University Times

Researchers study drug to treat shock in trauma patients

Pitt surgery department researchers are participating in a study to determine the effectiveness of a new drug in treating hemorrhagic shock in trauma patients. Researchers hope the experimental drug will help reduce the incidence of multiple organ failure and death from trauma.

UPMC Health System is participating in the study with other sites nationwide.

An experimental drug, called Hu23F2G, will be given to trauma patients to treat the harmful side effects of shock and possibly prevent death.

People in shock have very low blood pressure and decreased blood flow, usually because they have lost blood. Sometimes, when people are in shock, their white blood cells become too active and attack their own bodies. This may cause organ failure and death. The study drug may stop the white blood cells from sticking to the insides of blood vessels and causing damage. Every effort will be made to obtain consent for the study immediately upon patient arrival, researchers said. However, these patients are often very ill and family members are not initially available. In these situations, this study is made possible by guidelines, recently adopted by the U.S. Food and Drug Administration, that will allow consent to be waived in studies of emergency therapies for patients in life-threatening situations. Due to the nature of this study, patient consent may not be possible. Obtaining advance consent from family members will also be difficult because the drug must be given within three hours of hospital arrival. Patients or their family members will be notified as soon as possible about the study and given the option of whether or not to continue.

About 20 patients will be enrolled in the study at UPMC. Patients will be given all current standard treatments. Two-thirds of the patients will receive the drug in one of two dosage amounts. The other one-third will receive a saline solution.

Principal investigator in the study is Andrew Peitzman, professor in the Department of Surgery. Sub-investigators include: Brian Harbrecht, assistant professor of surgery; Timothy Billiar, Watson Professor of Surgery; Anita Courcoulas, assistant professor of surgery, and Russell D. Dumire, trauma fellow in the surgery department.

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Gene therapy advances reported

The field of gene therapy has changed dramatically, moving from its anticipated primary application of treating genetic disorders to managing chronic illnesses.

UPMC Health System researchers presented their recent findings on gene therapy research for a variety of musculoskeletal disorders at the 44th annual Orthopaedic Research Society (ORS) meeting, March 16-19 in New Orleans.

* Included was a progress report on the first human trial for arthritis gene therapy. Rheumatoid arthritis (RA), affecting an estimated 2.1 million Americans, has been connected to interleukin-1 (IL-1), a cellular substance thought to cause the painful inflammation and debilitating erosion in rheumatoid joints.

After January 1996 FDA approval, researchers injected cells genetically engineered to block the action of IL-1 directly into selected RA patients' joints. This gene encodes the interleukin-1 receptor antagonist protein, or IL-1Ra.

Seven of the nine gene transfer procedures approved by the FDA for this protocol have been completed, with preliminary, but promising results. No adverse effects have been reported. Gene expression has occurred in all patients tested thus far in the clinical trial, which provides a foundation for similar treatments of RA and related joint disorders.

"We are very encouraged by these results and are eager to begin the next phase of the study," commented principal investigator Chris Evans, Henry J. Mankin Professor of Orthopaedic Surgery at Pitt and director of UPMC's Ferguson Laboratory for Orthopaedic Research. "Now that we have established that the IL-1Ra gene is expressed, we hope that the next trial will involve intervening at earlier stages of the disease, with the intent of eliminating or delaying the need for surgery."

The early phase of this research in humans is not designed to treat disease, but to ensure the safety of the procedure and to confirm that gene transfer to human joints is possible. The protocol is the result of extensive pre-clinical safety testing and more than eight years of exhaustive preparatory studies. The procedure entails the removal of a number of the patient's own cells, which are then cultured and genetically modified to carry the IL-1Ra gene that blocks the binding of IL-1 to its receptor. The transformed cells are injected into the joints one week prior to the patient undergoing previously scheduled joint replacement. During joint replacement surgery, researchers remove joint lining and fluid and then examine them post-operatively to determine the success of the gene transfer.

