Abstract
Purpose :
Small molecule pharmacological inhibition of dominant human genetic disease is a feasible treatment that does not rely on the development of individual, patient-specific gene therapy vectors. However, the consequences of protein inhibition as a clinical therapeutic are not well-studied. In advance of human therapeutic trials for CAPN5 vitreoretinopathy, genetic inactivation can be used to infer the effect of protein inhibition in vivo.
Methods :
We created a photoreceptor-specific knockout mouse for Capn5 and compared the retinal phenotype to both wild-type and an existing Capn5 knockout mouse model. In humans, CAPN5 loss-of-function gene variants were ascertained in large exome databases from 60,706 unrelated subjects without severe disease phenotypes.
Results :
Ocular examination of the inner retina of Capn5 knockout mice by histology and electroretinography showed no significant abnormalities. In humans, there were 22 loss-of-function CAPN5 variants located throughout the gene and in all major protein domains. Structural modeling of coding variants showed these loss-of-function variants were nearby known disease-causing variants within the proteolytic core and in regions of high homology between human CAPN5 and 150 homologs, yet the loss-of-function of CAPN5 was tolerated as opposed to gain-of-function disease-causing variants.
Conclusions :
These results indicate that localized and systemic inhibition of CAPN5 is a viable strategy for hyperactivating disease alleles.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.