Human Gene Therapy: Present and Future

James M. Wilson
Institute for Human Gene Therapy, University of Pennsylvania

In his presentation at the 1998 Cambridge meeting, James Wilson characterized gene therapy as a novel approach in its very early stages. Its purpose, he said, is to change the expression of some genes in an attempt to treat, cure, or ultimately prevent disease. Current gene therapy is primarily experiment based, with a few early human clinical trials under way.

Theoretically, he continued, gene therapy can be targeted to somatic (body) or germ (egg and sperm) cells. In somatic gene therapy the recipient's genome is changed, but the change is not passed along to the next generation. This form of gene therapy is contrasted with germline gene therapy, in which a goal is to pass the change on to offspring. Germline gene therapy is not being actively investigated, at least in larger animals and humans, although a lot of discussion is being conducted about its value and desirability.

Gene therapy should not be confused with cloning, which has been in the news so much in the past year, Wilson continued. Cloning, which is creating another individual with essentially the same genetic makeup, is very different from gene therapy.

Listing three scientific hurdles in gene therapy, Wilson emphasized the concept of vehicles called vectors (gene carriers) to deliver therapeutic genes to the patients' cells. Once the gene is in the cell, it needs to operate correctly. Patients' bodies may reject treatments, and, finally, there is the need to regulate gene expression. Wilson expressed optimism that many groups are making headway and cooperating to overcome all these obstacles.

Viruses have evolved a way of encapsulating and delivering their genes to human cells in a pathogenic manner. Scientists have tried to take advantage of the virus's biology and manipulate its genome to remove the disease-causing genes and insert therapeutic genes. These gene-delivery vehicles will make this field a reality, he said.

In the mid-1980s, the focus of gene therapy was entirely on treating diseases caused by such single-gene defects as hemophilia, Duchenne's muscular dystrophy, and sickle cell anemia. In the late 1980s and early 1990s, the concept of gene therapy expanded into a number of acquired diseases. When human testing of first-generation vectors began in 1990, scientists learned that the vectors didn't transfer genes efficiently and that they were not sufficiently weakened. Expression and use of the therapeutic genes did not last very long.

In 1995, Wilson continued, a public debate led to the consensus that gene therapy has value although many unanswered questions require continued basic research. As the field has matured over the last decade, it has caught the attention of the biopharmaceutical industry, which has begun to sort out its own role in gene therapy. This is critical because ultimately this industry will bring gene therapies to large patient populations.

Wilson reviewed several specific gene-therapy cases involving high cholesterol, hemophilia, and cystic fibrosis. He emphasized that the response to any therapy in a heterogeneous patient population will be quite variable.

He asked the audience to think about gene therapy, not necessarily to treat genetic disease but as an alternative way to deliver proteins. Protein therapeutics currently are manufactured by placing genes in laboratory-cultured organisms that produce the proteins coded by those genes. Examples of such manufactured proteins include insulin, growth hormone, and erythropoietin, all of which must be injected frequently into the patient.

Recent gene therapy approaches promise to avoid these repeated injections, which can be painful, impractical, and extremely expensive. One method uses a new vector called adeno-associated virus, an organism that causes no known disease and doesn't trigger patient immune response. The vector takes up residence in the cells, which then express the corrected gene to manufacture the protein. In hemophilia treatments, for example, a gene-carrying vector could be injected into a muscle, prompting the muscle cells to produce Factor IX and thus prevent bleeding. This method would end the need for injections of Factor IX --a derivative of pooled blood products and a potential source of HIV and hepatitis infection. In studies by Wilson and Kathy High (University of Pennsylvania), patients have not needed Factor IX injections for more than a year. In gene therapies such as those described above, the introduced gene is always "on" so the protein is always being expressed, possibly even in instances when it isn't needed. Wilson described a newer permutation in which the vector contains both the protein-producing gene and a type of molecular rheostat that would react to a pill to regulate gene expression. This may prove to be one of gene therapy's most useful applications as scientists begin to consider it in many other contexts, he said. Wilson's group is conducting experiments with ARIAD Pharmaceuticals to study the modulation of gene expression.

Wilson stated that only so much can be done in academia and that the biopharmaceutical industry has to embrace gene therapy and handle issues of patents, regulatory affairs, and the optimum business model. An example of a dilemma that society may be facing can be seen in the treatment of hemophilia. Infusing a patient with the replacement protein, which stops bleeding episodes but doesn't prevent them, currently costs about $80,000 a year. Why would a vector to prevent bleeding for 5 to 10 years be commercialized when it would displace such a lucrative treatment, and how would this gene therapy be delivered to the public?

Wilson concluded his presentation by outlining future milestones in the field: proof of concept in the next few years in model inherited diseases, followed by cancer and cardiovascular diseases; continued explosive activity in technological development; development of regulatory policy (with the Food and Drug Administration); and commercial development.

http://www.ornl.gov/sci/techresources/Human_Genome/publicat/hgn/v10n1/15wilson.shtml