Leveraging mouse models and retinal organoids to optimize a gene therapy for IMPG2-associated retinal degeneration

About This Grant

PROJECT SUMMARY IMPG2 is a crucial extracellular matrix protein for maintaining photoreceptor structure and function. Mutations in IMPG2 are linked to two forms of visual impairment: juvenile-onset rod-cone dystrophy and adult-onset vitelliform macular dystrophy. While no treatment currently exists, packaging IMPG2 amino acid sequences into adeno-associated viruses (AAVs) offers promise for a sight-preserving therapy. We recently generated human retinal organoid (RO) and mouse models to enable us to rapidly engineer a gene augmentation therapy for IMPG2-associated retinal dystrophy (RD). The retinal organoids (ROs), grown from either patient-derived (human) induced pluripotent stem cells (hiPSCs) or gene-edited embryonic stem cells (hESCs), recapitulate the lack of photoreceptor outer segments observed in advanced IMPG2-RD. This fully penetrant phenotype provides a biomarker for assessing functional IMPG2 expression after AAV-mediated gene transfer. Although patient-derived ROs are tractable in vitro models of clinical relevance, their use in assessing viral vector designs for gene therapy development is best complemented by in vivo assessment of safety and efficacy in animal models. Accordingly, we will assess therapeutic safety and efficacy using the Impg2-knockout (KO) model mice, as these mice exhibit gliosis, subretinal deposits, photoreceptor degeneration, retinal detachment, and reduced electroretinogram (ERG) responses that are similar to the human condition. Here, we will accelerate a preclinical program to test our central hypothesis that gene augmentation can prevent retinal pathology in an IMPG2-RD mouse model and patient-derived ROs. To lay the groundwork for a clinical IMPG2 gene therapy, we will complete the following Aims: (1) Use Impg2-KO mice to define endpoints for preclinical trials, (2) optimize a gene therapy viral vector design using Impg2-KO mice and IMPG2 patient-derived and gene-edited ROs, and (3) establish preclinical gene therapy safety and efficacy in Impg2-KO mice. Synergistically employing mouse models and human ROs will accelerate the development of a gene therapy that will meaningfully improve the lives of individuals with IMPG2-RD. More broadly, this work will demonstrate the power of a dual-model platform to advance safe and effective therapeutics with high predictive value for treating inherited retinal disorders.