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Replacing a bad gene with a good gene to help cure disease… It sounds like a script from a science fiction movie. In fact, one sci-fi TV show, Stargate Atlantis, is centered around this concept. But, sci-fi sounding or not, gene therapy is real and is making great strides at St. Jude Children’s Research Hospital.
A fairly young area of research, gene therapy studies began in the 1980s. Then in 1990, the National Institutes of Health performed the first approved gene therapy procedure on a young child with a rare genetic disease called severe combined immune deficiency. Although not a cure, it was a crucial step for the field.
“The basic concept of gene therapy is to insert a properly designed gene, made in the laboratory, into the appropriate cells in order to confer a therapeutic effect either by fixing a broken gene or by endowing the cell with a new property,” says Brian Sorrentino, MD, director of Experimental Hematology and co-director of Transplantation and Gene Therapy.
A carrier molecule known as a vector is used to deliver the “normal” gene into the target cells.
“A vector is a virus that has been disabled,” Sorrentino explains. “It has a ‘payload’ that we insert. It efficiently infects the cell—as a virus should; but after it inserts the normal gene into the chromosome, it’s done its job and the virus is then permanently disabled.”
Gene therapy became a focus for St. Jude in the 1990s and was made a formal program by then-director Arthur Nienhuis, MD, now a member in the Department of Hematology.
St. Jude has studies devoted to the development of gene therapy in several areas including acute lymphoblastic leukemia (ALL), hemophilia, sickle cell disease, solid tumors and inherited immunodeficiencies. In collaboration with other St. Jude programs, the Transplantation and Gene Therapy Program is exploring research to advance the treatment of these catastrophic childhood diseases.
“The gene therapy activities at St. Jude are now taking place in both the Comprehensive Cancer Center and the Sickle Cell Disease Center,” Sorrentino says.
In one of the most recent studies, St. Jude researchers developed a model for studying new gene therapy vectors. This model has also been used to explain why gene therapy used to treat children with X-linked severe combined immunodeficiency (XSCID) at an institution in Europe caused some of the patients to develop leukemia.
XSCID is caused by a mutation in a gene called gamma C that prevents the immune system from forming B and T lymphocytes. B lymphocytes produce antibodies, and T lymphocytes perform a variety of tasks such as helping B cells and killing cells that are infected with viruses.
XSCID was the first disease to be successfully treated with gene therapy and was made famous by the story of the so-called “Bubble Boy” who lived inside a plastic bubble to shield him from infections.
In 2002, French researchers inserted normal gamma C genes into bone marrow stem cells removed from young children with the disease. Clinicians then infused the genetically modified stem cells back into the patients, restoring the ability of 11 children to develop normal immune systems. However, three of the patients eventually developed leukemia, an event that caused gene therapy researchers to pause and reconsider the safety of this approach.
“The pursuit of clinical trials was stalled by this unanticipated event, causing us and other investigators in the field to go back and restudy the problem of insertional mutagenesis, which is the random activation of cancer-causing genes by the gene therapy vector,” Sorrentino recalls.
Researchers later determined that the gamma C gene added to the stem cells had inserted itself into oncogenes (cancer-causing genes). The genetic on-switch that was part of the gamma C gene had turned on the oncogenes in the blood cells and caused them to multiply uncontrollably, causing leukemia.
Based on recent St. Jude studies, researchers concluded that XSCID itself may make children with this disease particularly susceptible to cancer caused by gene therapy.
“One important implication of this finding is that gene therapy for other forms of genetic blood diseases will likely pose less risk for causing cancer than was previously thought,” Sorrentino says.
Another St. Jude gene therapy study—a collaboration with the University of Cincinnati—focuses on making chemotherapy for brain tumors safer and more effective.
By inserting a gene into bone marrow cells, researchers can protect those cells against chemotherapy’s effects, which otherwise cause low blood counts. This approach is designed to allow researchers to give higher doses of the chemotherapy drug along with a second drug that improves the effectiveness of that chemotherapy in killing tumor cells.
“St. Jude was responsible for creating the vector for this study,” Sorrentino says.
Investigators at the hospital are also working on promising gene therapy studies for ALL. In this approach, Dario Campana, MD, of Oncology and his colleagues put a new gene into a certain type of immune system cell that can then attack and kill leukemia cells. Researchers anticipate that this approach will have fewer severe side effects than other forms of leukemia therapy.
Current therapy for hemophilia (a rare bleeding disorder that prevents blood from clotting properly) involves a specialized type of blood transfusion that is costly, must be given repeatedly and does not cure the disease. St. Jude researchers have developed a gene-therapy approach for curing hemophilia. Investigators are currently at the point of making clinical material in the Children’s GMP, LLC, a facility on the hospital campus that produces biological products and drugs.
Scientists at St. Jude are also developing a gene therapy approach to treat sickle cell disease, with the ultimate goal of a cure. The strategy is to insert the normal hemoglobin gene into the patient’s own bone marrow cells.
In addition, St. Jude is pioneering the use of genetically modified bone marrow cells to treat children who have a neurodegenerative disorder called lysosomal storage disease. This genetic disease kills brain cells and is lethal in infants and children.
Three diseases have been “unequivocally cured” through gene therapy studies, Sorrentino says. They are XSCID, adenosine deaminase deficiency (a rare genetic disorder caused by receiving a deficient ADA gene from both parents) and chronic granulomatous disease (a group of rare, inherited disorders of the immune system caused by defects in certain immune system cells). “The tools for gene therapy have steadily improved over the past several years allowing gene therapy researchers to achieve proof of principle in the clinical realm,” Sorrentino says.
He adds that St. Jude is in a strong position to lead the field in clinical gene therapy. “We have an outstanding gene therapy group that is second to none,” he says. “Having a high level of expertise in vector science along with the GMP facility on our campus is key and gives us a unique edge. Our focus for the immediate future is to expand our studies into clinical trials and to make an impact on the diseases that we have targeted with this approach.”
Reprinted from Promise magazine, autumn 2006.
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