Bone morphogenic proteins (BMPs) have been used to induce bone formation in spinal fusions with good results. But the high doses of BMPs needed can produce unwanted side effects, such as significant rates of inflammation and swelling in cervical fusion and ectopic ossification in lumbar fusion. “The patient’s body has a natural response to regulate the effects of BMP,” explained Louis G. Jenis, MD. “It is a negative regulatory cycle. My colleagues and I are trying to modify this natural response so we can use less BMP, still get good healing, and limit potential side effects.”
Published 2/1/2011
|
Annie Hayashi
OREF funds novel research to enhance the effect of BMP in spinal fusions
Although the number of spinal fusions has dramatically increased in recent years, a significant percentage—particularly in patients who are older or have had multiple fusions—do not achieve a solid bony arthrodesis.
Louis G. Jenis, MD |
The Orthopaedic Research and Education Foundation (OREF) awarded Dr. Jenis a research grant to study “Modulation of the Local Gene Expression Environment within the Developing Spinal Fusion Mass with RNA Interference Delivered by Gene Therapy.”
Dr. Jenis is a clinical associate professor of orthopaedic surgery at Tufts University School of Medicine; Ernest Terwilliger, PhD, is coprincipal investigator and assistant professor at Harvard School of Medicine.
Neutralizing the negative regulators
When a bone is healing, Dr. Jenis explained, the body responds with both “up” regulators and “down” regulators to bone formation. The use of BMPs initiates a very high bone formation cascade, but it will not continue indefinitely due to the negative regulators. To suppress negative regulators, larger doses of BMPs must be used.
One of the most potent negative regulators of BMP is a protein called noggin. “When BMP is put into a bone healing site, noggin levels rapidly increase and limit bone formation,” Dr. Jenis said.
“To block production of noggin, we will take advantage of the powerful emerging technology of ribonucleic acid interference (RNAi),” Dr. Jenis continued. “It is a popular technology used in bone formation that reduces the production of the genes. In a few short years, RNAi has become a virtual gold standard for research.”
Dr. Jenis and his colleagues hypothesize that the homeostatic balance of adult bone formation may be effectively and temporarily modulated in a controlled, localized fashion using a gene-silencing approach. They want to apply RNA interference technology to neutralize noggin expression.
“More specifically, we hypothesize that local suppression of noggin will lead to more efficient, rapid, and certain bone formation than can be achieved in either untreated controls or with BMP alone,” he said.
Testing the hypothesis
For this study, the researchers will use adult male rats as models and will perform posterior, bilateral, intertransverse process L5-L6 fusions.
They will place BMP7 in the wound and add RNAi, delivered by gene therapy. “Gene therapy uses the adeno associated virus (AAV). AAV delivers the product that will block noggin effectiveness,” said Dr. Jenis.
When placed in the wound with the BMP, “the AAV is incorporated by the normal cells and the cells start producing the interference for noggin,” he explained. As a result, noggin does not get produced in the site where the BMP is located.
“Genetic manipulation of orthopaedic environments using AAV has been validated previously,” Dr. Jenis said. “The ultimate goal is to increase patient safety and develop ways to decrease the clinical dosage of these very aggressive proteins.”
The study will compare cohorts with autograft and BMP7, with and without AAV-noggin short interfering RNA (siRNA). The researchers will also add nicotine to the model to simulate a clinical situation in which spinal fusion is difficult to achieve.
The team plans to establish a proof of concept—the cell effectively incorporating the AAV followed by a successful fusion. They will then increase the complexity of different and subsequent experiments. More subjects will be added to these experiments so statistically significant differences from the controls can be identified.
“We will raise the bar to conditions that simulate more challenging, but common, clinical situations that present greater barriers to successful therapy,” Dr. Jenis said.
OREF provides critical pathway
“This research grant is critical for me,” Dr. Jenis said. “It has really allowed me, as a clinician scientist, to develop important collaborations with basic science researchers. It is ultimately going to provide us with data that will enable us to obtain further funding. The OREF grant was absolutely essential for us to get started.”
As a clinician and researcher, Dr. Jenis stays focused on the patient. Patient safety is as important as improved fusion rates and reduced pain. “We have to work in the lab to make these proteins safer for patients and then use them in the operating room,” he said. “I tell patients the ultimate goal is to have the safest and best possible outcome. We want to reduce the risks while still elevating their chances of getting better.”
Annie Hayashi is a contributing writer for OREF and can be contacted at communications@oref.org