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Gene
therapy
A Genetic Interest Group Policy Paper
This spring researchers at Stanford University announced that
they had started a trial of gene therapy delivered by aerosol
to the lungs of patients with cystic fibrosis. The treatment
consists of using a nebuliser to blow a mist of viral particles
containing working copies of the CFTR gene into the patient's
mouth. The team conducting the trial are excited because the
procedure is showing signs of working—they were able to identify
the gene in sinus tissue, showing that gene transfer had been
accomplished. The lead researcher reports that they have also
detected clinical effects: "we saw a significant reduction
in inflammation in patients treated", he said.
Cystic fibrosis is a relatively common life-threatening genetic
disease. In the United Kingdom alone there are estimated to
be 7000 cases. When an individual inherits two defective copies
of the CFTR gene a channel which allows water and electrically
charged ions to flow in and out of cells fails to function
properly. Among other symptoms, inflammation, clogging mucus,
and infections affect the patient's lungs and sinuses. At
present, drugs and physiotherapy can mitigate symptoms, but
there is no cure. In this regard, cystic fibrosis is typical
of the estimated 4000-5000 single gene disorders that collectively
constitute a significant cause of ill health, disability and
reduced life expectancy.
As the work cited above indicates, progress in gene therapy
research has been made. Unfortunately it is limited. The gene
for cystic fibrosis was isolated ten years ago, but gene therapy
for the condition, or for any other condition, has not yet
progressed beyond Phase II clinical trials, in which treatments
are tested on small groups of people with the condition to
test for clinical effect. Nevertheless, it continues to offer
one of the best hopes for tackling conditions for which there
is currently little or no effective treatment. This paper
outlines some of the history of gene therapy and the barriers
to further progress.
Today, most people accept the principle of gene therapy as
a treatment for individuals with a genetic or acquired disorder.
But there are also concerns about potential risks associated
with the procedure to the patient, and perhaps to others if
changes are made inadvertently that affect the reproductive
cells—that is, germ-line changes. There are also concerns
about a 'slippery slope' towards deliberate tampering with
the germ-line or gene therapy for enhancement of normal traits.
This paper also provides a response to these concerns, in
part by outlining the regulatory framework that governs the
field today, and in part by examining whether the more radical
procedures might offer some benefits in the future.
A Brief Overview
Gene therapy as a treatment for single gene disorders is in
fact but one aspect of a procedure that has many possible
applications. In his overview, Gene therapy—where are we?,
Alan E Smith provides a useful summary of the technique, its
applications and its methods:
'Gene therapy is the use of nucleic acids as therapeutically
useful molecules. The approach has many potential applications;
the most obvious of which is to correct the defects in monogenic
inherited diseases such as cystic fibrosis (CF). However,
many other applications are possible and these include gene
transfer to stimulate a specific immune response, to mediate
specific cell killing, to activate a pro-drug, or to produce
a molecular decoy required for the replication of a virus.
A vector is the vehicle used to introduce the gene into the
target cell. Disabled viruses are commonly used because they
can perform many of the tasks necessary to achieve successful
gene transfer, such as bind to a target cell and deliver the
viral genome to the nucleus for transcription. Non-viral vectors,
based on plasmid DNA produced in bacteria and often complexed
with lipids, are also being used since they lack foreign proteins
and therefore may avoid immunological pitfalls common to engineered
viral vectors—albeit at the cost of lower efficiency.'
As Smith points out, there are applications to acquired as
well as monogenic inherited disorders. Indeed, whereas during
the second half of the 1980s the majority of research was
on single-gene disorders, from 1990 onwards attention has
shifted towards acquired disorders such as cancer and HIV.
Globally, as of 1 June 1999, 380 trials had been performed
involving a total of 3173 patients. Of these 240 were cancer
therapies involving 2166 patients and 53 were on monogenic
diseases involving 296 patients. It seems likely that this
trend will continue. Naturally, GIG's primary concern is the
monogenic disorders. But equally we welcome advances that
offer therapeutic solutions to other intractable conditions.
Furthermore, it is to be hoped that advances in other areas
will assist in the development of techniques for the monogenic
diseases, as well as providing specific treatment options
for some of the symptoms of the patients represented by GIG.
Put simply, somatic gene therapy for monogenic disorders involves
supplementing or replacing faulty variations of genes with
normally functioning ones in bodily cells. The changes made
are not passed on to the next generation. Monogenic disorders
for which gene therapy has been attempted include cystic fibrosis,
familial hypercholesterolaemia, mucopolysaccharidosis types
I and II, alpha-1-antitrypsin deficiency, severe combined
immunodeficiency and Gaucher's disease.
