Mouse model selection for pharmacological evaluation of AAV-based therapeutic agents for the treatment of Rod-Cone Dystrophies (RCD)

Abstract

Purpose : The selection of an appropriate pharmacology model is important for the successful development of any drug as it informs dose selection. This is paramount in the context of gene therapy where the clinical starting dose should provide meaningful benefits as patients cannot be redosed. To assess SPVN06 pharmacological activity, an AAV-based therapy that aims at slowing down cone degeneration, we evaluated 2 mouse models of RCD characterized by a loss of rods followed by a loss of cones eventually causing blindness. Functional and structural characterization of the retinal degeneration was performed in rd10 mice (Pde6b recessive) and in P23H/+ mice (Rho dominant mutation).

Methods : rd10 mice were housed either in normal light cycle (NLC) or, to delay retinal degeneration, were kept in darkness from birth to postnatal day (P) 30 before transfer to NLC on P31. P23H/+ mice were housed in NLC. Animals were evaluated up to P48 (rd10) or P220 (P23H/+). Retinal structure and function were evaluated by histology (H&E and IHC), OCT, optokinetic (OKT) and ffERG.

Results : In rd10 mice, the outer nuclear layer (ONL) was significantly reduced in light-reared animals at P30 while appeared intact in dark-reared mice followed by a rapid degeneration with only 1 layer of nuclei remaining at P48. In the P23H/+ mice, ONL thickness decreased very slowly starting from P70 with only 1-3 nuclei layers at P220. In both models, cone and rod function (ffERG) were drastically reduced in comparison to WT mice as early as the first timepoint evaluated (P39 for the dark-reared rd10 mice and P37 for P23H/+ mice). Visual acuity (OKT) in dark-reared rd10 mice was reduced by 25% as early as P38 and ~50% at P45. On the contrary, P23H/+ visual acuity was generally comparable to WT levels until P220. Dark-reared rd10 mice were eventually selected for the definitive pharmacological assessment. This housing condition allowed sufficient time for transgene expression following subretinal administration at P18 prior to onset of the degeneration following light exposure.

Conclusions : Our results highlight that the selection of the animal model, housing conditions and pharmacological assessments are critical and should be done in the context of the mechanism of action of the drug. Moreover, it is important that the model be characterized in the experimental conditions of the pharmacology study.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.