Results of Safety and Tolerability Studies of UshStat®, an EIAV-based Lentiviral-vector Therapy for USH1B and the Elucidation of Retinal Cell Types Responsible for USH1B Pathology

Abstract

Purpose: : Usher syndrome type 1B (USH1B) is a common and severe form of Usher syndrome, characterized by congenital deafness associated with retinitis pigmentosa. UshStat^® is an EIAV-based lentiviral vector expressing Myosin VIIa encoded by the USH1B gene. In UshStat^® this gene is expressed by the constitutive CMV promoter so Myosin VIIa is produced mainly in the RPE and photoreceptor (PR) cells. The safety and tolerability of UshStat^® was examined in a GLP study in Rhesus macaques. Using the same EIAV vector platform myosin VIIa will be expressed specifically in RPE or PR cells using tissue specific promoters to determine which cell type is responsible for retinal pathology.

Methods: : EIAV vectors have been developed that express human Myosin VIIa using the CMV (UshStat^®) or RPE-specific (VMD2) or PR-specific (RK) promoters. Safety and biodistribution assessments of UshStat^® were examined in macaques following subretinal delivery of UshStat^® or buffer. Regular ophthalmic examinations to monitor ocular inflammation and histopathological retinal morphology were recorded up to 3 months. A further study in P-3 shaker-1 mice will determine which retinal cell types are responsible for the USH1B disease pathology using tissue restricted EIAV vectors and assessing light induced α-transducin translocation and PR degeneration.

Results: : No UshStat^®-related adverse findings and no antibody responses against any vector components were detected in the macaques. Biodistribution analysis indicates that the vector is confined to the eye in the macaque. Long-term efficacy studies in shaker-1 mice following UshStat^® subretinal delivery have shown neuroprotection of PRs. The specificity of the VMD2 and RK promoters has been validated in vivo using the GFP gene and the retinal specific EIAV-MYO7A vectors have been subretinally delivered to shaker1 mice. The results will be presented.

Conclusions: : Subretinal delivery of UshStat^® vector in macaques was well tolerated with no evidence for changes to retinal function. Previous studies show that UshStat^® is efficacious in shaker-1 mice. Retinal specific EIAV-MYO7A vectors will be used to determine which cell types are principally responsible for ontogenesis of USH1B retinal pathology.

Keywords: gene transfer/gene therapy • pathology: human