The candidate's goals are to develop into an outstanding clinical scientist with an independent laboratory based research program within the next 5 years. The candidate, and candidate's department, is committed to the specialized study necessary to achieve this goal. Under the proposed plan, the candidate will transition from a full-time academic clinical surgeon into a clinical scientist through an intensive research experience under the guidance of world-renowned basic scientists in gene therapy, cartilage and bone biology. This proposed career development will capitalize on the candidate's recently completed (Jan 2002) 1-yr fellowship experience (F33AR08639-01) at the Center for Molecular Orthopedics at Brigham and Women's Hospital. The fellowship provided exposure to basic research skills in molecular biology of gene transfer, but further mentoring and greater time devotion will be necessary to generate an independent research effort. The goal of the proposed research project is to enhance the long-term healing of articular cartilage and subchondral bone injury. Injured or degenerate articular cartilage and underlying bone either does not heal or heals with a poor replacement tissue of inferior biomechanical function. We propose to deliver cartilage/bone morphogen genes and a chondroprotective gene efficiently to joints with cartilage injury using an appealing vector system for human gene delivery (AAV). We will investigate viral tropism to articular cells and develop novel AAV based vector systems for successful targeted delivery of our therapeutic genes to resident articular cells; chondrocytes, bone marrow-derived cells and synovial cells. Our objective is to use a gene delivery mechanism to compare the effectiveness of two growth factors, bone morphogenetic protein (BMP)- 2 and BMP-6, to promote the rate and integrity of cartilage repair, with and without the combination of an antagonist of cartilage degradation (Interleukin-1 receptor antagonist; Il-1 ra). The genes hBMP-2 and hBMP-6 offer therapeutic promise as supportive to chondrocyte proliferation and the endochondral ossification process necessary to heal articular cartilage defects and support the reformation of a secure cartilage-subchondral bone interface. IL-lra has already been demonstrated to ameliorate the articular cartilage degradation process to a degree that is clinically relevant in osteoarthritis models, including articular cartilage injury models. These genes, separately and in concert may significantly improve our current therapy options to the management of joint injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AR049201-05
Application #
7436105
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Wang, Fei
Project Start
2004-09-01
Project End
2010-05-31
Budget Start
2008-06-01
Budget End
2010-05-31
Support Year
5
Fiscal Year
2008
Total Cost
$124,713
Indirect Cost
Name
Ohio State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Ishihara, Akikazu; Weisbrode, Steve E; Bertone, Alicia L (2015) Autologous implantation of BMP2-expressing dermal fibroblasts to improve bone mineral density and architecture in rabbit long bones. J Orthop Res 33:1455-65
Ishihara, Akikazu; Ohmine, Ken; Weisbrode, Steve E et al. (2014) Effect of Intra-Medullar and Intra-Venous Infusions of Mesenchymal Stem Cells on Cell Engraftment by In-Vivo Cell Tracking and Osteoinductivity in Rabbit Long Bones: A Pilot Study. Orthop Muscular Syst 3:
Santangelo, K S; Pieczarka, E M; Nuovo, G J et al. (2011) Temporal expression and tissue distribution of interleukin-1? in two strains of guinea pigs with varying propensity for spontaneous knee osteoarthritis. Osteoarthritis Cartilage 19:439-48
Henderson, Sally E; Santangelo, Kelly S; Bertone, Alicia L (2011) Chondrogenic effects of exogenous retinoic acid or a retinoic acid receptor antagonist (LE135) on equine chondrocytes and bone marrow-derived mesenchymal stem cells in monolayer culture. Am J Vet Res 72:884-92
Murray, Shannon J; Santangelo, Kelly S; Bertone, Alicia L (2010) Evaluation of early cellular influences of bone morphogenetic proteins 12 and 2 on equine superficial digital flexor tenocytes and bone marrow-derived mesenchymal stem cells in vitro. Am J Vet Res 71:103-14
Santangelo, Kelly S; Baker, Sarah A; Nuovo, Gerard et al. (2010) Detectable reporter gene expression following transduction of adenovirus and adeno-associated virus serotype 2 vectors within full-thickness osteoarthritic and unaffected canine cartilage in vitro and unaffected guinea pig cartilage in vivo. J Orthop Res 28:149-55
Ishihara, Akikazu; Zekas, Lisa J; Litsky, Alan S et al. (2010) Dermal fibroblast-mediated BMP2 therapy to accelerate bone healing in an equine osteotomy model. J Orthop Res 28:403-11
Ishihara, A; Zekas, L J; Weisbrode, S E et al. (2010) Comparative efficacy of dermal fibroblast-mediated and direct adenoviral bone morphogenetic protein-2 gene therapy for bone regeneration in an equine rib model. Gene Ther 17:733-44
Zachos, Terri A; Bertone, Alicia L; Wassenaar, Peter A et al. (2007) Rodent models for the study of articular fracture healing. J Invest Surg 20:87-95
Zachos, Terri; Diggs, Alisha; Weisbrode, Steven et al. (2007) Mesenchymal stem cell-mediated gene delivery of bone morphogenetic protein-2 in an articular fracture model. Mol Ther 15:1543-50