* Osteoporosis, which involves increased bone fragility, has potential gene therapy treatment options as well. Evans and Paul Robbins, director of UPMC's Vector Core Facility and Pitt associate professor of molecular genetics and biochemistry, are pursuing the possibility that estrogen-related bone loss may be diminished by blocking the production of certain cell products, namely IL-1 and tumor necrosis factor (TNF ), both thought to be involved in the progression of the disease. "Inserting receptor blocking genes, similar to those seen in RA treatment studies, could abate the bone loss more efficiently than current treatment options that deliver such 'blocker' proteins directly," Robbins said. Because IL-1Ra and TNF receptor antagonist proteins are broken down easily, frequent and repeated injections are required. In their study, researchers employed a viral vector to insert the genes into an animal's cells. The cells then produced these healing substances both locally and throughout the body. The researchers found that a single injection of cells containing the IL-1Ra gene led to decreased bone loss in the animal trials. These preliminary data, along with other current strategies to simultaneously block the effects of both IL-1 and TNF, suggest that gene therapy might treat not only local, but systemic diseases, including osteoporosis and RA.

* Research using muscle cells to treat a variety of musculoskeletal problems also is underway at Pitt. "Skeletal muscle cells have great potential for treating muscle disorders like muscular dystrophy, but can also be used as a vehicle to deliver genes to improve muscle healing after common muscle injuries," said Johnny Huard, assistant professor of orthopaedic surgery. Growth factors affect the regeneration of injured muscle (lacerations, contusions and strains), and researchers at Pitt are exploring delivery systems for genes of such growth factors. In this study, Huard has delivered a "marker" gene packaged in a virus to muscle cells. The marker gene, while not therapeutic, allows researchers to determine whether they can successfully transfer genes to tissues. Some muscle-injured animals received direct injections of the virus/marker gene complex. In other animals, Huard's group first removed some muscle cells and genetically altered them. Then, these cells were injected back into the injured muscle. Using both delivery systems, researchers found that this "marker" is expressed in muscle tissue up to 15 days after insertion.

"Although there remain hurdles to overcome for the gene treatment of muscle damage, this study indicates that we may soon provide growth factors for muscle regeneration through gene therapy, accelerating and even improving muscle healing post-injury," Huard predicted.

* Osteogenesis imperfecta (OI) encompasses a variety of disorders characterized by excessive bone fragility. OI leads to repeated life-threatening fractures and extremely short stature in affected patients. Scientists know that an error in the genes encoding for type 1 collagen, an extremely strong protein found in bone, is responsible for the bone fragility seen in OI. UPMC researchers are attempting to remedy disease complications through gene therapy in an animal model of the disease. In one study, researchers investigated the capacity of certain bone marrow cells to navigate back to bone. Researchers tracked genetically marked bone marrow cells from the injection site at one leg bone and subsequently detected them at other organs and bones of the treated mice. Presumably, these cells trafficked through the circulatory system.

While the cells were cleared from other organs at 10 days after the injection, genetically marked cells remained in the bone 30 days after transplantation. "This means that these bone marrow cells can in fact 'find' their way preferentially to bone and express newly inserted genes. Now that we know the procedure works, we can explore using such cells to deliver therapeutic collagen genes to bones of OI patients so that we could potentially reduce bone fractures," said Chris Niyibizi, assistant professor of orthopaedic surgery, who heads this research.

* Treatment for growth deficiencies that often accompany bone fragility of OI patients is currently limited to daily growth hormone injections to affected children. UPMC researchers have sought to employ genetically engineered bone cells as a more efficient method of providing the hormone. "After only a single treatment, these enhanced cells would deliver the growth hormone to the child, a significantly more convenient treatment option for OI patients," explained Niyibizi, presenter of a study that uses an animal model to test growth hormone gene expression.

Researchers confirmed that both in laboratory cell cultures and in a mouse's body, engineered bone cells exhibited high efficiency in expressing an introduced growth hormone gene.

"Confirmation of gene expression itself is very exciting," Niyibizi said, "but we have already taken the next step in seeing how much and for how long the hormone actually affects mice." UPCI reports cancer findings University of Pittsburgh Cancer Institute (UPCI) scientists presented a wide range of cancer and cancer-treatment-related findings at the annual meeting of the American Association for Cancer Research held March 29-April 1 in New Orleans.

