? Aseptic loosening has become the major complication of total joint replacement, with an incidence of as high of 34%. Our long-term goal is to develop therapeutic approaches to prevent or retard the process of aseptic loosening of prosthetic joint. Our hypothesis is that wear debris-associated inflammation and osteolysis are separate but related mechanisms in the periprosthetic tissue, and both anti-inflammatory therapy and antiosteolytic therapy are required to inhibit aseptic loosening. Delivery of the generally short half-life therapeutic agents to the loosening prosthetic joint is highly problematic. Gene therapy, though still in its infancy, provides attractive avenue for targeted delivery and sustained expression of therapeutic protein(s). The objective of this proposal is to validate a murine long-term model of a prosthetic joint failure due to wear debris stimulation for the evaluation of combination gene therapy against inflammation and osteolysis. This will be accomplished by pursuing the following specific aims: (1) to characterize the biomechanical and pathological aspects of a longterm mouse model of debris-associated bone resorption and joint prosthesis failure; (2) to evaluate the efficacy of combination anti-inflammatory and anti-osteolytic gene therapy in preventing or treating debris-associated implant loosening; and (3) to examine the influence and cell trafficking of a cell-gene (ex vivo) therapy, and compare it with in vivo gene transfer on the aspects of transgene expression and dissemination, long-term effectiveness, and potential adverse effects. The successful outcome of the study will validate a useful tool for the investigation of aseptic loosening, and lay important foundations for virus-mediated gene delivery of therapeutic proteins, especially OPG in combination with pro-inflammatory cytokine blockers, as a promising therapeutic regimen for debris-associated prosthetic loosening. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Small Research Grants (R03)
Project #
1R03AR054929-01
Application #
7251712
Study Section
Special Emphasis Panel (ZAR1-EHB-H (J1))
Program Officer
Panagis, James S
Project Start
2007-06-15
Project End
2010-05-31
Budget Start
2007-06-15
Budget End
2008-05-31
Support Year
1
Fiscal Year
2007
Total Cost
$75,250
Indirect Cost
Name
Wayne State University
Department
Orthopedics
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
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