A collaborative team of scientists has applied an AAV gene therapy approach to combatting the deficits of cellular therapies for mucopolysaccharidosis type 1 (MPS1) corneal blindness in a canine model.
MPS1 is a progressive lysosomal storage disease which can be potentially lethal if developed within the first decade of life. Whilst techniques such as cell therapy via bone marrow transplantation have proven successful in prolonging life, non-lethal MPS1 manifestations can severely disrupt and decrease a patient’s quality of life.
The team reported at the American Society of Gene & Cell Therapy Annual Meeting (29 April–2 May 2019; DC, USA) that approximately 90% of MPS1 patients present corneal opacity with about 50% of cases leading to complete vision loss. As previous studies have revealed that corneal transplantation is concurrent with a high incidence of rejection, there is currently no effective treatment for MPS1 corneal blindness.
Addressing this gap in treating and preventing MPS1 corneal blindness, researchers investigated an AAV corneal IDUA gene addition approach in MPS1 canines, following validation of the therapy in MPS1 patient cells and human corneas ex vivo.
The findings reported that whilst instrasomal AAV-IDUA injections were difficult with variable drug dispersion, they were well tolerated in presymptomatic as well as diseased corneas. Clearing of lysosomal storage and extensive vascularization was observed as early as 1 week post-treatment, while corneas injected at early disease remained vascular free.
The contralateral corneas injected with a control vector continued to show MPS1 disease progression, exhibiting zero indications of storage prevention or reversal. Furthermore, AAV-IDUA administration resulted in clear corneas in post-symptomatic corneas, despite the occurrence of transient corneal edema in either the IDUA or control eye. Post-mortem analyses reportedly revealed reduced corneal thickness, corneal vascularization, high IDUA abundance and alpha smooth muscle actin staining, with H&E pathology grading almost completely corrected.
A second cohort of experiments in younger, largely presymptomatic MPS1 canines AAV-IDUA vector injections exhibited similar results in that the corneas cleared at the lowest does of 1e9 viral genomes, with transient corneal edema observed in a subset of patients.
A longer observational period allowed for the return of signs of lysosomal storage disease in AAV-IDUA injected corneas that had previously been corrected and vector biodistribution analysis detected genomes in peripheral organs, yet the majority of subjects did not present capsid neutralizing bodies post-treatment.
The team reported that the results demonstrated AAV-IDUA corrects MPS1 corneal disease, concluding the meeting abstract: “…although a transient edema was encountered in a subset of canines, it remains a likely possibility that prior hematopoietic stem cell transplantation, which tolerizes MPS1 patients to human IDUA, may eliminate these suspected immunological concerns resulting in complete therapy.”
Source: Llanga TA, Miyadera K, Conatser L et al. AAV Gene Therapy in a Canine Model of MPS1 Prevents and Reverses Corneal Blindness. Presented at: American Society of Gene & Cell Therapy Annual Meeting. Washington, DC, USA. 2019