Liver-Targeted AAV8 Gene Therapy Ameliorates Skeletal and Cardiovascular Pathology in a Mucopolysaccharidosis IVA Murine Model

Abstract

Mucopolysaccharidosis type IVA (MPS IVA) is due to the deficiency of GALNS (N-acetylgalactosamine 6-sulfate sulfatase) and is characterized by systemic skeletal dysplasia. We have evaluated adeno-associated virus 8 (AAV8) vectors expressing different forms of human GALNS under a liver-specific promoter. The vectors were delivered intravenously into 4-weekold MPS IVA knockout (KO) and immune tolerant (MTOL) mice at a dose of 5 Â 10 13 genome copies (GC)/kg. These mice were monitored for 12 weeks post-injection. GALNS enzyme activity was elevated significantly in plasma of all treated mice at 2 weeks post-injection. The activity observed was 4-to 19-fold higher than that in wild-type mice and was maintained throughout the monitoring period. Treatment with AAV vectors resulted in a reduction of keratan sulfate (KS) levels in plasma to normal levels 2 weeks post-injection, which were maintained until necropsy. Both vectors reduced the storage in articular cartilage, ligaments, and meniscus surrounding articular cartilage and growth plate region as well as heart muscle and valves. Our results suggest that the continuous presence of high levels of circulating enzyme increases the penetration into bone and heart and reduces the KS level, thereby improving storage in these regions. The current data support a strategy for developing a novel treatment to address the bone and heart disease in MPS IVA using AAV gene therapy.

Liver-directed gene therapy corrects neurologic disease in a murine model of mucopolysaccharidosis type I-Hurler

“…For example, liver-directed AAV8 gene therapy significantly improves disease phenotypes in MPS I, MPS IVA, and Pompe disease models, including skeletal and cardiovascular damage, demonstrating the potential value of this treatment approach. [5][6][7][8] Nonetheless, because lysosomal enzymes do not effectively cross the BBB, this treatment approach is ineffective for treating central nervous system (CNS) manifestations. In addition, phase I/II gene therapy with an intracisternally administered AAV9 vector containing an IDUA expression cassette (RGX-111) is currently being tested as a strategy to directly target the CNS of individuals with MPS I (ClinicalTrials.gov: NCT03580083).…”

Delivering gene therapy for mucopolysaccharide diseases

“…Galns −/− (MPSIVA) mice demonstrate KS accumulation throughout the body, however the skeletal dysplasia seen in MPSIVA patients is absent ( Tomatsu et al, 2003 ). Tomatsu and colleagues recently published a liver-directed AAV gene therapy that generated up to 19-fold greater than wild-type expression of GALNS enzyme in the plasma of MPSIVA mice and resulted in reductions in KS storage throughout the body over untreated KO mice ( Sawamoto et al, 2020 ). More recently, a rat model was described by Bertolin and colleagues in which disease progression far more closely resembles the human skeletal disease ( Bertolin et al, 2021 ).…”

Mammalian Sulfatases: Biochemistry, Disease Manifestation, and Therapy

“…Its major symptoms are manifested in the bones and the visceral organs but not in the CNS. In an animal study, the tested AAV8-based vector provided prolonged expression of GALNS enzyme activity for over 6 months after administration, ameliorating the accumulation of keratin sulfate and improving a variety of pathological markers in the growth plate and the articular disc of the knee joint as well as the valve and muscle of the heart [ 59 ].…”