Advances in Gene Therapy

While genetically modified foods are proving increasingly controversial, genetically modified humans are much in demand.

The search for a way to introduce “healthy” genes into humans that lack them has gone on for 35 years. A trio of Nobel Prize winners (Ed Tatum, Joshua Lederberg, and Arthur Kornberg) suggested in 1964 that it should be possible to cure often-fatal genetic disorders like cystic fibrosis, muscular dystrophy, and multiple sclerosis — just replace the defective gene with a functional one.

To a modern ear conditioned by the success of gene technology in agriculture, such gene therapy sounds direct and simple, but it has not proven to be so. Like a well-crafted play, the gene therapy saga has an exciting beginning, a catastrophic letdown, and a hopeful rebirth.

The exciting beginning was in 1990, when two girls were cured of a rare, sometimes-fatal blood disorder due to a defective gene for the enzyme adenosine deaminase. Scientists isolated working copies of this gene and introduced them into bone marrow cells taken from the girls. The gene-modified bone marrow cells were allowed to proliferate, then injected back into the girls. The girls recovered, and stayed healthy. For the first time, a genetic disorder was cured by gene therapy.

Like hounds to a hot scent, researchers set out to apply the new approach to one of the big killers, cystic fibrosis. This is the place in the gene therapy saga where the catastrophic letdown occurs.

The defective gene, labelled CFTR, had been isolated in 1989. In 1995 scientists placed healthy copies of the CFTR gene into adenovirus, a virus that causes colds. They then squirted the gene-bearing virus into the lungs of cystic fibrosis patients. The well publicized experiment had worked fine in preliminary trials with mice, and the world looked on, confident of success. And for eight weeks the gene therapy did seem successful. Then disaster. The gene-modified cells in the patients’ lungs came under attack by the patients’ own immune systems. The “healthy” CFTR genes were lost, and with them any chance of a cure.

Other attempts at gene therapy met with similar results, eight weeks of hope followed by failure. In retrospect, the problem with these early attempts seems predictable, although it wasn’t obvious then. Adenovirus causes colds. Do you know anyone who has never had a cold? All of us have antibodies directed against adenovirus, from previous contact with it. We were introducing therapeutic genes in a vector our bodies are primed to destroy. In 1995 the newly appointed head of the NIH, Harold Varmus, held a comprehensive review, and then called a halt to all further human clinical trials of gene therapy. “Go back to work in the laboratory,” he told researchers, “until you get a vector that works.”

Now it looks like we have one. This new gene-carrier is a tiny virus called adeno-associated virus (AAV). It has only two genes, both of which can be removed. The shell that remains is still quite infective, and can carry human genes into patients. Importantly, AAV does not elicit a strong immune response — cells infected with AAV are not eliminated by a patient’s immune system.

This summer AAV successfully cured anemia in rhesus monkeys. In mammals, red blood cell production is stimulated by a protein called erythropoietin (EPO). People with anemia (that is, low red blood cell counts), like dialysis patients, get regular injections of EPO. Using AAV to carry a souped-up EPO gene into the monkeys, scientists were able to greatly elevate their red blood cell counts, curing the monkeys of anemia — and they stayed cured.

A similar experiment using AAV cured dogs of an eye disease called retinitis pigmentosa. These dogs lacked a gene for an enzyme necessary for proper pigment production in the retina, and were blind. Injection of AAV bearing the needed genes into the fluid-filled compartment behind the retina restored their sight.

This is the hopeful rebirth of the gene therapy saga. Human clinical trials are now underway again. Late this summer, scientists performed the first gene therapy experiment for muscular dystrophy, injecting genes into a 35-year old South Dakota man. He is an early traveller on what is likely to become a well-travelled therapeutic highway. Trials are also underway for cystic fibrosis, rheumatoid arthritis, hemophilia, and a wide variety of cancers. The way seems open, the possibility of progress once again tantalizingly close.

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