Abstract
Lysophosphatidylcholine acyltransferase 1 (LPCAT1) is necessary for photoreceptors to generate an important lipid component of their membranes. The absence of LPCAT1 results in early and rapid rod and cone degeneration. Retinal degeneration 11 (rd11) mice carry a mutation in the Lpcat1 gene, and are an excellent model of early-onset rapid retinal degeneration (RD). To date, no reports have documented gene therapy administration in the rd11 mouse model at different ages. In this study, the AAV8 (Y733F)-smCBA-Lpcat1 vector was subretinally injected at postnatal day (P) 10, 14, 18, or 22. Four months after injection, immunohistochemistry and analysis of retinal morphology showed that treatment at P10 rescued about 82% of the wild-type retinal thickness. However, the diffusion of the vector and the resulting rescue were limited to an area around the injection site that was only 31% of the total retinal area. Injection at P14 resulted in vector diffusion that covered approximately 84% of the retina, and we found that gene therapy was more effective against RD when exposure to light was limited before and after treatment. We observed long-term preservation of electroretinogram (ERG) responses, and preservation of retinal structure, indicating that early treatment followed by limited light exposure can improve gene therapy effectiveness for the eyes of rd11 mice. Importantly, delayed treatment still partially preserved M-cones, but not S-cones, and M-cones in the rd11 retina appeared to have a longer window of opportunity for effective preservation with gene therapy. These results provide important information regarding the effects of subretinal gene therapy in the mouse model of LPCAT1-deficiency.
Highlights
Inherited retinal degeneration (RD) is caused by a group of eye diseases that result from mutations in various genes
At postnatal days 2 (P2), both strains of mice appeared to have similar retinal structure across sections, which consisted of only a neuroblastic layer (NL), an outer layer, and an inner ganglion cell layer (GCL)
After P14, the thickness of rd11 retinas was markedly reduced with progressive thinning and loss of the outer segments (OS) and the outer nuclear layer (ONL) due to RD (Fig 1)
Summary
Inherited retinal degeneration (RD) is caused by a group of eye diseases that result from mutations in various genes. There are several modes of inheritance, such as autosomal dominant, autosomal recessive, X-linked recessive, digenic, and mitochondrial. Dominant mutations can arise through loss-of-function, gain-of-function, and dominant-negative mutations, whereas recessive mutations only present a deficiency in functional wild-type gene protein products [1]. Gene Therapy in a Mouse Model of Retinal Degeneration. Cn/Company/report/CR_apply.aspx?type=0&id=9240, HZ), the National Natural Science Foundation of China (81371060, https://isisn.nsfc.gov.cn/egrantweb/ contract/index?datetimestamp=1457056907909###, JP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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