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Preclinical Programs
Therapeutic Angiogenesis
Therapeutic angiogenesis, the ability to pharmacologically induce new blood vessel growth, is a promising approach for treating ischemic heart disease and peripheral vascular disease. The clinical goal is to establish new blood supplies to ischemic tissue, thereby increasing tissue survival and function, as well as relieving patient symptoms such as angina and leg pain.
In 2001, 1.5 million angioplasty and stent procedures were performed. An additional 516,000 coronary arterial bypass graft procedures were performed in the same time period. Yet there is still a major need for improvement over current modalities, specifically for those individuals who are unsuitable for bypass surgery and in whom medical therapy is unsuccessful.
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GAM fills a unique niche in the field of therapeutic angiogenesis. Tissue damage resulting from chronic ischemia contains progenitor repair cells that infiltrate a GAM and lead to highly localized transgene expression and protein activity. GAM can either be administered alone or in combination therapy with surgery. Based on its ability to promote and remodel wound repair, GAM delivery of growth factor genes to ischemic sites may allow for the enhanced angiogenesis needed to achieve more robust clinical responses.
Tissue Repair Company now has a GAM product candidate ready to advance through the preclinical phases needed to enter Phase I human studies. This product’s potential has been demonstrated in a number of animal models. For example, GAM’s ability to induce blood vessel formation in muscle wounds was illustrated by filling such wounds with a GAM containing the gene for FGF2. Three weeks later, new blood vessels (labeled with arrows) had developed within the muscle tissue. Antibody staining confirmed that most of these vessels were muscular arterioles, a vessel type appropriate for bringing new blood supplies to ischemic tissues. Similar responses were not seen in wounds treated with either a control GAM or recombinant FGF2 protein. These findings confirm numerous preclinical and clinical findings, suggesting that gene therapy is a more promising approach to therapeutic angiogenesis than the use of recombinant proteins.
Orthopedics
In 1999 there were an estimated 3.5 million target patients for orthopedic tissue-engineered products in the U.S., representing a potential market opportunity of over $8.4 billion. This population encompasses patients with bone fractures, soft tissue injuries (e.g. ligament, tendon, meniscus), spine fusion and cartilage repair. By 2010 the target patient population is forecast to reach 5.4 million with a market opportunity of over $13.2 billion.
Current available therapies for hard tissue repair have many limitations. Bone grafts are commonly used to fill defects or voids resulting from bone loss due to trauma as well as to augment the healing of fractures or fusions. Allograft is difficult to work with and limited in supply, and it poses a safety risk. Devitalized graft materials (synthetic and natural) stimulate low, unpredictable amounts of endogenous bone and are subject to fatigue degradation and catastrophic failure. It is estimated that bone grafts were used in approximately 450,000 surgical procedures performed in 1999. Nearly 60% of these procedures utilized the patient’s own tissue and 34% employed allogenic bone.
The ability to manufacture therapeutic agents in vivo at a specific site makes hard tissue repair an attractive application for GAM technology. Tissue Repair Company has developed a GAM product prototype for hard tissue repair, which may be used for the treatment of spinal fusions and long bone fractures.
In the figure, adenovirus containing an osteogenic gene was delivered surgically in a collagen matrix into a rabbit defect model. Bone formation filled the surgical site 6 weeks after treatment. Mature bone was formed in osteogenic GAM treated tissues (Upper Panel). In contrast, bone formation was not detected in animals treated with matrix alone (Lower Panel).
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