Proven in vivo efficacy is a key requirement for novel gene therapies proceeding to clinical trial. No gene therapies for corneal dystrophies have been able to progress into patient-led studies due to a lack of suitable animal models expressing a disease phenotype comparable to that which develops in humans. Herein, we show an allele-specific siRNA targeting the L132P KRT12 mutation, causative of a severe form of Meesmann Epithelial Corneal Dystrophy (MECD), when complexed with silicon-stabilized hybrid lipid nanoparticles (sshLNP), and applied topically twice daily for seven days, results in restoration of corneal thickness in a humanized mouse model (Krt12+/hL132P) for MECD. Furthermore, expression of disease biomarkers elevated in the MECD mouse model and verified in corneal epithelial cells of MECD family members, was reduced to that observed in unaffected wild-type (Krt12+/+) mice. This represents the first successful use of topical mutant allele-specific siRNA in the treatment of an autosomal genetic corneal dystrophy. The successful silencing of disease biomarkers after topical siRNA treatment indicates expected clinical benefit. Furthermore, we demonstrated that siRNA-sshLNPs can be successfully formulated in sodium hyaluronate-containing eye-drops without impairing efficacy of the siRNA.
