Correction of Hunter syndrome in the MPSII mouse model by AAV2/8-mediated gene delivery

Abstract

Mucopolysaccharidosis type II (MPSII; Hunter syndrome) is a lysosomal storage disorder caused by a deficiency in the enzyme iduronate 2-sulfatase (IDS). At present, the therapeutic approaches for MPSII are enzyme replacement therapy and bone marrow transplantation, although these therapies have some limitations. The availability of new AAV serotypes that display tissue-specific tropism and promote sustained expression of transgenes offers the possibility of AAV-mediated gene therapy for the systemic treatment of lysosomal diseases, including MPSII. We have characterized in detail the phenotype of IDS-deficient mice, a model of human MPSII. These mice display a progressive accumulation of glycosaminoglycans (GAGs) in many organs and excessive excretion of these compounds in their urine. Furthermore, they develop skeleton deformities, particularly of the craniofacial bones, and alopecia, they perform poorly in open-field tests and they have a severely compromised walking pattern. In addition, they present neuropathological defects. We have designed an efficient gene therapy approach for the treatment of these MPSII mice. AAV2/8TBG-IDS viral particles were administrated intravenously to adult MPSII mice. The plasma and tissue IDS activities were completely restored in all of the treated mice. This rescue of the enzymatic activity resulted in the full clearance of the accumulated GAGs in all of the tissues analyzed, the normalization of the GAG levels in the urine and the correction of the skeleton malformations. Overall, our findings suggest that this in vivo gene transfer approach has potential for the systemic treatment of patients with Hunter syndrome.

CNS-directed gene therapy for the treatment of neurologic and somatic mucopolysaccharidosis type II (Hunter syndrome)

“…Following i.v. administration of 4 × 10 12 vg/kg of recombinant AAV8-TBG-IDS vector to adult MPSII mice, plasma concentrations of IDS were 16-to 70-fold higher than in WT, and complete correction of somatic disease was achieved (61). However, efficacy in the brain was limited, with only partial reduction of GAGs observed in this organ, likely due to the fractional amount of IDS that crossed the BBB despite the high concentration of circulating enzyme.…”

“…Here, we report CNS-directed gene therapy developed for the treatment of the severe phenotype of MPSII and provide evidence of the therapeutic efficacy of the approach to treat not only neurologic but also somatic pathology in animals with already established disease. Previous attempts to treat neurologic MPSII with AAV tested systemic vector delivery to achieve supraphysiological concentrations of circulating IDS (60,61). This strategy was based on earlier work with ERT for different forms of LSD that suggested that when high levels of enzyme are present in the bloodstream, a portion of the protein manages to cross the BBB (62, 63).…”

Modulation of tolerance to the transgene product in a nonhuman primate model of AAV-mediated gene transfer to liver

“…[1][2][3][4][5][6][7][8][9] However, despite long-term efficacy data in experimental animals, in the only human study of AAV-mediated, liver-directed gene transfer, expression of the donated F.IX gene was short-term in hemophilic men, 10 persisting for approximately 4 weeks, then gradually declining over the ensuing 6 weeks. Loss of F.IX expression was accompanied by a transient asymptomatic transaminase elevation, also beginning 4 weeks after vector infusion.…”

Sulfatase modifying factor 1 trafficking through the cells: from endoplasmic reticulum to the endoplasmic reticulum

“…The AAV2/8 serotype transduces hepatocytes with high efficiency and the TBG promoter is liver specific; therefore, SUMF1 can only be expressed by the liver (Cardone et al, 2006). We transduced 2-month-old wildtype mice (n ¼ 3) by tail-vein injection with a total of 2.8 Â10 11 viral particles.…”