Age-sensitive response of systemic AAV-mediated gene therapy in a newly characterized feline model of mucolipidosis II.

Mucolipidosis II (MLII) is a lysosomal storage disorder (LSD) caused by mutations in GNPTAB and loss of mannose 6-phosphate-dependent targeting of lysosomal enzymes. Affected children exhibit cognitive deficits, skeletal dysplasia, and cardiopulmonary disease, with death typically occurring before age 10. A naturally occurring feline model of MLII results from a nonsense mutation in GNPTAB; cats develop elevated lysosomal enzyme activities, growth retardation, skeletal deformities, blindness, cardiomegaly, and die prematurely. Most LSDs exhibit central nervous system disease, which is a primary contributor to morbidity and mortality. Therefore, we evaluated nervous system disease in feline MLII. MLII cats lived to approximately 5 months of age, had impairments in hearing and sensory nerve conduction, hydrocephalus, and increased expression of lysosomal associated membrane protein 1. Quantification of cytokines and chemokines revealed dysregulation, elucidating potential pathomechanisms and non-invasive biomarkers. We then evaluated adeno-associated virus (AAV)-mediated gene therapy. MLII cats were treated with AAV9 encoding feline GNPTAB. High-dose AAV9-fGNPTAB intervention in the first week of life was fatal; however, delaying treatment to 4 weeks was tolerated. Correction was not complete, however, the highest dose resulted in the greatest correction of ophthalmic, skeletal, and cardiac disease associated with MLII.