Correction of monogenic heritable diseases by gene augmentation using adeno-associated viral vectors has made substantial progress in treating diseases caused by genes whose coding sequences are within the capacity of the vector. To treat diseases caused by large genes whose coding sequences exceed this capacity, alternate strategies need to be developed. In this study, I evaluated the strategy of pre-mRNA trans-splicing for correction of two large genes that cause retinal degeneration: CEP290, which principally causes Leber Congenital Amaurosis type 10, and ABCA4, which principally causes Stargardt disease. To investigate if such an approach could be used to develop a treatment for these large genes, I designed a workflow to rapidly analyze DNA coding sequences and determine a target region that would allow for maximum correction of each gene. I then investigated these regions with a reporter gene (green fluorescent protein (GFP)) reconstitution assay to find efficacious binding domains for directing pre-mRNA trans-splicing molecules to the target sequences. I demonstrated endogenous gene editing of CEP290 pre- mRNA in vitro in HEK293T cells, as well as in vivo in photoreceptors of a mini-CEP290 mouse model following sub-retinal injection. I also identified a putative binding domain to edit ABCA4. However, a lack of models where ABCA4 is expressed limited my ability to assess endogenous splicing with this construct. Therefore, I worked to develop such model systems. I conducted a pilot study of ABCA4 expression where dCas9-VPR activated the endogenous ABCA4 locus in HEK293T cells and identified a 118 kDa variant of ABCA4 that is expressed in HEK293T, Y79, and WERI cells. Finally, I derived fibroblasts from a macaque that had macular spots and characterized two novel ABCA4 mutations in these cells. Collectively, my thesis work provides a paradigm for (1) generating trans-splicing molecules that can be used to treat mutations in large genes and (2) developing model systems where preclinical investigations into gene therapy strategies can be performed.