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Age-sensitive response of systemic AAV-mediated gene therapy in a newly characterized feline model of mucolipidosis
Nettie K Pyne1, Jessica Bagel2, Charles Shyng3
1Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH 43215, USA.
Abstract:
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.
Insights
Mucolipidosis II (MLII), a lysosomal storage disorder, causes severe nervous system and organ damage in cats. Gene therapy showed promise, with delayed treatment improving outcomes but not fully correcting the disease.
Area of Science:
- Biochemistry
- Genetics
- Veterinary Medicine
Background:
- Mucolipidosis II (MLII) is a severe lysosomal storage disorder (LSD) stemming from GNPTAB mutations, leading to impaired lysosomal enzyme targeting.
- Affected individuals experience significant cognitive deficits, skeletal dysplasia, and cardiopulmonary issues, often with fatal outcomes before age 10.
- A spontaneous feline model of MLII mirrors human disease, exhibiting growth retardation, skeletal deformities, blindness, and premature death.
Purpose of the Study:
- To investigate the neurological manifestations of MLII in a feline model.
- To identify potential biomarkers for MLII-related nervous system disease.
- To evaluate the efficacy and safety of adeno-associated virus (AAV)-mediated gene therapy for MLII.
Main Methods:
- Characterization of neurological and systemic disease in MLII cats, including auditory and nerve conduction tests.
- Analysis of lysosomal enzyme activity, lysosomal-associated membrane protein 1 expression, and cytokine/chemokine profiles.
- Administration of AAV9 encoding feline GNPTAB (AAV9-fGNPTAB) at different ages and doses to MLII cats.
Main Results:
- MLII cats displayed hearing and sensory nerve conduction deficits, hydrocephalus, and increased LAMP1 expression, with premature death around 5 months.
- Cytokine and chemokine dysregulation was observed, suggesting potential pathomechanisms and non-invasive biomarkers.
- Early high-dose AAV9-fGNPTAB gene therapy was lethal; delayed treatment (4 weeks) was tolerated, showing partial correction of ophthalmic, skeletal, and cardiac defects.
Conclusions:
- Feline MLII models exhibit significant nervous system pathology, highlighting the need for effective therapies.
- AAV-mediated gene therapy shows potential for MLII treatment, but optimal timing and dosage are critical for safety and efficacy.
- Further research is needed to achieve complete disease correction and address the complexities of MLII treatment.
