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Gay Men's Health Crisis
On the Edge: Gene Therapy in AIDS
Michael Ravitch
May 1, 1993
GMHC Treatment Issues 1993 May 1; 7(4): 2

An expanding number of researchers believe that medicine is on the threshold of a revolution. Using the tools of molecular biology, researchers hope to manipulate directly an individual's deoxyribonucleic acid (DNA) to cure many diseases, including inherited genetic disorders like sickle cell anemia, many forms of cancer, and viral diseases, such as AIDS. While some dismiss "gene therapy" as a distant frontier of medicine, over thirty clinical trials are ongoing, start-up companies are developing gene therapy commercially, and the NIH has devoted a large share of its research spending to this field. Gene therapy could contribute to HIV treatment within the foreseeable future.

DNA is the master plan of life. DNA contains approximately 50,000 to 100,000 genes, each of which controls the production of one protein. Proteins form the basic building blocks of life--they control the structure, functioning, and reproduction of cells. Genetic diseases occur when a mutation alters a gene, resulting in the production of an unwanted protein, or the lack of an essential protein. It is a common misconception that all genetic diseases are inherited. Many diseases, including some forms of cancer and AIDS, originate in genetic mutations acquired after birth.

What Is Gene Therapy? Gene therapy does not refer to a specific substance, but to a distinct and emerging branch of medicine, in which new, manufactured genes are inserted into patients to fight disease. Gene therapy includes a wide variety of approaches. While the basic aim is to insert genes which create proteins that fight disease, these proteins can perform many functions. They can compensate for other deficient proteins, inhibit abnormal cellular functioning, or regulate the expression of another gene.

Approximately 1-2 percent of infants in the U.S. are born with a genetic birth defect caused by the absence, or in some cases even the presence, of a single gene. Inherited genetic disorders of this sort provide the clearest example of gene therapy's potential. ADA-deficient Severe Combined Immunodeficiency (SCID) is a disease of profound immune suppression similar to AIDS in symptoms, but not in cause. ADA- deficient SCID results from the lack of the gene which produces adenoside deaminanse (ADA), a protein crucial to the workings of the T-cell, an important immune cell.

Scientists implanted the ADA gene into the T-cells of children with the disease. Since 1990, two little girls with the disease have been transfused with their own gene-corrected T-cells. There is yet to be a controlled clinical study; no real evidence of benefit can be garnered so far. However, it is very encouraging that the gene seems to perform inside the body and the T-cells function normally. This indicates that, despite many technical hurdles, gene therapy is feasible.

The optimism engendered by the ADA work has to be tempered by the profound technical hurdles which remain. The greatest technical challenge thus far is how to insert the right genes into the right cells in the body. Disabled viruses are the most commonly used delivery method. One way to understand this is to remember how a virus works. A virus is essentially a piece of genetic material which survives by integrating itself into DNA of other organisms. Scientists can immobilize a virus, such as an adenovirus (a family of viruses which cause disease in the respiratory tract and eyes), and insert new genes into it. The immobilized virus does not have the ability to replicate itself, or cause disease, but does retain its capacity to infect cells and transmit the synthesized gene.

However, there are serious safety concerns with the use of viruses as delivery methods. It is possible that defective virus can recombine in the body and create new, pathogenic viruses. Last year, investigators at the NIH reported that three monkeys in a gene therapy protocol developed malignant lymphomas after receiving a contaminated viral preparation. For this reason, the NIH and FDA have developed strict, and some say time-consuming, regulations to govern gene therapy experiments.

Technical Problems Another dilemma is that, in order for these viruses to target specific cells, they can only be inserted into cells outside the body. Researchers must first extract the designated cells from the patient's blood, expand those cells in the test tube, and infect them with the viruses carrying the desired gene. Subsequently, the gene-modified cells are reintroduced into the patient. This is a cumbersome and expensive process, with many technical difficulties.

There are other technical problems as well. Into which cells should the therapeutic gene be implanted? And how can the right cells be targeted without damaging them? Some raise the concern that random insertion of new genes could cause changes in host cell DNA and thereby cause disease. Theoretically, this may be possible, but it has yet to occur in any gene transfer experiments to date.

Other options for delivering genes into cells are also emerging. One of the most exciting is the prospect of "naked DNA" injections, whereby DNA is directly injected into the target cells. In some experimental models, DNA is packaged in a liposomal complex (a fatty covering) to help it bypass the cell walls. Other researchers are successfully injecting DNA directly into muscle tissue. In one notable experiment, patients with advanced melanoma (a type of skin cancer) are receiving DNA injections directly into their tumors. Scientists at the NIH are considering direct injection of therapeutic DNA into the lymph nodes of people with AIDS.

Gene Therapy in AIDS HIV, like all viruses, can be described as an acquired genetic disease. HIV integrates itself into human DNA to transform cells into factories for creating copies of itself. HIV-infected cells produce viral proteins and then assemble them into new viruses. Ultimately, viral infection and replication destroy the host cell. Scientists have identified many of the proteins which play a part in the replication of HIV. These include enzymes such as reverse transcriptase, protease, and tat.

