Abstract
AbstractMucopolysaccharidosis type IVA (MPSIVA) or Morquio A disease, a lysosomal storage disorder, is caused by N-acetylgalactosamine-6-sulfate sulfatase (GALNS) deficiency, resulting in keratan sulfate (KS) and chondroitin-6-sulfate accumulation. Patients develop severe skeletal dysplasia, early cartilage deterioration and life-threatening heart and tracheal complications. There is no cure and enzyme replacement therapy cannot correct skeletal abnormalities. Here, using CRISPR/Cas9 technology, we generate the first MPSIVA rat model recapitulating all skeletal and non-skeletal alterations experienced by patients. Treatment of MPSIVA rats with adeno-associated viral vector serotype 9 encoding Galns (AAV9-Galns) results in widespread transduction of bones, cartilage and peripheral tissues. This led to long-term (1 year) increase of GALNS activity and whole-body correction of KS levels, thus preventing body size reduction and severe alterations of bones, teeth, joints, trachea and heart. This study demonstrates the potential of AAV9-Galns gene therapy to correct the disabling MPSIVA pathology, providing strong rationale for future clinical translation to MPSIVA patients.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
Reference71 articles.
1. Singh, J., Ferrante, N., Di, Niebes, P. & Tavella, D. N-acetylgalactosamine-6-sulfate sulfatase in man. J. Clin. Invest. 57, 1036–1040 (1976).
2. Tomatsu, S. et al. Mucopolysaccharidosis type IVA (Morquio A Disease): clinical review and current treatment: a special review. Curr. Pharm. Biotechnol. 12, 931–945 (2011).
3. Tomatsu, S. et al. Morquio A syndrome: diagnosis and current and future therapies. Pediatr. Endocrinol. Rev. 12, 141–151 (2014).
4. Byers, S., Vaidyanathan, S., L.K, A. & S.A, D.-R. Chondrogenesis and osteogenesis are delayed by MPS IVA keratan sulphate but not normal keratan sulphate. Mol. Genet. Metab. 123, 174 (2018).
5. Montaño, A. M., Tomatsu, S., Gottesman, G. S., Smith, M. & Orii, T. International Morquio A Registry: Clinical manifestation and natural course of Morquio A disease. J. Inherit. Metab. Dis. 30, 165–174 (2007).
Cited by
18 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献