title: AAV8-mediated expression of N-acetylglucosamine-1-phosphate transferase attenuates bone loss in a mouse model of mucolipidosis II.
abstract: Mucolipidoses II and III (ML II and ML III) are lysosomal disorders in which the mannose 6-phosphate recognition marker is absent from lysosomal hydrolases and other glycoproteins due to mutations in GNPTAB, which encodes two of three subunits of the heterohexameric enzyme, N-acetylglucosamine-1-phosphotransferase. Both disorders are caused by the same gene, but ML II represents the more severe phenotype. Bone manifestations of ML II include hip dysplasia, scoliosis, rickets and osteogenesis imperfecta. In this study, we sought to determine whether a recombinant adeno-associated viral vector (AAV2/8-GNPTAB) could confer high and prolonged gene expression of GNPTAB and thereby influence the pathology in the cartilage and bone tissue of a GNPTAB knock out (KO) mouse model. The results demonstrated significant increases in bone mineral density and content in AAV2/8-GNPTAB-treated as compared to non-treated KO mice. We also showed that IL-6 (interleukin-6) expression in articular cartilage was reduced in AAV2/8-GNPTAB treated ML II mice. Together, these data suggest that AAV-mediated expression of GNPTAB in ML II mice can attenuate bone loss via inhibition of IL-6 production. This study emphasizes the value of the MLII KO mouse to recapitulate the clinical manifestations of the disease and highlights its amenability to therapy.
authors: Clinical Research Center, Samsung Biomedical Research Center, Seoul, Republic of Korea; Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors: Ah-Ra
authors: AR
authors: Ko
authors: Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Electronic address: jindk@skku.edu.
authors: Dong-Kyu
authors: DK
authors: Jin
authors: Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors: Sung Yoon
authors: SY
authors: Cho
authors: Department of Pediatrics, Cheil General Hospital and Woman's Health Care Center, Dankook University College of Medicine, Seoul, Republic of Korea.
authors: Sung Won
authors: SW
authors: Park
authors: Sanofi Genzyme, Framingham, MA, USA.
authors: Malgorzata
authors: M
authors: Przybylska
authors: Sanofi Genzyme, Framingham, MA, USA.
authors: Nelson S
authors: NS
authors: Yew
authors: Sanofi Genzyme, Framingham, MA, USA.
authors: Seng H
authors: SH
authors: Cheng
authors: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors: Jung-Sun
authors: JS
authors: Kim
authors: Department of Pediatrics, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Republic of Korea.
authors: Min Jung
authors: MJ
authors: Kwak
authors: Department of Pediatrics, Myongji Hospital, Seonam University College of Medicine, Goyang, Republic of Korea.
authors: Su Jin
authors: SJ
authors: Kim
authors: Department of Medical Genetics, Ajou University Hospital, Ajou University School of Medicine, Suwon, Republic of Korea.
authors: Young Bae
authors: YB
authors: Sohn
mesh_terms: D000818:Animals; D018488:Bone Demineralization, Pathologic / Q000175:diagnosis / Q000209:etiology* / Q000628:therapy; D015519:Bone Density; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D015870:Gene Expression; D023061:Gene Order; D018390:Gene Targeting; D056426:Genetic Loci; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D005838:Genotype; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009081:Mucolipidoses / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D010641:Phenotype; D014161:Transduction, Genetic; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics*
chemical_list: D017855:Transferases (Other Substituted Phosphate Groups); C030012:UDP-N-acetylglucosamine-lysosomal-enzyme-N-acetylglucosaminephosphotransferase
keywords: Adeno-associated viral vector; Bone pathology; Gene therapy; Lysosomal disorder; Mucolipidosis II; N-acetylglucosamine-1-phosphate transferase