The simplest way of performing gene therapy in monogenic disorders
is to treat the patient repeatedly with the normally functioning
gene. For this approach to work, integration and extended
replication of the gene is not necessary; it must merely express
itself long enough to produce an effect. This is the approach
being taken by researchers working on cystic fibrosis. True
gene therapy involves the permanent replacement of damaged
genes, perhaps in stem cells, or the introduction of normally
functioning genes, perhaps in artificial chromosomes, alongside
the abnormal ones. At present, this approach has not made
it beyond basic research into clinical trials. To appreciate
the obstacles to success faced by researchers today, it is
useful first to summarise the history of the subject.
The promises and dangers of gene transfer were first discussed
in the late 1960s. During the 1970s, some of the basic techniques
were developed and widely discussed within the scientific
community. Basic research was taken further in the 1980s.
And then, to much fanfare, the first ever human gene therapy
trial was attempted in the United States in 1990. A young
girl called Ashanthi DeSilva received gene therapy for a form
of immunodeficiency. She had been born with a defective version
of the gene that normally makes the essential enzyme adenosine
deaminase (ADA). The therapy seemed to work. When she appeared
before the House Science Committee four years later, the then
chair George Brown was moved to declare that she was "living
proof that a miracle has occurred." And yet, just one year
later, in 1995, the gene therapy community had to face up
to the fact that for all the early enthusiasm, and media hype,
there was no evidence that gene therapy was actually working.
Indeed, even the data from the pioneering ADA trials were
inconclusive: Ashanthi and others treated with gene therapy
were also being given the conventional treatment for the disorder—injections
of synthetic ADA—which might have been responsible for their
good health.
This prompted a call, led by the National Institutes of Health,
for less hype and more research. Looking back on this period
from the vantagepoint of today, Elizabeth Nabel outlines both
the positive effect of the correction to expectations and
the issues research is now addressing:
'The field had gone through at least five years of highly
visible and publicised clinical studies but the hype and the
hope clearly exceeded the accomplishments. Responding to concerns
of investigators and the public alike, NIH director Harold
Varmus established an advisory committee; their report (http://www.nih.gov/news/panelrep.aspl)
had a remarkably positive effect on the field. Renewed efforts
were made to understand the basic biology of gene transfer,
the molecular biology of vectors and the cellular mechanisms
of vector uptake and gene expression. The stampede to clinical
trials abated. The field had undergone a "market correction".'
Of the three problems highlighted, many researchers would
isolate gene delivery as the most important at the moment.
And to Nabel's three issues, we should also add the related
issue of dealing with the host's immune response if viruses
are used to transfer the normally functioning genes. Work
on all these areas over the last four years has generated
new insights and a steady return of confidence to the field.
In the UK, the Gene Therapy Advisory Committee reports that
during 1997 new approaches and renewed financial support for
the field indicates that 'gene therapy is moving into an expansive
phase'. In 1998, the European Working Group on Human Gene
Transfer and Therapy was rechristened the European Society
for Gene Therapy to reflect the move "from working hypotheses
into clinical studies", in the words of its president Oliver
Danos. And in his 1999 Presidential Address to the American
Society of Gene Therapy, James Wilson outlined innovative
approaches to clinical trials that might yield data faster
and accelerate the process of commercialisation.
Patient groups play an active part in raising money for and
in securing patient participation in trials, and GIG and sister
organisations in other countries lobby at the political level
to secure market incentives to speed up the process of commercialisation
that James Wilson spoke of. We all look forward to the fillip
gene therapy will receive from the completion of a detailed
and highly accurate map of the human genome, which should
be in hand within four years. By then, further advances in
some of the techniques already discussed should create the
platform for an intensive period of research on all fronts.
Clearly there is a long way to go before treatments become
a reality. Equally clearly much progress has been made. For
some, both sides of this equation are a cause for concern.
They worry that the lack of progress indicates that we don't
know enough about the risks of the procedures we are currently
trying, and they worry that enthusiasm for the progress that
has been made and the further progress that will be made in
the future means that we might use the power of gene therapy
to begin 'genetic engineering' on humans. GIG does not share
these concerns.
Risks in Context
Gene therapy, in the UK and elsewhere, is highly regulated.
