8 October 2002
PREDICTED HAZARD OF GENE THERAPY A REALITY
"What we need is a comprehensive review of gene therapy and other transgenic technologies such as genetic modification of animals and plants for biomedical and agricultural uses, as the methods and constructs used are similar, and so are the risks involved."
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Predicted Hazard of Gene Therapy A Reality
ISIS was almost a lone voice warning of cancer from foreign genes inserting
into the genome in Œgene therapy‚ and other exposures to transgenic DNA.
Regrettably, this has now become reality. Dr. Mae-Wan Ho [m.w.ho@i-sis.org.uk]
calls for a comprehensive review of gene therapy and other transgenic technologies,
for they carry similar risks.
The French team that made news in 2000 treating children with severe combined immune deficiency (SCID) had to call a halt to the gene therapy trial. One of the ten children treated has developed what looks like leukaemia.
SCID is attributed to a mutation in a gene on the X-chromosome. Alain Fischer and Marina Cavezzena-Calvo at the Necker Hospital in Paris pioneered the ex vivo procedure, in which bone marrow cells taken from the patient are transformed outside the body, using a vector carrying a normal copy of the mutated gene to insert the gene into the genome. The transgenic cells are then re-introduced into the patient.
This was hailed as a breakthrough for gene therapy, as it avoided most of the risks of in vivo treatments in which the transgenes are directly introduced into the patient. This has put patients at immediate risks from toxicities of the vector, which killed teenager Gelsinger in 1999. In addition, infectious viruses could be generated from the vector, and cancer could result from the insertion of the vector into the wrong places in the genome. As in the genetic modification of plants and animals, the genetic modification of human beings is severely hampered mainly because precisely targeted gene insertion is still not technically feasible. It is hoped that by modifying the cells outside the patient‚s body, the patient will not be directly exposed to high doses of the vector, and any cells that develop cancer, or any infectious viruses that are generated could be selected out.
Unfortunately, a routine check of their 4th patient last Spring revealed that the child had a high number of T cells in his blood, and by August, the T cell count reached 200 000 cells per litre. The child was admitted to hospital.
Molecular analysis showed that the T cells were a single clone derived from one original cell that has multiplied out of control The retroviral vector used ˆ mouse Moloney leukaemia virus ˆ had jumped into a gene on chromosome 11 that is "aberrantly expressed" in a form of acute leukaemia.
Fischer thinks that the vector caused an "insertional mutagenesis", splicing itself into a "dangerous gene", causing it to become over-expressed.
"Everyone was aware" of the theoretical risk, he said, but believed it was "very small", claiming that the phenomenon did not turn up in animal experiments.
He is wrong on both counts and more. "Insertional carcinogenesis" is an identified, if not established clinical entity in the cancer literature (reviewed in Slipping Through the Regulatory Net, ŒNaked‚ and ŒFree‚ Nucleic Acids, TWN Biotechnology Series, 2001, available on ISIS and TWN online bookstore). At least one experiment with a retroviral vector had caused leukaemia in all the experimental animals, and the risks of cancer not just restricted to retroviral vectors either. Another experiment with the most commonly used adeno-associated vector (AAV) also caused high incidence of cancers in animals (see "Failures of gene therapy", Science in Society 16, out now.) Furthermore, the mouse Moloney leukaemia virus vector used was among the very first gene therapy vectors, and has been phased out by many gene therapists due to safety concerns.
One aspect of the finding that has not been commented on is the location of the insert in the T cell clone that had proliferated out of control. The target of gene therapy for SCID is the X chromosome, so why did the insert get into chromosome 11? Were the original transgenic bone marrow cells checked to see where the insert had landed - to make sure it did not land in a "dangerous gene" - before they were re-introduced into the patient? If so, did the insert move subsequent to the transgenic cells being put back into the patient, as we had predicted it could?
A planned clinical trial by researchers in the National Institutes of Health (NIH) in the United States using the same procedure was cancelled. Four other groups, including the Children Hospital in London, has been using or planning similar trials.
NIH's recombinant DNA Advisory Committee is reported to be preparing a broad review of the case.
What we need is a comprehensive review of gene therapy and other transgenic technologies such as genetic modification of animals and plants for biomedical and agricultural uses, as the methods and constructs used are similar, and so are the risks involved (See Science in Society 2002, 16, out now).
Source: Science, News of the Week, 4 October 2002.
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This article can be found on the I-SIS website at http://www.i-sis.org.uk/PHGT.php
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