Orthobiologics
Orthobiologics is a rapidly growing segment of the orthopedics market and represents biologically-active products designed to enhance musculo-skeletal repair and regeneration. According to one industry research report, orthobiologics is the fastest growing segment in orthopedics with an estimated growth rate of 17% and total worldwide sales of $4.2 billion in 2007. The global market for such products is projected to almost double from 2007 levels by 2012.

Bone Fracture Repair
TRC’s initial orthobiologics focus will be on the development of Osteorate™, a DNA-based non-surgical injectable bone graft gel to repair bone fractures and regenerate tissue in certain medically-compromised patient populations. It is estimated that there are more than 6.8 million bone fractures annually in the United States. Of these fractures, 5% to 10% do not heal properly due to non-union or delayed union of the bone due to the extreme severity of the fracture or because the patient is medically impaired due to an illness such as diabetes or osteoporosis or life style choices such as smoking. These non-healing fractures, known as non-union fractures, are costly and debilitating. 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. The ability to manufacture therapeutic agents in vivo at a specific site makes hard tissue repair an attractive application for Tissue Repair Company’s Gene Activated Matrix™ (GAM™) technology.

Osteorate will be based on a reformulation of TRC’s DNA-based Excellarate wound healing product candidate, now in late-stage clinical development, which is designed to stimulate localized and sustained cellular production of platelet-derived growth factor-B (PDGF-B) protein as a treatment for patients with non-healing diabetic foot ulcers. Based on recently announced formulation advances, Osteorate would be developed as a pre-mixed ready-to-use-syringe that would be stored in a physician’s office at a temperature of about 4 degrees Celsius. PDGF-B protein is a well known bone growth mediator and is already used in several FDA approved products and medical devices for soft and hard tissue healing.

Spinal Fusion
The Gene Activated Matrix technology platform is expected to be further expanded in order to biologically enhance surgical spinal fusion procedures in patients with degenerative disc disease. Market data indicates that there are more that 500,000 surgical spine fusion procedures performed annually in the U.S. These surgical fusion procedures utilize autograft, bone graft substitutes or Bone Morphogenetic Proteins (BMPs) to facilitate vertebrae fusion. The use of BMP growth factor proteins is becoming more widely adopted in part to reduce the need for harvesting surgical procedures and the inherent risks associated with these surgeries. Exemplary genes that will be evaluated using the GAM technology include a chimeric variant of BMP-4 (chBMP4).

The BMP-4 protein is considered to be one of the more potent members of the Bone Morphogenetic Protein (BMP) family. By creating a chimeric variant that further improves the BMP-4 construct, the resulting protein was found to be produced very efficiently and to be highly effective.

In the figure below, GAM chBMP4 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 GAM chBMP4 treated tissues (Upper Panel). In contrast, bone formation was not detected in animals treated with matrix alone (Lower Panel).

Significant new bone growth with GAM chBMP4 (top) compared to GAM placebo (bottom) at 6 weeks.

Periodontal Tissue Engineering
Recent preclinical research has demonstrated the potential benefits of TRC’s GAM technology for accelerating and enhancing periodontal tissue repair and oral implant osseointegration (Chang, et al., Gene Therapy; 10 September 2009; doi: 10.1038/gt.2009.117). Oral implants are widely accepted in dental medicine as a reconstructive treatment for tooth replacement due to gum disease, tooth decay, injury or congenital defects. In 2006, the combined U.S. market for dental bone graft substitutes and other biomaterials was valued at slightly over $150 million. The market is expected to increase to over $415 million by 2013, as the number of bone graft procedures associated with dental implants increases.

The preclinical research, conducted at the University of Michigan, demonstrated that collagen-mediated delivery of an adenovector encoding PDGF-B (AdPDGF-B/collagen) accelerates and enhances oral implant osseointegration, and leads to significantly higher bone-implant contact, defect fill, bone area and tissue mineral density than placebo. The study also reported that AdPDGF-B/collagen was safe, with no dissemination of the vector away from the treatment site, and no alteration of hematological and clinical chemistry parameters associated with the AdPDGF-B/collagen treatments.