Reversal of established bone pathology in MPS VII mice following lentiviral-mediated gene therapy

Ainslie L K Derrick-Roberts; Kavita Panir; Carmen E Pyragius; Krystyna H Zarrinkalam; Gerald J Atkins; Sharon Byers

doi:10.1016/j.ymgme.2016.09.003

Reversal of established bone pathology in MPS VII mice following lentiviral-mediated gene therapy

Mol Genet Metab. 2016 Nov;119(3):249-257. doi: 10.1016/j.ymgme.2016.09.003. Epub 2016 Sep 24.

Authors

Ainslie L K Derrick-Roberts¹, Kavita Panir², Carmen E Pyragius², Krystyna H Zarrinkalam², Gerald J Atkins³, Sharon Byers⁴

Affiliations

¹ Genetics and Molecular Pathology Directorate, SA Pathology, Adelaide, SA, Australia; Department of Paediatrics, The University of Adelaide, Australia. Electronic address: ainslie.derrickroberts@adelaide.edu.au.
² Genetics and Molecular Pathology Directorate, SA Pathology, Adelaide, SA, Australia.
³ Centre for Orthopaedic and Trauma Research, Discipline of Orthopaedics and Trauma, University of Adelaide, Adelaide, SA 5005, Australia.
⁴ Genetics and Molecular Pathology Directorate, SA Pathology, Adelaide, SA, Australia; Department of Paediatrics, The University of Adelaide, Australia; Department of Genetics and Evolution, School of Molecular & Biomedical Science, The University of Adelaide, Australia.

PMID: 27692945
DOI: 10.1016/j.ymgme.2016.09.003

Abstract

Severe, progressive skeletal dysplasia is a major symptom of multiple mucopolysaccharidoses (MPS) types. While a gene therapy approach initiated at birth has been shown to prevent the development of bone pathology in different animal models of MPS, the capacity to correct developed bone disease is unknown. In this study, ex vivo micro-computed tomography was used to demonstrate that bone mass and architecture of murine MPS VII L5 vertebrae were within the normal range at 1month of age but by 2months of age were significantly different to normal. The difference between normal and MPS VII BV/TV increased with age reaching a maximal difference at approximately 4months of age. In mature MPS VII bone BV/TV is increased (51.5% versus 21.5% in normal mice) due to an increase in trabecular number (6.2permm versus 3.8permm in normal mice). The total number of osteoclasts in the metaphysis of MPS VII mice was decreased, as was the percentage of osteoclasts attached to bone. MPS VII osteoblasts produced significantly more osteoprotegerin (OPG) than normal osteoblasts and supported the production of fewer osteoclasts from spleen precursor cells than normal osteoblasts in a co-culture system. In contrast, the formation of osteoclasts from MPS VII spleen monocytes was similar to normal in vitro, when exogenous RANKL and m-CSF was added to the culture medium. Administration of murine β-glucuronidase to MPS VII mice at 4months of age, when bone disease was fully manifested, using lentiviral gene delivery resulted in a doubling of osteoclast numbers and a significant increase in attachment capacity (68% versus 29.4% in untreated MPS VII animals). Bone mineral volume rapidly decreased by 39% after gene therapy and fell within the normal range by 6months of age. Collectively, these results indicate that lentiviral-mediated gene therapy is effective in reversing established skeletal pathology in murine MPS VII.

Keywords: Gene therapy; Lentiviral vector; Micro-CT; Mucopolysaccharidosis type VII; Skeletal pathology.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bone Density / genetics*
Disease Models, Animal
Gene Transfer Techniques
Genetic Therapy*
Glucuronidase / administration & dosage
Glucuronidase / genetics*
Humans
Lentivirus / genetics
Mice
Mucopolysaccharidosis VII / diagnostic imaging
Mucopolysaccharidosis VII / genetics
Mucopolysaccharidosis VII / pathology
Mucopolysaccharidosis VII / therapy*
Osteoprotegerin / genetics
X-Ray Microtomography

Substances

Osteoprotegerin
Tnfrsf11b protein, mouse
Glucuronidase