It is worth quoting from the House of Commons Science and
Technology Committee's 1995 report Human Genetics: The Science
and its Consequences at some length on this:
'There is no evidence of any possibility of a Frankenstein
emerging from a test tube, by genetic manipulation. The effects
of modest genetic changes even limited to a single individual
in his lifetime, need, and get, scrupulous consideration.
The Committee on the Ethics of Gene Therapy under the Chairmanship
of Sir Cecil Clothier (the Clothier Committee) considered
gene therapy in 1991… The Committee's recommendations formed
the terms of reference for the Gene Therapy Advisory Committee
(GTAC), which was established in November 1993. GTAC reviews
all proposals for gene therapy studies in the United Kingdom.
In addition, such proposals must also be considered by the
Local Research Ethics Committees of the authorities in which
the research will take place.'
GTAC applies six principles when considering gene therapy
for adults and children. They ensure that therapies currently
in trial are tightly regulated and limited to certain classes.
They also aim to balance the risks and benefits for the individual
undergoing what is still an experimental procedure rather
than a course of treatment. The principles are:
(a) gene therapy is research and not innovative treatment;
(b) only somatic therapy should be considered;
(c) in view of safety and ethical difficulties germ line interventions
are off limits at present;
(d) gene therapy should be restricted to life threatening
disorders where no current alternative effective treatments
are available;
(e) patients should take part in gene therapy research trials
only after a full explanation of the procedures, risks and
benefits and after they have given their informed consent,
if they are capable of doing so; and
(f) recognising that some people, including young children,
may not be able to give such consent, therapeutic research
involving such patients must not put them at disproportionate
risk.
Similar controls exist in other countries. GTAC and other
regulatory bodies have also performed risk assessments on
the possibility of inadvertent germ-line modification during
somatic gene therapy, on both fetuses and people, as well
as other possible side effects of current trials. But what
of the future: are we in danger of allowing a technology to
develop that will one day slip beyond our control?
There are two parts to the answer to this question. In the
first place, GIG does not believe that real benefits should
be discarded simply because the same technology may be used
in untoward ways at some point in the future. Secondly, we
should be careful not to rule out forever novel applications
of gene therapy that may become possible, and safe, given
further scientific development. Such applications may not
be untoward at all.
In 1982, gene therapy pioneer French Anderson introduced the
four well-known categories of human gene therapy into the
scientific literature. This is Maurice A. M. De Wachter's
summary:
1) somatic cell gene therapy: here a genetic defect in the
somatic, or body, cells of a patient are being corrected;
2) germ-line gene therapy: here a genetic defect in the germ,
or reproductive cells of a patient are being corrected so
that offspring of the patient would also be corrected;
3) enhancement genetic engineering: here a gene is being inserted
in order to try to enhance or improve a specific characteristic,
for example adding an additional growth hormone to increase
height;
4) eugenic genetic engineering: here genes are being inserted
in order to try to alter or improve complex human traits that
depend on a large number of genes as well as on extensive
interactions with the environment, for example intelligence,
personality, character.
Some might prefer to subsume the fourth category within the
third. Some might also choose to label the second and third
eugenic as well. At its simplest, the division highlights
that beyond somatic therapy we can imagine germ-line alterations
and enhancement therapy. Should these be rejected in principle
and forever? GIG does not believe so.
In a discussion of germ-line modification six years ago, Nelson
Wivel and LeRoy Walters pointed out that many of the techniques
of germ-line modification are being developed in animal models.
The starting point of this work is the fact that 'in 1980,
it was demonstrated that direct injection of foreign genes
into the pronucleus of the fertilized mouse egg, followed
by oviductal implantation of the surviving zygotes, resulted
in the integration and apparent retention of exogenous genes
in all cells of the newborn animal; the foreign genes were
transmitted to the offspring.'
Currently, germ-line gene therapy is not being actively researched
in anything other than animals, but there is a lot of discussion
about its value and desirability within the scientific community
and elsewhere. James Watson believes that the procedure will
become a reality in humans within 20 years, and a good thing
too. He is reported as saying that any international attempt
to prevent germ-line engineering would be "a complete disaster".
Others however question the need for germ-line gene therapy.
In a response to Watson, the UK's Anne McLaren argued that
'the simpler and safer technique of preimplantation genetic
diagnosis, already in clinical use, renders germline gene
therapy for genetic disease virtually pointless.' Some go
further, questioning its desirability as well as its value.
Billings, Hubbard and Newman mount an absolute objection:
'Human germline interventions would necessarily alter the
lives of individuals who are yet to be born. Informed consent
by the affected individuals is not yet possible. Extension
of the parental right to consent for minors would be required.
