Reversal of established bone pathology in MPS VII mice following lentiviral-mediated gene therapy
| Autor: | Ainslie L.K. Derrick-Roberts, Gerald J. Atkins, Kavita Panir, Carmen E. Pyragius, Sharon Byers, Krystyna H. Zarrinkalam |
|---|---|
| Přispěvatelé: | Derrick-Roberts, Ainslie LK, Panir, Kavita, Pyragius, Carmen E, Zarrinkalam, Krystyna H, Atkins, Gerald J, Byers, Sharon |
| Rok vydání: | 2016 |
| Předmět: |
musculoskeletal diseases
0301 basic medicine Micro-CT Pathology medicine.medical_specialty Bone disease Bone density Endocrinology Diabetes and Metabolism Mucopolysaccharidosis VII Metaphysis Biochemistry 03 medical and health sciences Mice Endocrinology Osteoprotegerin Osteoclast Bone Density Internal medicine Genetics Medicine Animals Humans Molecular Biology Glucuronidase Bone mineral gen therapy biology business.industry Lentivirus Gene Transfer Techniques Genetic Therapy X-Ray Microtomography medicine.disease Disease Models Animal 030104 developmental biology medicine.anatomical_structure RANKL skeletal pathology biology.protein business |
| Zdroj: | Molecular genetics and metabolism. 119(3) |
| ISSN: | 1096-7206 |
| Popis: | 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 1 month of age but by 2 months 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 4 months 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 (6.2 per mm versus 3.8 per mm 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 beta-glucuronidase to MPS VII mice at 4 months 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 6 months of age. Collectively, these results indicate that lentiviral-mediated gene therapy is effective in reversing established skeletal pathology in murine MPS VII. (C) 2016 Elsevier Inc All rights reserved. usc Refereed/Peer-reviewed |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect