Targeted Genetics Corp. is beginning its second HIV gene transfer trialtoday. The study will be conducted in 15 HIV seropositive asymptomaticpatients at Fred Hutchinson Cancer Research Center in Seattle.

The trial involves isolating CD8+ cytotoxic T cells from HIV-positivesubjects, modifying the cells to contain the HyTK suicide gene, and thenreinserting them into the patients. The HyTK gene serves as a marker,showing the migration and survival of the CD8+ cells.

The gene is referred to as a suicide gene because it is susceptible to theantibiotic ganciclovir. If toxic side effects occur, ganciclovir will beadministered to eliminate the modified CD8+ cells.

Study participants will receive a maximum of four infusions of thegenetically modified CD8+ cells at progressively increasing cell doses. Theinfusions will be administered at two-week intervals, and participants willbe followed for 13 months. The study is being directed by Philip Greenbergand Stanley Riddell of the Hutchinson Center.

Targeted Genetics of Seattle, a gene therapy company spun off fromImmunex Corp., began a trial with this gene marker last year in HIVseropositive patients undergoing allogeneic bone marrow transplant.Patients are still being accrued for this trial, which the company expects tobe completed next year.

Stewart Parker, president and chief executive officer of Targeted Genetics,said it will be possible to obtain more long-term data with the second trialsince patients are not as ill as those undergoing bone marrow transplant.

The National Institutes of Health's Recombinant DNA Advisory Committee(RAC) approved the trial protocol in September. It is technically a genemarker trial, although the procedure could have a therapeutic effect.

Tom Reynolds, director of development at Targeted Genetics, explainedthat the HyTK gene transfer "will not in and of itself be of therapeuticbenefit to patients." It is beneficial because it allows researchers toeliminate the modified CD8+ cells if they cause toxicity. A subset of threepatients will be ablated with ganciclovir to confirm this effect.

In addition, the gene marker will enable researchers to recover the cellsfrom the blood of patients six months or a year after treatment todetermine how many cells still exist and if they are still functional.Furthermore, Reynolds said, researchers will conduct a lymph node biopsyin a subset of patients to see if the CD8+ cells go to the lymph nodes,which are known to be a reservoir of viral burden.

Viagene Inc. is the only other company to have a gene therapy trial underway. That study, which involves direct intramuscular injection of a murineretroviral vector encoding HIV-1 genes into asymptomatic HIV seropositivepatients, was launched in August (See BioWorld, Aug. 11). It is considereda gene therapy trial since the goal is to prime patients' immune systems tostimulate a killer T-cell response. The principal investigators are JeffreyGalpin of the University of Southern California and Dennis Casciato of theUniversity of California, Los Angeles.

The RAC has approved three other HIV protocols.

-- NIH's Robert Walker is conducting a study of the adoptive transfer ofgenetically marked syngeneic lymphocytes in HIV infected identical twins.The protocol for the gene marker study was approved by RAC inSeptember 1992.

-- In June, RAC approved a protocol by Gary Nabel of the University ofMichigan Medical Center for a gene therapy trial involving thetransdominant form of Rev.

-- In September, RAC approved a gene therapy protocol by Flossie Wong-Staal, of the University of California, San Diego. The protocol involves useof a murine retrovirus carrying the gene for a catalytic ribozyme thattargets some of HIV's conserved RNA and severs a specific site on thesequence of HIV-1, thus inhibiting viral replication.

-- Brenda Sandburg News Editor

(c) 1997 American Health Consultants. All rights reserved.