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After a decade of struggling, gene therapy finally seems to
have become a robust scientific discipline with potential
to target not only genetic disorders, as originally believed,
but a whole host of new indications. However the degree to
which gene therapy can deliver these promises is dependent
on a number of issues.
The story so far
From its heady beginnings - when the concept of gene therapy
promised to revolutionise medicine - the field of gene therapy
has suffered many setbacks. One of the biggest problems was
the technological struggle of introducing genetic material
into targeted cells and ensuring its expression.
More recently, the death of a volunteer in a gene therapy
trial heightened public concern as to the safety of such treatments.
However, gene therapy finally seems to be turning the corner,
with the American Society for Gene Therapy (ASGT) meeting
in June bringing cautious optimism in response to the reporting
of positive results
from preclinical and clinical studies.
Current status of gene therapy trials
The proportion of gene therapy products (being developed
in Phases I-III) relating to specific clinical applications
can be seen in Figure 1: this indicates the major disease
targets, at present, for such agents.
Unexpectedly, cancer has become the most frequently targeted
indication in current clinical trials, as opposed to the original
target - genetic diseases. Other surprises are that, along
with genetic diseases (for example, cystic fibrosis, enzyme
deficiencies, and haemophilia), cardiovascular disease and
HIV also make up a significant proportion of the potential
targets.
Figure 1: Relative proportions of indications being covered
in gene therapy clinical trials (Phases I-III)
Source: R&Dfocus, Jul 2000
Where are we headed?
This is a complicated question and the answer is dependent
on many future events (see below).
By looking into the gene therapy products being researched
in preclinical studies, it may give us an indication as to
the types of diseases that will be targeted by gene therapy
in the future.
Using data from R&Dfocus,
Figure 2 (below) details indications emerging as targets for
gene therapy based treatment in preclinical trials.
Figure 2: Emerging indications being treated using gene
therapy technology
N.B. Novel indications are represented where more than one
preclinical gene therapy study is underway
Source: R&Dfocus, Jul 2000
The number of targets has expanded a great
deal, with a much broader range of indications being represented.
In particular, rheumatoid arthritis, diabetes, infectious
diseases and neurological diseases look as though they may
become significant targets for gene therapy.
Also, according to R&Dfocus, the proportion
of gene therapy products for cardiovascular disease has risen
in preclinical studies to 12.1% (compared to only 7.4% in
Phases I-III), thus indicating that gene therapy may increasingly
become an important treatment basis for cardiovascular disease.
Factors that will influence the future development of gene
therapy
- Overcoming the technological obstacles
Although much effort has been made over the past decade
towards establishing model delivery systems and methods
for long-term expression of genes, progress has been slow.
As such, the field still needs to overcome these complications.
A discussion of these issues will be covered in a future
article.
- Analysis of the 'Human Genome'
Now that the bulk of the 'Human Genome Project' has
been completed, the important work of analysing the data
can begin. The hope is that by examining the DNA sequence
established from the 'Human Genome Project', genes involved
in disease will be identified. These genes could then
form the basis of gene therapy products.
- Expansion of the diagnostic industry
It is now well established that responses to drug treatments
can vary greatly between patients, and that genetic factors
have a major role in treatment outcome.
Using new diagnostic tools (such as gene chip arrays)
researchers believe they can identify DNA variations (polymorphisms)
responsible for drug reactions and susceptibility to disease.
This new discipline, termed pharmacogenomics,
has important implications for the gene therapy field.
In particular researchers believe that the information
resulting from this sort of genotyping will enable patient-specific
gene therapy treatments to be designed.
- Public acceptance of gene therapy
Finally, a large determinant of gene therapy's success
is how well the public accepts the idea of 'improving'
one's own genetic makeup.
Episodes like last year's backlash against the agricultural
industry over 'Genetically Modified' foods are warning
signals of what could happen unless measures are taken
to ensure the public are kept well informed as to the
potential risks and benefits of gene therapy.
However, if a recent MORI survey is correct the industry
can breathe a sigh of relief. The poll showed that, after
the concept of gene therapy was explained to a sample
group of parents, 74% agreed gene therapy was acceptable
if it was tightly controlled.
Nevertheless, the relationship between industry and the
public is fragile, and in order to sustain society's trust
pharmaceutical companies would be well advised to enforce
communication programmes.
Also, it may be the case that the public will 'condone'
the use of gene therapy for the treatment of life-threatening
diseases, but may find it harder to accept the idea of
gene therapy for less aggressive indications.
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