Among the highlights of the presentations were that:

* Researchers have found the first bladder-cancer specific marker that distinguishes tissues from individuals with bladder cancer from those without the disease and that can be easily isolated from urine.

* Certain women who smoke while pregnant are at high risk of passing along genetic damage to their babies.

* Animal models indicate that blocking two cellular growth pathways between certain proteins causes tumor cells to die.

* A new chemical agent, curacin A, affects cell division, effectively inducing programmed cell death, or apoptosis, in a variety of cancer cell lines ordinarily resistant to other forms of chemotherapy.

* A form of vitamin D appears to exert an anti-cancer effect in animals with prostate cancer by modulating the cancer cells' life cycle and inducing apoptosis.

* Ovarian cancer patients treated with interleukin-2 (IL-2) promote a large population of dendritic cells in fluid-filled sacs called ascites. Dendritic cells are thought to play a key role in waging an effective immune response against cancer.

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UPMC study on aneurysm repair announced

A study by surgeons at UPMC Health System has found that many patients may benefit from a new treatment for an abdominal aortic aneurysm called endovascular surgery. An aneurysm is a ballooning or bulging of the main artery in the abdomen which, left untreated, may rupture without warning and bleed, causing death in up to 80 percent of patients.

In endovascular surgery, the aneurysm is repaired from inside the aorta using a catheter instead of through a large incision extending over the entire abdomen. About 90 percent of the 50 patients who underwent the procedure were discharged within two or three days compared to an average of 5.8 days for open procedure patients. The findings were presented by Michel Makaroun, Pitt associate professor of surgery, director of endovascular surgery and principal investigator in the study, at the 26th annual Symposium of Vascular Surgery of the Society for Clinical Vascular Surgery, held in Coronado, Calif.

"This procedure may prove to be safer, especially in high-risk patients," Makaroun said. "We estimate that we have applied this procedure in one-third of our patients with aneurysms. In the future, new types of devices will allow us to treat up to 70 or 80 percent of patients with this technique."

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UPMC using genetically engineered protein in congestive heart failure study

In a new clinical study at UPMC Health System and Baylor University Hospital, cardiologists are treating congestive heart failure with a genetically engineered protein to "mop up" and control a naturally occurring compound, called TNF-alpha, that causes inflammation and heart damage.

This "mopping up" prevents TNF-alpha from impacting on heart tissue and may lead to an improvement in some of the symptoms of congestive heart failure patients. The protein, called TNFR:Fc, inhibits the activity of TNF-alpha. People with congestive heart failure have elevated levels of TNF-alpha, and it has been suggested that TNF-alpha may play a role in the development of heart failure, according to Arthur Feldman, Harry S. Tack Professor of Medicine, chief of cardiology at UPMC Presbyterian and professor of cell biology and physiology.

"TNF-alpha can produce dysfunction of the heart, heart remodeling, pulmonary edema and cardiomyopathy," Feldman said. "It is known to be produced by the failing heart but not by the non-failing heart. In our Cardiovascular Research Center, we developed transgenic mice which overexpressed TNF-alpha. They subsequently developed severe myocarditis or inflammation of the heart."

In an earlier preliminary clinical trial carried out in Houston by Douglas Mann, professor of medicine at Baylor College of Medicine and principal investigator of the current study, patients with congestive heart failure who received a single injection of TNFR:Fc were able to walk farther and felt better than before therapy. There also was an improvement in the heart's ability to pump blood.

"Current therapies for congestive heart failure are less than adequate," said Feldman, principal investigator at UPMC. "This is the first time a genetically engineered, specifically targeted drug has been developed for congestive heart failure. This trial will investigate whether we can use this therapy safely in congestive heart failure and whether we can improve heart function and the quality of life of our heart failure patients." An estimated 4.8 million Americans have congestive heart failure, in which the heart cannot maintain adequate circulation of the blood because it fails to pump blood properly. It is the chief cause of about 40,000 deaths in the United States each year and is a major contributing factor in an additional 225,000 deaths.

TNFR:Fc is an investigative product developed and manufactured by Immunex Corporation, a Seattle biopharmaceutical company, under the trademark Enbrel.