BOSTON - The man who launched gene therapy's ship five yearsago is now charting the technique's second generation - well into the21st century.

On Sept. 14, 1990, pioneer gene therapist W. French Anderson, thenat the National Institutes of Health (NIH), restored missing adenosinedeaminase genes to a four-year-old girl with severe combinedimmune deficiency disease.

That first-ever gene therapy maneuver leads the list of DNA-replacement trials approved by the Recombinant DNA AdvisoryCommittee (RAC) to NIH. RAC's roster of clinical gene therapyinterventions, as of its latest meeting on June 9, now numbers 113protocols. (See BioWorld Financial Watch, Sept. 19, 1994, p. 1.)

The world's maiden gene recipient, little Ashanti da Silva, now goingon nine, "is doing beautifully," Anderson said here on Wednesday atthe 6th Annual Biopharm Conference '95.

He and other gene therapists will celebrate her fifth "rebirthday" onSept. 14 in da Silva's home town of Cleveland. (See BioWorldToday, Sept. 16, 1993, p. 3.)

To date, over 600 gene therapy patients are enrolled in some 130protocols worldwide, Anderson said, "without any reported orreportable side-effects." Nearly all of these, he explained, are nowreceiving therapeutic gene sequences by one of two routes, ex vivo orin vitro.

Ex vivo means attaching the gene to a vector, which inserts it intocells removed from the patient's body, then transferring thetransfected cells back into the patient.

"A second way of doing gene therapy," Anderson continued, "isputting the gene where the pathology is, for example, in cysticfibrosis," by spraying an aerosolized vector into the patient's airways.Genzyme Corp., of Cambridge, Mass., recently won RAC's OK to trythis approach in cystic fibrosis patients.

Other corporate examples he cited were the committee's allowancesfor Genetic Therapies Inc. (GTI), of Gaithersburg, Md. and VicalInc., of San Diego to directly inject cDNA-armed vectors into tumorsor muscle.

A quiverful of tame viruses are the vectors now available to genetherapists for this reverse cellular burglary _ breaking and entering acell to supply rather than rob it.

Vectors currently in use or investigation include the retroviral,adenoviral and adeno-associated viruses.

Anderson Honored For Benefiting Industry

Anderson addressed a luncheon audience at the conference, whichawarded him its third annual "Person-of-the-Year" prize for"benefiting the North American biotechnical industry."

He now directs the University of Southern California's (USC) genetherapy laboratories in Los Angeles. A major underwriter of thisresearch facility is GTI.

Answering a question from the floor, Anderson said, "Reportingresearch in my laboratory falls under the category of `What have youdone for us lately?'"

Besides a number of clinical protocols under way, he observed,"which are no worse or better than lots of others," what's exciting tome is what we are accomplishing in our research program - trying todevelop the next generation of gene therapy.

"What will really revolutionize medicine - we're talking aboutdecades now, of course - isn't just making genes, putting them in andhoping they work, but being able to inject them, find the properbinding cells into the chromosome, in the normal way, in the properquantities, and be able to regulate it," he said.

In these areas, he's having most success with targeted gene delivery,by getting the retroviral envelope to recognize the specific targetcell's surface antigen. Here, he is trying two approaches: the naturalligand molecule or a single-gene monoclonal antibody.

Anderson's USC lab, which is allied to the university'sComprehensive Cancer Center, has taken as its first clinical targetgene therapy for breast cancer.

"Specifically," he explained, "we are urging breast cancer genes tooverexpress tumor suppressor oncogenes." In hot pursuit of thisobjective, "we hope to have a vector, and undertake primate studies,within a year. Then, in two or three years, do our first clinical trials."

He went on: "Gene therapy is talked about as a treatment, a cure. Thefact is, [as Anderson has advised White House policy planners], "itsreal promise, why it is a priority, is gene therapy's potential for theprevention of disease."

Retrofitting Human Genes For Modern Living

Harking to the Human Genome Project, Anderson observed that "allof our expressing genes number 65,000, give or take 5,000. Whatwill be possible over the next century," he went on, "is to screen eachother, and our children, to determine that our genes express theoptimum level that was not possible in the environment when theyarose.

"The point is," he added, "that our genes developed over millions ofyears, to provide us with optimal protection when we were living inthe wild, as hunter-gatherers."

For a brief period of human existence, he observed, "we have beenliving in cities, and our genes are not optimal for our presentexistence."

Anderson predicted that "Over the next decade it will be possible toscreen many of our genes, and over the next century, all 65,000 ofthem."

Meanwhile, he added, "breast cancer can't wait. Rather than waitingfor it to develop, then treating it, we must give the genes in advance,so the breast cancer never develops in the first place."

He and the USC oncologists are now "attempting prototypes of genetherapy, treating patients who have familial polyposis - colon polypsthat a genetic predisposition turns into in situ cancers.

"We have a sufficient number of patients," Anderson said, "withcolons that have a sufficient number of precancerous polyps, to beable to say with some certainty that over the next years these willbecome cancerous."

His strategy is to block off segments of colon, transfer tumorsuppressor genes directly into the cells of the polyps, then comparewith an untreated control portion of intestine. "Over a number ofyears," Anderson said, "it may be possible to show that in factprevention is possible by gene therapy.

"At the moment," he concluded, "gene therapy has a lot of hype butalso a lot of hope." n

-- David N. Leff Science Editor

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

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