Abstract
Patients with progressive neurodegenerative disorder retinitis pigmentosa (RP) are diagnosed in the midst of ongoing retinal degeneration and remodeling. Here, we used a Pde6b-deficient RP gene therapy mouse model to test whether treatment at late disease stages can halt photoreceptor degeneration and degradative remodeling, while sustaining constructive remodeling and restoring function. We demonstrated that when fewer than 13% of rods remain, our genetic rescue halts photoreceptor degeneration, electroretinography (ERG) functional decline and inner retinal remodeling. In addition, in a water maze test, the performance of mice treated at 16 weeks of age or earlier was indistinguishable from wild type. In contrast, no efficacy was apparent in mice treated at 24 weeks of age, suggesting the photoreceptors had reached a point of no return. Further, remodeling in the retinal pigment epithelium (RPE) and retinal vasculature was not halted at 16 or 24 weeks of age, although there appeared to be some slowing of blood vessel degradation. These data suggest a novel working model in which restoration of clinically significant visual function requires only modest threshold numbers of resilient photoreceptors, halting of destructive remodeling and sustained constructive remodeling. These novel findings define the potential and limitations of RP treatment and suggest possible nonphotoreceptor targets for gene therapy optimization.
Highlights
When patients with degenerative diseases are diagnosed, they have usually already suffered irreversible cell loss [1]
We had two goals: first, to test the ability of genetic rescue therapy, administered at late disease stages, to halt and/or reverse the progressive loss of photoreceptor structure and function in retinitis pigmentosa (RP) retinas; second, to understand, at a cellular level, how the retina remodels to adapt to RP disease progression, and how our gene therapy model impacts that remodeling
In Pde6bSTOP/STOP mice treated at 24 weeks of age, rod bipolar cell dendrite retraction seemed to continue
Summary
When patients with degenerative diseases are diagnosed, they have usually already suffered irreversible cell loss [1]. The goal of gene therapy, is to halt further degeneration, even at late disease stages, to retain some function This is certainly the case with retinitis pigmentosa (RP), an inherited progressive blinding disease driven, most often, by dysfunction of rod photoreceptor cells that leads to their death, and secondarily, the death of cone photoreceptors [2]. 148 Page 2 of 18 middisease stages stops further photoreceptor loss and progressive degradation in retinal function [3] It is not known whether gene therapy restores vision at late disease stages, when the vast majority of photoreceptors (rods and cones) have degenerated. The inner retinal neurons, especially the rod bipolar cell dendrites and horizontal cell processes, remodel extensively [7,8,9] This disease-driven remodeling has been described to be either maladaptive/degradative or constructive. Data suggest that constructive remodeling can compensate functional loss [13, 14]
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