Abstract
Purpose :
To determine the clinical circumstances under which viral mediated gene therapy can rescue cone function in a nonhuman primate model of PDE6C achromatopsia.
Methods :
Infant rhesus macaques homozygous for the PDE6C R565Q mutation were generated through a selective breeding program at the California National Primate Research Center (CNPRC). Their genotypes were confirmed by genetic sequencing in the first few months of life. Infants and adult homozygous animals were treated in the right eye with adeno-associated virus (AAV5) carrying the rhesus macaque PDE6C gene under the control of the PR1.7 cone-specific promoter. The left eye was used as a control. Animals were tested in each eye by full-field and multifocal electroretinography before and after injection. A total of 7 homozygous animals have been treated with the therapeutic virus.
Results :
The virus was found to be generally safe, but with variable inflammatory response. There were no obvious alterations in retinal lamination in treated eyes. The therapeutic virus transduced retinal cells efficiently and was expressed specifically in cone photoreceptors. Pre- and post-treatment systemic steroids led to minimal to moderate inflammatory response. Gene therapy partially restored the cone responses on ERG within one month of injection in infants, but not in older animals. If restored, the rescued cone responses were sustained and durable for over a year. Chromatic ERG testing showed restoration of amplitudes in all three cone subtypes.
Conclusions :
AAV-mediated gene therapy for PDE6C is safe in the nonhuman primate model. It partially restored cone function in all cone subtypes. The rescue effect of the cone signal on ERG was durable. Management of inflammation may be important to outcomes. The older animals showed a decreased degree of rescue suggesting age may be a factor in treating PDE6C-disease. These experiments suggest similar approaches in human patients may warrant investigation.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.