Predicted Hazard of Gene Therapy A Reality
ISIS was almost a lone voice warning of cancer from foreign genes
inserting into the genome in gene therapy and other exposures
to transgenic DNA. Regrettably, this has now become reality.
Dr. Mae-Wan Ho 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
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 patients
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 mouse Moloney leukaemia virus 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
"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, Naked
and Free Nucleic Acids, TWN Biotechnology Series, 2001,
available on ISIS and TWN
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",
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.
NIHs 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
Society 2002, 16, out now).
Source: Science, News of the Week, 4 October 2002.