The genetic blueprint of living things is a beautiful tapestry, one might say. Genes are perfectly woven together to produce life—individually or in tandem with others, these genes trigger all the functions that are needed for life.
Scientists have been studying the human genetic tapestry for many years, and now are poised to mount a full-scale attack on diseases such as cancer by correcting the underlying genetic problems. The age of "gene therapy" has dawned.
Health Science Center researchers are among those designing strategies to intervene where a gene is missing or broken. The insertion of new genes to correct a disease state is called gene therapy. It's a way to reweave unraveled threads in the genetic tapestry.
Michael F. Sarosdy, MD, professor of surgery at the Health Science Center, is one of several principal investigators around the country for a new multi-center gene therapy intervention trial in human patients with recurrent bladder cancer. The trial, supported by CANJI Inc. of San Diego and starting this summer, will be the first of its kind conducted in patients with this form of cancer. The work involves design of a vector, or carrier, that would allow the gene product to most successfully penetrate a bladder tumor or the bladder lining where a new tumor might form.
Gene therapy for bladder cancer will seek to infuse "tumor-suppressor" genes such as those studied by Wen-Hwa Lee, PhD, director of the Health Science Center's Institute of Biotechnology (IBT) and professor of molecular medicine. These genes, which act as brakes on cancer, include retinoblastoma (RB) and p53. "As the clinical trial proceeds, it may become clear that more than one gene product may be needed to stop the cascade of genetic defects that result in a cancerous lesion," Dr. Sarosdy said.
The bladder cancer testing will be conducted with particular attention to side effects and toxicity as the dosage level of the gene product is increased. Researchers will seek to assess whether instillation of the gene product directly into the bladder via catheter will achieve a lasting, durable change in the genetic makeup of the bladder tissue, thereby preventing future cancer recurrence. Preventing "superficial" bladder tumors is especially important because, in 30 percent to 50 percent of cases, these lesions on the surface of the bladder lining precede development of more dangerous 'muscle-invasive' tumors. Treatment of the muscle-invasive tumors usually requires removal of the bladder, Dr. Sarosdy said.
"Efforts will be made to measure the levels of gene product in the bloodstream and in other tissues, to ensure there is no damage caused by the gene product elsewhere," he said. Patients will be seen in San Antonio at University Hospital, Audie L. Murphy Memorial Veterans Hospital and the Cancer Therapy and Research Center.
Gene therapy was first attempted by scientists at the National Institutes of Health (NIH). In late 1990, the first genetically altered cells were given to a girl with an immune-deficiency syndrome made famous in the movie "The Boy in the Plastic Bubble." (The movie dramatized the life of a real Houston teenager who lived in a small, sterile-environment enclosure because exposure to germs would prove lethal.) The NIH team replaced a defective gene that normally produces adenosine deaminase, a critical immune system enzyme. Subsequently, another girl received the same therapy. The regimen worked; the two girls developed stronger immune systems and the replacement genes could be seen in their white blood cells more than four years later.
Currently, more than 100 human trials of gene therapies involve nearly 600 patients worldwide. Areas of intervention include cancer, AIDS and genetic disorders such as familial hypercholesterolemia, a defect that causes very high blood cholesterol levels. Despite some early successes, however, technical problems with gene therapy have prevented commercialization and widespread testing, said Barbara D. Boyan, PhD, professor of orthopaedics at the Health Science Center and director of its Industry-University Cooperative Research Center. "The biggest question about gene therapy is how to control gene activity, or expression, once the gene is introduced into the body," Dr. Boyan noted.
Gene therapy can be accomplished by inserting the gene directly into a target cell, or by placing the gene into a vector or carrier that can infiltrate the target cell and release the gene product efficiently. "This is very complicated work," Dr. Boyan said. The company OsteoBiologics Inc., a Health Science Center spin-off, is working with scientists at the University of California, San Diego on scaffolds for putting genetically engineered cells into cartilage and bone. The purpose is cartilage repair.
Meanwhile, Dr. Lee's group studies gene therapy in several model systems. "Can cancer's rampant multiplying be slowed?" the scientists ask. They've found that inserting tumor-suppressor genes (such as retinoblastoma) into cancer cells does have the desired effect—the cancer is arrested. The first experiments involved cultured human cancer cells; later, the same concept was proven in a more accurate animal model. These findings provide a "solid foundation" for designing clinical trials of gene therapy in human cancer patients, the researchers concluded in a recent published paper.
"People are doing clinical trials using one of our findings," Dr. Lee said. In fact, many centers in the United States and abroad are conducting clinical trials of p53, a tumor-suppressor gene, to treat many types of cancers, noted Tatta Nagabhushan, PhD, senior vice president of biotechnology at Schering-Plough Corp. and head of CANJI Inc., a wholly owned subsidiary of Schering-Plough. The company is underwriting many gene therapy studies.
"Dr. Lee was instrumental in developing the tumor-suppressor gene concept," Dr. Nagabhushan said. "The p53 tumor-suppressor is one of the first to be explored. Retinoblastoma gene therapy, meanwhile, is in preclinical studies. Scientists are looking at the utility of the RB (retinoblastoma) gene in hyperproliferative diseases other than cancer. Examples of that are restenosis following angioplasty (reclosure of an artery after surgery) and age-related macular degeneration, a disease of the retina in the eye."
Many scientists at the Health Science Center are investigating the potential of gene therapy, Dr. Boyan said. Holding a magnifying glass to the genetic tapestry, they are searching out core causes of genetic disorders in the laboratory. "Generally, the applications are not immediately translatable to the layperson," Dr. Boyan said, "but the basic research conducted on this campus will contribute to the rise of clinical treatment such as that administered in Dr. Sarosdy's bladder cancer trial."
Cancer researcher Douglas Yee, MD, is another investigator working on the genetic tapestry. Dr. Yee, associate professor of medicine at the Health Science Center, recently published a paper on gene therapy with coauthor Savio Woo, PhD, of Mount Sinai Medical Center in New York City. The researchers sought to test a gene therapy strategy in a model of disseminated breast cancer. "The challenge with breast cancer is that it becomes pretty widespread in the body, not localized," Dr. Yee said.
"We used a virus to transfer a 'suicide' gene to breast cancer cells growing in the abdominal cavity of mice," he said. "While we could show benefit in our model system, it was clear that significant improvements will be required before patients can be treated with this type of therapy." For example, Drs.Yee and Woo found that the vector carrying the gene penetrated only 10 percent of the tumor cells. A better vector for delivering the gene product must be designed, they concluded.
Currently gene therapy is limited to the simpler applications, Dr. Boyan noted. "Where it's clear that a very major gene is missing, that's one thing to correct," she said. "But right now, to do something systemically such as give a person more bone (to correct osteoporosis), that's quite another."
"Every application is different," Dr. Yee agreed. "For example, people interested in treating hemophilia (the inherited blood-clotting disorder) are interested in maintenance, in a low-level expression of certain genes over the person's life span. But for cancer treatment, that may not be necessary or desirable. We want to get in, kill the tumor cell and get out."
When might gene therapy come into widespread use? Different researchers offer different viewpoints. "We are on the way to all different levels of gene therapy," Dr. Lee said. "Within five to ten years we should see the human application." Dr. Boyan estimated it could be 15-20 years before widespread application. "It's a very young technology, but it is growing and it will definitely happen in humans in our lifetimes," she said.
Meanwhile, scientists keep looking for unraveled threads in the beautiful tapestry, with the aim of weaving new threads in the form of new genes.