Abstract
Purpose :
Even with recent successes of gene therapy approaches, there remains a large unmet need for retinitis pigmentosa (RP) treatment. For most RP, a single substitution in the human rhodopsin gene (P23H) is responsible. The P23H transgenic rat model was developed to study the disease course. Here, we present the results of a multi-modal natural history study to inform RP pathogenesis using state-of-the-art tools for preclinical R&D in P23H rats.
Methods :
Eight each homozygous (HO) and hemizygous (HE) P23H-1 as well as Sprague-Dawley (SD) rats (background strain) were examined by Optical Coherence Tomography (OCT, Heidelberg), electroretinography (ERG) - including multifocal ERG (mfERG, Diagnosys), color fundoscopy (Phoenix), optomotor kinetic response (ORK, Striatech), and histopathology. Animals were evaluated at weeks 4-20 after birth. Outer nuclear layer (ONL) and total retina thickness were measured at the timepoints above. Scotopic and photopic a-, b, and -c-wave amplitudes, along with flicker-responses were analyzed. mfERG was performed utilizing 19-hexagons around the optic nerve head. Rows of ONL nuclei were counted from histology slides.
Results :
Significantly lowered ERG amplitudes, ONL and total retina thickness, as well as reduced rows of nuclei compared to SD rats were observable at week 4 in HO and HE rats. Changes were progressive in both HO and HE but accelerated in HO animals. Significant differences (p>0.05) in (ERG, OCT, cell counts) between HO and HE animals developed by week 6, ERG waves and ONL thickness became non-existent in HO rats by week 8. Scotopic ERG parameters were affected more than photopic, indicating rod degeneration over time. HE rats followed the course slower but by week 20 they reached levels similar to 8-week-old HO rats. Interestingly, these retina changes did not lead to gross abnormalities associated with overall eye health. mfERG and OKR detected the loss of photoreceptor density.
Conclusions :
Our natural history study demonstrated early-onset retina degeneration in HO animals. Degeneration was slower in HE animals but still progressive. Multimodal evaluations confirmed similar trends across evaluation modes. These results inform model validation and enable objective evaluation of therapeutic interventions that will be investigated for the improvement of vision in patients suffering from RP.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.