UPMC Researchers Report On Gene Therapy Advances

March 17, 1998

PITTSBURGH, March 16 -- The field of gene therapy has transformed dramatically, moving from its anticipated primary application of treating genetic disorders to managing chronic illnesses. The University of Pittsburgh Medical Center (UPMC) is at the forefront of gene therapy research for a variety of musculoskeletal disorders including arthritis, osteoporosis, muscle strains and osteogenesis imperfecta (OI). Several UPMC scientists are presenting their findings at the 44th annual Orthopaedic Research Society (ORS) meeting being held March 16 - 19 in New Orleans.

Among the most exciting in terms of clinical application includes 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, Ph.D., Henry J. Mankin Professor of Orthopaedic Surgery at UPMC 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. Dr. Evans and Paul Robbins, Ph.D., director of UPMC's Vector Core Faculty and associate professor of molecular genetics and biochemistry at the University of Pittsburgh, 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 a (TNFa), 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," said Dr. Robbins. Because IL-1Ra and TNFa 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 TNFa, 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 is also underway at the University of Pittsburgh.

"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," commented Johnny Huard, Ph.D., assistant professor of orthopaedic surgery, University of Pittsburgh School of Medicine.

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, Dr. 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, Dr. 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, the 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" predicted Dr. Huard.

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," commented Chris Niyibizi, Ph.D., assistant professor of orthopedic surgery, University of Pittsburgh, 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 Dr. 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," said Niyibizi, "but we have already taken the next step in seeing how much and for how long the hormone actually affects mice," he continued.

University of Pittsburgh Medical Center

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