Efficacy, Safety And Tolerability Of StargenTM, A Lentiviral-vector Based Gene Therapy For The Treatment Of Stargardt Disease, In Rabbits And Macaques

Abstract

Purpose: : StarGen^TM is a new lentiviral vector-based gene therapy for the treatment of Stargardt disease designed to express normal ATP-binding cassette transporter gene ABCA4 in the retina. The safety and tolerability of StarGen^TM was examined in GLP regulatory studies in rabbits and non-human primates (NHPs).

Methods: : The efficacy of StarGen^TM was assessed in the Abca4 knockout mouse model following subretinal injection. Safety assessment of StarGen^TM was examined in Dutch-belted rabbits, and Rhesus macaques. StarGen^TM was injected subretinally and compared to control animals treated with formulation buffer. Ophthalmic examinations were performed on a regular basis using slit-lamp microscopy and inflammation/ocular toleration measures were recorded up to 6 months. Retinal function was assessed by ERG prior to dosing and at 6 months in both species. Histopathological examinations of eyes were performed periodically in the rabbits and at 6 months in the macaques to examine retinal morphology.

Results: : Stargen, when dosed to neonatal Abca4 knockout mice, resulted in the attenuation in the accumulation of the lipofuscin, A2E in the retina, versus eyes that were untreated resulting from effective introduction of human ABCA4 protein in the retina. No overt toxicity was observed in animals treated with either StarGen^TM or formulation buffer. Subretinal dosing of StarGen^TM did not result in any abnormal clinical findings. The level of inflammation observed following a subretinal injection of StarGen^TM was slightly higher in the anterior and posterior ocular chambers compared to control treated eyes in both rabbits and macaques. However, the inflammation was transient in both species. There was no StarGen^TM-associated rise in intraocular pressure or abnormal ERG responses in either rabbits or macaques. Histopathological examination of the eyes at 3 days, 1 week, 1 month, 3 months and 6 months in the rabbits, and at 6 months in the NHPs, did not reveal any detrimental changes due to subretinal StarGen^TM administration in the eye.

Conclusions: : StarGen demonstrated efficacy in the murine model of Stargardt disease. Subretinal delivery of StarGen^TM vector in Dutch-belted rabbits and rhesus macaques was well tolerated with no toxicity issues arising and no evidence for changes to retinal function.

Keywords: gene transfer/gene therapy • drug toxicity/drug effects • macula/fovea