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Being Alive
Gene Transfer Strategies for the Treatment of HIV Infection
Henry E. Chang
August 5, 1993
Being Alive 1993 Aug 5: 7

During the last few years, considerable progress has been made in the development of antiviral treatments for HIV infection. To date, available antiviral medications such as AZT, ddI, and ddC seem to slow down HIV replication in infected persons, but side effects associated with prolonged use and the development of viral resistance to these drugs may inevitably diminish their usefulness.

Given these reasons, it is clear that alternate therapies for HIV infection are urgently needed. Among the various potential treatments is gene transfer therapy. As of June 1993, 47 clinical trials of gene transfer therapy had been newly approved by the National Institute of Health Recombinant DNA Advisory Committee (NIH-RAC). Most of these studies have been ongoing to determine the effectiveness of gene therapy to treat diseases such as the rare adenosine deaminase (ADA) deficiency and cancer. Because of its enormous potential, gene therapy will affect treatment of not only inherited genetic diseases, but also infectious diseases such as HIV infection and AIDS. Recent progress made in determining the feasibility of using gene therapy for HIV infection both in the laboratory and, preliminarily, in infected individuals will be summarized here briefly.

GENERAL STRATEGIES Gene therapy strategies to treat HIV infection usually involve the insertion of a gene into cells that are able to be infected by HIV. The gene specifically interferes with virus replication or causes the death of an infected cell. The goal is to prevent virus spread. Since hematopoietic bone marrow stem cells seem to be the primary targets for HIV infection, introduction of a specific gene into these cells might be a good antiviral strategy. Because stem cells continue to divide and differentiate into a full range of blood cells, this would be viewed as a more long-term and efficient approach.

In contrast, mature CD4 cells from infected individuals could be targeted and modified directly. This requires drawing blood from a patient, isolating CD4 target cells, and culturing them for a period of time in the laboratory. During the time of culture, the gene of interest is introduced into the cells. Finally, the modified cells are returned to the same patient where they should function normally. This type of so-called "ex vivo" approach necessitates cumbersome, repeated administration of modified cells to patients.

An alternative approach takes the antiviral gene directly to the patient. The ideal system would allow intramuscular injection, with the antiviral gene carried by a retroviral vector (a gene delivery vehicle) that would home in on the target cells. Using the direct injection gene transfer strategy not only avoids costs and time associated with removing and culturing patients' cells, but also has the potential to become a simple, out-patient office procedure.

THERAPEUTIC TACTICS There are two general classes of agents which might be utilized for viral intervention in gene therapy. The first class includes potential antiviral agents that eliminate HIV-infected cells from an individual. The second class consists of potential antiviral agents that specifically interfere or inhibit HIV replication at one or more steps of the viral life cycle.

KILLING OF INFECTED CELLS At its June meeting in Bethesda, Maryland, NIH-RAC unanimously approved a protocol sponsored by Viagene Inc., a San Diego-based biopharmaceutical company, designed to evaluate safety and biologic effects of gene transfer therapy to delay or prevent the onset of AIDS in asymptomatic HIV-infected individuals. A limited number of study participants will receive intramuscular injections of a murine retroviral vector carrying the HIV envelope and rev genes. The rationale for using this vector is to cause healthy cells to make the HIV envelope protein, which would then in turn induce a cytotoxic T-lymphocyte (CTL, or "killer T-cells") response, in hope that an enhanced CTL response will slow or reverse disease progression. This study will be conducted by Shared Medical Research Foundation in Tarzana, whose co-founders, Drs. Jeffrey Galpin and Dennis Casciato, are the study investigators.

Another gene transfer strategy to eliminate HIV-infected cells has been proposed by French and US researchers; this strategy involves the use of thymidine kinase (TK) gene from herpes simplex virus. TK is an enzyme, which by itself is not toxic for mammalian cells, that converts certain specific drugs such as ganciclovir and acyclovir into their "active" forms inside the cells with the help of other cellular enzymes. The now "active" ganciclovir and acyclovir would shut down the synthesis of cellular genetic information and result in cell death. Based on this information, researchers have artificially constructed a "suicide gene" which is a TK gene under the control of HIV tat protein. The rationale is that if one inserts the "suicide gene" into an HIV-infected cell, the virus tat protein will induce the expression of TK gene resulting in the production of TK enzyme. Treatment of the TK-expressing cell with either ganciclovir or acyclovir causes death or suicide of the cell. For example, giving acyclovir to HIV-infected patients after transferring the "suicide genes" into them may represent an efficient therapeutic strategy in eliminating HIV-infected cells.

INTERFERING WITH VIRUS REPLICATION Another HIV protocol approved by the NIH-RAC at the June meeting was submitted by Dr. Gary Nabel of the University of Michigan Medical Center. Using the "ex-vivo" gene transfer approach, Dr. Nabel and his colleagues plan to transfer a mutant form of the HIV rev gene into T-cells of AIDS patients. The hypothesis is that cells which contain the resulting mutant rev protein will be less able to support HIV replication. The purpose of this study is to determine whether expression of the HIV rev gene can prolong the survival of certain T-cells in AIDS patients.

Antisense oligonucleotides or molecules have been proposed as a major class of new drugs designed to block the action of specific genes. In general, antisense molecules are designed to bind to the messenger RNA (which mediates translation of genetic information of DNA into specific proteins), thereby crippling the ability of the messenger RNA to dictate the manufacture of proteins. Working in conjunction with researchers at Hybridon, Inc., Dr. Julianna Lisziewicz and her colleagues at the National Cancer Institute have recently shown that two antisense molecules of the same length inhibited HIV production in chronically infected cells in test tubes for more than 80 days.

Hybridon Inc., a biotechnology firm based in Worcester, MA, filed an Investigational New Drug (IND) application with the Food and Drug Administration in November of 1992 for its antisense AIDS treatment Gene Expression Modulation (GEM) molecule called GEM 91. Initial clinical studies with GEM 91 in HIV-infected patients are planned by the AIDS Clinical Trials Group, under the auspices of the National Institute of Allergy and Infectious Diseases.

(Henry E. Chang is a treatment activist and the director of research and development at Shared Medical Research Foundation in Tarzana. He can be reached at 818.345.2172.) 

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