Evaluation of subretinally delivered Cas9 ribonucleoproteins in murine and porcine animal models highlights key considerations for therapeutic translation of genetic medicines.

Genetic medicines, including CRISPR/Cas technologies, extend tremendous promise for addressing unmet medical need in inherited retinal disorders and other indications; however, there remain challenges for the development of therapeutics. Herein, we evaluate genome editing by engineered Cas9 ribonucleoproteins (eRNP) in vivo via subretinal administration using mouse and pig animal models. Subretinal administration of adenine base editor and double strand break-inducing Cas9 nuclease eRNPs mediate genome editing in both species.

Transcriptomic Analysis of Metastatic Uveal Melanoma and Differences in Male and Female Patients.

Background/aim: Uveal melanoma is an ocular malignancy whose prognosis severely worsens following metastasis. In order to improve the understanding of molecular physiology of metastatic uveal melanoma, we identified genes and pathways implicated in metastatic vs non-metastatic uveal melanoma.

Patients And Methods: A previously published dataset from Gene Expression Omnibus (GEO) was used to identify differentially expressed genes between metastatic and non-metastatic samples as well as to conduct pathway and perturbagen analyses using Gene Set Enrichment Analysis (GSEA), EnrichR, and iLINCS.

Heterogeneity in the progression of retinal pathologies in mice harboring patient mimicking Impg2 mutations.

Biallelic mutations in interphotoreceptor matrix proteoglycan 2 (IMPG2) in humans cause retinitis pigmentosa (RP) with early macular involvement, albeit the disease progression varies widely due to genetic heterogeneity and IMPG2 mutation type. There are currently no treatments for IMPG2-RP. To aid preclinical studies toward eventual treatments, there is a need to better understand the progression of disease pathology in appropriate animal models.

Nonviral base editing of KCNJ13 mutation preserves vision in a model of inherited retinal channelopathy.

Clinical genome editing is emerging for rare disease treatment, but one of the major limitations is the targeting of CRISPR editors' delivery. We delivered base editors to the retinal pigmented epithelium (RPE) in the mouse eye using silica nanocapsules (SNCs) as a treatment for retinal degeneration. Leber congenital amaurosis type 16 (LCA16) is a rare pediatric blindness caused by point mutations in the KCNJ13 gene, a loss of function inwardly rectifying potassium channel (Kir7.