Controlling IGF-I/Scaffold Binding to Enhance Gene Therapy for Cartilage Repair

Cornell University, Ithaca NY

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Abstract

DESCRIPTION (provided by applicant): Osteoarthritis is a disease that causes cartilage degradation in approximately 27 million Americans age 25 and older, affecting both men and women. It is estimated that by 2030, 67 million people will have doctor-diagnosed arthritis. Although patients become symptomatic later in life, the disease initiates earlier in life with a lesion that could happened as early as in the early 20s. However, because articular cartilage does not self-repair, these lesions are unable to heal. For almost two decades focal cartilage lesions have been treated using chondrocyte transplantation therapy. Such therapy would be enhanced by increasing the chondrocyte matrix synthesis. One of the most potent anabolic regulators of chondrocyte metabolism is insulin-like growth factor (IGF-I). As such, much effort has been focused on controlling IGF-I synthesis by chondrocytes via gene therapy. However, in these systems enhanced IGF-I production persists only one to two weeks. An alternative strategy to increase the time of cell's exposure to IGF-I is based on fabricating new materials to control IGF-I transport. Specifically, by grafting peptides from IGF-I binding proteins (IGFBPs) 18,22 to alginate, through carbodiimide chemistry, can delay release of IGF-I, and that this release depends on the binding affinity and the concentration of the peptide. The goal of this proposal is to combine these two technologies to control production of IGF-I by chondrocytes via gene therapy and extend the time of their exposure to IGF-I by delaying its release using alginate gels modified to contain peptides that bind to IGF-I. The current proposal contains three specific aims that will contribute to the goal. Specific aim 1 is to create an adeno-associated virus based plasmid (pAAV)/IGF-I in 3D alginate scaffolds and to measure IGF-I release, ECM accumulation, and mechanical properties of gel over 36 days in culture. Specific aim 2 is to characterize IGF-I release, matrix synthesis, and mechanical properties of control and KPLHALL-modified alginate containing chondrocytes transfected with pAAV/IGF-I. Finally, Specific aim 3 is to compare IGF-I release, matrix synthesis, and mechanical properties of constructs seeded with pAAV/IGF-I transfected chondrocytes in alginate gels modified with longer and shorter the sequences (PRQDEEKPLHALL, KPLHALL, and ALL) from the mini-IGFBP-5. We believe that controlling both their cellular production and extracellular binding of IGF-I will synergistically enhance chondrocyte biosynthesis and facilitate generation of tissue engineered cartilage.