Such legal permission to specifically alter the lives of generations
of unborn individuals would be unprecedented and unjustified.'
In the popular and sociological literature phrases such as
'playing God', or 'colonising the future' are widely used
to express this and related absolute objections to germ-line
therapy.
The Clothier Report, which as we have already seen established
the regulatory framework for human gene therapy in the UK,
makes a firm distinction between somatic and germ-line gene
therapy. It proposed firm regulation of the former, but it
did not regard it as fundamentally novel. It does not, they
argued, 'represent a major departure from established medical
practice; nor does it …pose new ethical challenges.' They
took a different view on germ-line gene therapy. However,
and significantly, while they recommended that the procedure
be ruled out, they did not say that this prohibition should
be an indefinite one, and nor did they mount absolute objections
to it. Indeed, they rejected arguments similar to those mounted
by Billings et al by pointing out that selective termination
of an affected pregnancy followed by the birth of an unaffected
child has the same effect on future generations as germ-line
gene therapy.
GIG agrees with the approach taken in the Clothier Report
on this subject. Everything we do affects future generations.
Germ-line changes or the consequences of selective termination
or pre-implantation diagnosis will be felt by generations
to come. But so will the consequences of not interfering in
the genetic lottery of life—diseases as well as genetic modifications
run in families. At present, germ-line gene therapy should
be ruled out on grounds of safety. But if a number of scientific
issues can be addressed—including achievement of precise insertion
and deletion of genetic changes—the possibility of germ-line
therapy for some conditions should be considered. One possible
advantage of the procedure for the individual and the family
is that it could allow them to reproduce freely without the
worry of passing on the condition to future generations. According
to many scientists the procedure might also be easier to perform
than somatic therapy—and more complete in that the changes
would integrate into all the bodily cells. Some experimental
procedures currently being considered, such as in-utero gene
therapy, have been criticised on the grounds that they run
an increased risk of inadvertently causing germ-line changes
with unpredictable and potentially hazardous consequences.
Perhaps in the future, deliberate germ-line modification at
this stage might be considered the best way to realise the
benefits of early therapy while controlling for the risks.
But what about Anne McLaren's more practical objection?—that
'the simpler and safer technique of preimplantation genetic
diagnosis, already in clinical use, renders germline gene
therapy for genetic disease virtually pointless.' Her view
is that, this being the case, interest in germ-line modification
must be about something other than extending somatic therapies
for disease. She went on 'or is it germline engineering for
enhancement towards which he wishes to proceed unhindered?
If it is the latter, he should say so. How about it Jim?'
We have already outlined why we believe that there are some
specific reasons to keep an open mind on germ-line therapy
for the treatment of disease. And conceptually, as well as
practically, it is possible to maintain a distinction between
therapy and enhancement. But Anne McLaren is also surely right
that a lot of the interest in the field is due to the possibility
of enhancement at some point in the future. Leaving aside
the thorny issue of character and behavioural traits outlined
in French Anderson's fourth category, gene therapy, including
germ-line gene therapy, as a tool to enhance resistance to
acquired diseases, including the cancers, is a distinct possibility.
In GIG's view, research relating to these matters should be
allowed. It should then be left up to future generations to
decide whether such options amount to an extension of the
humanist goals of medicine or a eugenic policy of social control,
and accordingly whether they should be used.
NOTES
Smith, A. E. (1999), 'Gene therapy—where are we?, Supplement
to the Lancet: Molecular medicine, 354: SI1. http://www.wiley.co.uk/genetherapy/clinical/diseases.aspl.
Cited in Marshall, E. (1995), 'Gene Therapy's Growing Pains',
Science, 269: 1050-1055.
Nabel, E. G. (1999), 'The Development of Human Gene Therapy',
Nature Medicine, 5 (7): 728.
House of Commons Science and Technology Committee, Third Report:
Human Genetics: The Science and its Consequences, 1, London,
HMSO, 1995: xlvi.
De Wachter, M. A. M. (1993), 'Ethical Aspects of Human Germ-Line
Gene Therapy', Bioethics, 7 (2/3): 166-177.
Wivel, N. A. and Walters, L. (1993), 'Germ-Line Gene Modification
and Disease Prevention: Some Medical and Ethical Perspectives',
Science, 262: 533-538.
McLaren, A. (1998), 'Problems of germline therapy', Nature,
392: 645.
Billings, P. R., Hubbard, R., and Newman, S. A. (1999), 'Human
germline gene modification: a dissent', The Lancet, 353: 1873-1874.
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