Anti-HIV drugs function by attacking these proteins. For example, drugs like AZT, ddI, and ddC are aimed at the reverse transcriptase enzyme; the protease inhibitor is aimed at the protease enzyme. The great disadvantage of this approach is that it does not halt the production of these malignant proteins at their source. The drug must be given in high doses, to disable every copy of the protein, and must be given for the lifetime of the patient. Gene therapy, on the other hand, acts against the origin of the disease, the malignant HIV genome.

Many strategies are being considered to fight HIV at the genetic level. Some scientists seek to engineer genes which protect a cell from infection; others create genes which regulate HIV into harmlessness. Although there are encouraging words from initial test tube models, none of these approaches has been tested in humans. Theoretically, gene therapy has at least one great advantage over current therapies; by implanting the mechanism for fighting disease within our genetic code, the treatment would last as long as the host cell. There is great hope for the future that if researchers can manage to implant therapeutic genes into stem cells (the progenitor cells of all blood cells), every blood cell could be immunized against HIV infection.

To help understand the future direction of AIDS gene therapy, it's useful to examine the first two ongoing AIDS gene therapy protocols. The two clinical studies attempt to bolster the immune systems of people with AIDS through insertion of new genes. This approach attempts to marshall the natural defenses of the body against HIV. Researchers at Viagene, a San Diego-based biotechnology company, have developed a gene therapy intended to work like a gp160 therapeutic vaccine. They plan to insert a gene expressing the HIV envelope protein gp160 into cells from patients' arms. The production of this protein is expected to induce specific and potent immunological responses against HIV in a way similar to the well-known gp160 vaccine. In vitro and animal studies show no evidence of toxicity. The significant difference between the gene therapy product and the therapeutic vaccine is that the viral protein would be produced inside the cell, rather than introduced from outside. Viagene scientists claim that this method stimulates a better immune response than the conventional vaccine product. For information about Viagene's trial, and future protocols, call 619/452-1288.

The other ongoing gene therapy trial in HIV takes place at the Fred Hutchinson Cancer Center in Seattle. Dr. Phil Greenburg is conducting a trial in HIV-infected individuals with lymphoma (cancer of the lymph system). This is a significant protocol, not only because it offers a radical option for people with terminal lymphoma, but because of how it might advance our knowledge.

It is quite a complex trial. Patients receive high-dose radiation and chemotherapy to destroy the lymphoma. Then the patients are given a bone marrow transplant from a genetically similar sibling (not necessarily an identical twin). At that point, the recipient should generate an entirely new immune system. In order to prevent reinfection with HIV, the patient will be given AZT as well as gene-modified HIV-specific Cytotoxic T Lymphocytes (hereafter CTLs). CTLs are a type of immune cell involved in fighting viral infection.

The gene that has been added to the CTLs serves only one purpose: a safety precaution. If the patient is unable to tolerate such a massive introduction of CTLs, the implanted gene allows the researchers to kill off all the new cells and save the patient. If the gene is successfully expressed in the reimplanted cells, it confirms the validity of this approach. Once scientists learn if gene therapy can be used to alter CTLs, more powerful CTLs can be produced which do not need to be extracted from the patient. Conclusion Gene therapy is rapidly expanding right now. Money is pouring in, interest and publicity increasing. Some researchers fear that disappointment will inevitably follow the hype, and the tide of support will recede. Furthermore, safety concerns about gene therapy are grave, and research is proceeding slowly and cautiously.

The doubts about gene therapy are not all scientific. Some worry that gene therapy researchers are playing god. They fear that it will inevitably be used to damage (or, worse yet, improve) future generations. These arguments must be taken seriously, for they are significant. However, one must recognize a distinction between genetic manipulation of the genes which control reproduction and gene therapy directed at genes which only function after birth. Modification of genes which function after birth would, as a medical treatment, not affect the human gene pool any more significantly than an organ transplant.

But then there is the enormous cost, possibly reaching $200,000 per patient at the present time. This is a legitimate concern, especially when so few have basic health care. Furthermore, it is difficult to imagine bone marrow transplants and ex vivo gene transfer becoming available to the projected 100 million HIV-infected people around the world.

Yet gene therapy in such forms as naked DNA could be quite simple and inexpensive. Moreover, gene therapies that now are extremely expensive may become less so as technology advances. Also, knowledge from gene therapy experiments today may help to develop entirely new approaches in the future. Nevertheless, it is still likely that researchers will have to overcome very complex and cumbersome technical problems before a safe, effective, and affordable gene therapy arrives.

Copyright (c) 1993 - Gay Men's Health Crisis, New York City, NY Noncommercial reproduction encouraged. Distributed by AEGIS, your online gateway to a world of people, knowledge, and resources.