Dusty Miller to speak on virus targeting for gene therapy

Dusty Miller Photo by Jordan Rehm

As the curious eyes of the world shifted recently to a sheep named Dolly and the possibility of human cloning, some geneticists may have been breathing sighs of relief.

Researchers in gene therapy, after all, have been the ones in the public spotlight since the mid-1980s, when predictions first started that their work would lead to cures for virtually every human genetic disease. With an estimated 3,000 to 4,000 diseases caused by genetic defects, the task for these researchers is monumental. Expectations are high.

"The fact is gene therapy has yet to provide a complete cure for any disease," says Dr. A. Dusty Miller, an expert investigator in gene therapy at the Fred Hutchinson Cancer Research Center (FHCRC).

But why not?

Miller will discuss that question and the problems facing gene therapy in a lecture on Friday, Feb. 6, from noon to 1 p.m. in room T-625 of the Health Sciences Center. The lecture, fourth in this year's Science in Medicine Lecture Series, is titled "Changing Pathogenic Viruses into Therapeutic Tools."

Scientists spend too much time touting preliminary findings that have been blown out of proportion, Miller says. What is needed for gene therapy to move forward is vigorous attention to fundamental problems, he added.

In gene therapy, researchers typically use viruses to transfer DNA to cells with genetic defects. Retroviruses promote stable integration of their genes into the DNA of the target cell, allowing persistent expression of therapeutic genes carried by the virus.

Specific rules regulate how the viruses recognize their target cells, moreover. The human immunodeficiency virus (HIV), for instance, infects T-cells because it "recognizes" the CD4 receptor on the target cells. The receptor acts as a beacon of sorts that the virus locks onto to navigate into the cell.

Miller and his colleagues at the FHCRC created the retroviruses used in the first human gene therapy trial in 1990 at the National Institutes of Health. The trial was conducted in two children with severe combined immunodeficiency (SCID), which is caused by a genetic defect in the adenosine deaminase (ADA) gene.

Patients with SCID have very low numbers of circulating T cells and experience recurrent severe infections. The researchers used a retrovirus to pass along DNA to the children that corrected the mutation. After treatment, the children's T cell levels returned to nearly normal levels.

"The idea is to take the best properties the viruses have evolved for causing disease and use them for curing disease," said Miller. Today, seven years later, the T cells in one of the children are still expressing the healthy gene, he said.

Since the gene therapy was applied in conjunction with conventional treatment for SCID, it can't be called a cure. But the treatment definitely had some therapeutic value, Miller said.

What, then, are the stumbling blocks?

For one, in most cases, the efficiency of the gene transfer is too low. In the case of the SCID patients, success was measured by the fact that the healthy gene was being expressed in many of their T cells. However, the gene is only transferred to T cells, leaving the rest of the cells in the body uncorrected.

Another difficulty is that our immune systems do not distinguish between bad viruses and the viruses used in gene therapy. When our immune system detects a foreign invader, it responds by producing cells to fight it, regardless of whether researchers have placed DNA inside the invader.

Miller said he and his colleagues have seen animals develop immunity to viruses that were thought to be promising for gene therapy. Even though a reasonable transfer occurs initially between the virus and the target cell, the body creates antibodies that block the readministration of the virus.

Miller says steps are being made to neutralize this response by using drugs to block the immune system from recognizing the virus. Viruses can be made to seem less of a threat to the immune system.

The sheer number of diseases being targeted for gene therapy treatment and the number of genetic mutations responsible for certain diseases, like cancer, makes curing human disease with gene therapy a monumental task.

Yet, Miller is optimistic. "There have been exciting advancements, but they arrive one step at a time in cell biology and basic research," he said.

Researchers at the FHCRC, for instance, recently found a new ape leukemia virus that effectively targets hematopoietic (red blood cell producing)cells in bone marrow. They have seen gene transfers "take" in up to 20 percent of target cells in monkey transplantation experiments.

"If we can translate these results from monkeys to humans, we have a much better chance to cure genetic disease," Miller said.

Miller received a B.S. in engineering and a B.A. in math from Brown University in 1975. He earned a Ph.D in pharmacology from Stanford University in 1982, completed a fellowship at the Salk Institute in La Jolla, Calif. in 1984 and then became an assistant member at the FHCRC.

In 1993, Miller became a member of the FHCRC and an affiliate professor of pathology. He is on the editorial board of several prominent publications, an associate editor of Human Gene Therapy, and has served on the Recombinant DNA Advisory Committee at the National Institutes of Health. ¶ Will Morton