Adenovirus-mediated direct gene therapy with bone morphogenetic protein-2 produces bone

D. S. Musgrave, P. Bosch, S. Ghivizzani, P. D. Robbins, C. H. Evans, J. Huard

Research output: Contribution to journalArticlepeer-review

225 Scopus citations

Abstract

The need to improve bone healing permeates the discipline of orthopedic surgery. Bone morphogenetic proteins (BMPs) are capable of inducing ectopic and orthotopic bone formation. However, the ideal approach with which to deliver BMPs remains unknown. Gene therapy to deliver BMPs offers several theoretical advantages over implantation of a recombinant BMP protein, including persistent BMP delivery and eliminating the need for a foreign body carrier. A replication defective adenoviral vector was constructed to carry the rhBMP-2 gene (AdBMP-2). The direct in vivo gene therapy approach was applied in both immunodeficient and immunocompetent animals to produce intramuscular bone as early as 2 weeks following injection. Radiographic and histologic analysis revealed radiodense bone containing mature bone marrow elements. Adenovirus-mediated delivery of a marker gene (β-galactosidase) into control animals produced no bone but indicated the cells transduced with the AdBMP-2 vector. Furthermore, comparisons between immunodeficient and immunocompetent animals illustrated the magnitude and significance of the immune response. Gene therapy to deliver BMP-2 has innumerable potential clinical applications from bone defect healing to joint replacement prosthesis stabilization. This study is the first to establish the feasibility of in vivo gene therapy to deliver active BMP-2 and produce bone. Copyright (C) 1999 Elsevier Science Inc.

Original languageEnglish (US)
Pages (from-to)541-547
Number of pages7
JournalBone
Volume24
Issue number6
DOIs
StatePublished - Jun 1999
Externally publishedYes

Bibliographical note

Funding Information:
Recipient of the AOA-Zimmer Travel Award for Orthopaedic Residents, 1999. The authors thank the Genetics Institute (Cambridge, MA) for graciously providing the rhBMP-2 plasmid and Stephen Hardy, Ph.D., for providing the Cre-lox adenoviral system. In addition, the technical and secretarial contributions of Ryan Pruchnic, Marcelle Pellerin, Arvydas Usas, Dana Och, and Megan Mowry are sincerely appreciated. This work was supported by grants to Dr. Johnny Huard from the National Institute of Health (NIH; 1P60 AR44811-01) and the Pittsburgh Tissue Engineering Initiative (PTEI).

Keywords

  • Adenovirus
  • Bone
  • Bone morphogenetic protein (BMP)
  • Direct gene transfer
  • Gene therapy
  • Skeletal muscle

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