were also assessed. Between RhoP23H/+ and RhoP23H/+/NgR1-/- mice, the RhoP23H/+/NgR1-/- mice decline significantly quicker for photopic and scotopic VA in late-stage disease. Accelerated thinning of the ONL is also observed. The absence of NgR1 in RhoP23H/+mice alters the progressive loss of vision in a detrimental way. In Chapter Four, I used a humanized P23H murine model (hRHOP23H/+) of adRP to evaluate a neuroprotective, mutation-independent oral supplement treatment, deuterated docosahexaenoic acid (D-DHA), to maintain cone-mediated vision. In hRHOP23H/+ mice fed D-DHA, photopic and scotopic VA is maintained 90 and 70 days longer, respectively, than natural docosahexaenoic acid (H-DHA) fed mice. The cone photoreceptors were maintained longer in the D-DHA treated mice. This data suggests that D-DHA may be a possible treatment to aid in maintaining cone-mediated vision in patients with adRP.