SAN DIEGO — As the 74th Annual Meeting of the American Academy of Orthopaedic Surgeons (Rosemont, Illinois) convened here yesterday morning, even the famed Southern California sun and stunning ocean views couldn't draw attendees away from the panels. Topics such as "orthopedic war injuries" and "international perspectives on rotator cuff disease" drew standing room-only crowds as conference-goers packed the convention center.
One topic addressed at the AAOS conference, as well as at recent medical meetings such as the Transcatheter Cardiovascular Therapeutics conference, is gene therapy.
Regis O'Keefe, MD, PhD, professor of orthopedics with the University of Rochester Medical Center (Rochester, New York), billed gene therapy as a "hot topic across all areas of medicine."
Since the high-profile death of young patient Jesse Gelsinger in 1999, which resulted in a halt of gene therapy trials (MDD, Jan. 23, 2003) and the resultant flurry of negative media coverage, the field has been steadily — and much more quietly — moving forward.
Clinical trials are ongoing for indications such as cancer, and orthopedic surgeons are becoming increasingly interested in the potential of this strategy for applications targeting arthritis, osteoporosis, orthopedic tumors and tissue repair.
In fact, orthopedics may be the field to "get gene therapy out into the public," according to Steven Goldstein, PhD, a professor of orthopedic surgery at the University of Michigan Medical School (Ann Arbor).
His rationale: that orthopedics would seem to require a more transient delivery of gene therapy, such as stimulation of protein production just long enough to repair a bone, rather than the permanent alterations required in the treatment of other diseases and genetic disorders.
The specific strategies required for delivery is a core issue in gene therapy, with researchers trying to capture the efficacy of viral vectors, as well as the safety and cost-effectiveness of non-viral approaches. Goldstein pointed to studies that have used direct injection of the gene of interest into a wound and emphasized the promise of "direct matrix" delivery, an off-shoot of this approach that involves coating the genes onto a three-dimensional surface which is then implanted into the injury site.
In the case of bone repair, Goldstein told Medical Device Daily, the 3-D surface could be a bone graft, a collagen sponge, a metal implant or a bioresorbable implant.
The advantage of this approach in healing musculoskeletal injuries would be the ability to help bone "come back to life," O'Keefe said. He pointed to the fact that bone grafts used following the removal of osteosarcomas are "dead" bone, thus not capable of establishing vasculature. And so the microfractures that occur due to everyday life worsen until the bone fractures, which can cause failure of the graft and result in amputation.
In a study published in Nature Medicine (11 (3): 291-7, 2005), O'Keefe and his team coated a section of murine bone with recombinant viral vectors, encapsulating the genes that encode for RANK ligand and VEGF. When the coated bones were re-implanted into mice, the surrounding bone took up and expressed the proteins, resulting in bone repair.
He said that his group is currently in discussions with the FDA, with the hope of initiating a clinical trial of the technique in the next year or two.
Goldstein said he could see this application of gene therapy being used in combination with — and also potentially as a "next-generation" alternative to — current treatments, such as recombinant bone morphogenetic protein (rhBMP-2). The Infuse Bone Graft product from Medtronic (Minneapolis) contains rhBMP-2 to stimulate bone regeneration.
For the second fiscal quarter, ended Oct. 27, 2006, Medtronic reported 36% revenue growth for the Infuse Bone Graft, which is approved for use in spinal surgery and which an FDA advisory panel recommended for approval in oral maxillofacial procedures in November 2006.
Recombinant proteins, such as rhBMP-2, are limited by their rapid degradation inside the body. Gene therapy could potentially offer the ability to secrete proteins of interest over a much longer period of time.
Goldstein predicted that clinical trials using gene therapy in orthopedic settings will become more common "within five years." He noted recent advances in other indications, such as cancer, cardiac ischemia, Parkinson's disease and sickle-cell disease.
In the orthopedic space, Targeted Genetics (Seattle) is conducting a Phase I/II trial of tgAAC94, a tumor necrosis factor-alpha inhibitor delivered via a viral vector to treat inflammatory arthritis.
Earlier this week, the company reported interim data indicating the approach is well-tolerated and demonstrating a reduction of tenderness and swelling of the injected joint following injection.
Additionally, Tissue Repair Company (San Diego) has conducted early-stage clinical research in wound healing using a collagen matrix coated with virally-delivered human Platelet-Derived Growth Factor-B (PDGF-B).
Non-profit and government agencies are also increasing their funding for gene therapy research in the orthopedic space.