AAV Gene Therapy in a Canine Model of MPS1 Prevents and Reverses Corneal Blindness

Abstract

Purpose : Mucopolysacharidosis type 1 (MPS1) is a devastating lysosomal storage disease that can be lethal in the first decade of life. Bone marrow transplantation has proven effective at prolonging life by decades, however, the patient’s quality of life is compromised due to non-lethal MPS1 manifestations including blindness. In particular, approximately 90% of MPS1 children present corneal opacity with about 50% of cases causing complete vision loss. There is no effective treatment for MPS1 corneal blindness, which is the deficit we seek to address in this work using a viral based gene addition strategy. This technology is envisioned as complementary therapeutic to approaches such as cell therapy that address systemic MPS1 disease symptoms.

Methods : A codon optimized IDUA cassette was packaged in a chimeric AAV capsid identified efficient for cornea transduction. Previous evaluations in human corneas ex vivo demonstrated supraphysiological IDUA activity and safety following intrastromal injection of AAV8G9-optIDUA. These optimistic data warranted an efficacy study in naturally occurring MPS1 canines that also suffer from corneal clouding. Three canines with advanced (13 m.o.) and one with early (9 m.o.) corneal diseases were administered AAV8G9-GFP (negative control) in one eye and AAV8G9-optIDUA in the contralateral eye via cornea stromal injections. These canines have been monitored by slit lamp biomicroscopy and corneal imaging currently out 14 weeks post-injections.

Results : Corneal clearing, encompassing both the actual cloudy storage disease and regression of associated vascularization was apparent as early as 1 week and near complete disease reversal is now evident 13 weeks in all corneas injected with AAV-8G9-optIDUA in the symptomatic cohort. In the younger animal with the early disease, corneal disease progression continued in the control eye while the AAV8G9-optIDUA injected cornea demonstrated clearance of microscopic storage materials and did not develop vascularization. No adverse effect was observed specific to the injection or either of the transgenes, except for transient reversible corneal edemas that developed in each eye of one animal at 6 and 10 weeks post injection.

Conclusions : The collective data of a corneal gene addition strategy using AAV vectors for MPS1 blindness demonstrate safety and efficacy and lend support for the evaluation of this technology in MPS1 children.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.