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Genes and Medicines
Discovering
and Developing New Medicines
Scientists are using new genetic technologies to
increase our understanding of disease at its molecular
level. They study DNA from people with a particular
disease and their family members to look for genes
that may make someone more susceptible to that illness.
Based on this information from human studies and existing
knowledge about the functions of various proteins
and enzymes, they then look for a 'target' or a particular
gene sequence that they believe might affect the course
of a specific disease. A target is any way that a
medicine can alter disease processes without seriously
affecting normal body functions. Possible targets
include proteins (e.g., receptors and enzymes), nucleic
acids, gene sequences and genes - any of whose function
can be altered to interfere with the disease mechanism.
After researchers identify and validate a gene sequence
or target associated with a particular condition,
they study the role of the protein encoded by the
gene. Typically, proteins have proven to be good drug
targets, so with the rapid progress recently made
in the identification of genes, an explosion in the
number of potential drug targets is occurring.
Once a target has been identified, chemists develop
compounds that may affect that particular target.
To screen these compounds, a suitable assay or laboratory
test is developed to indicate when a compound has
interacted with a target. Scientists may screen more
than a million compounds to find a promising lead.
Using an automated robotics system, scientists can
test thousands of compounds daily.
Using this information about the protein and having
an identified target can help scientists develop compounds
that might interact with the gene sequence to alter
how it affects a biochemical pathway and ultimately,
the disease. It also may point to other targets for
a new drug - for example, places in a biochemical
pathway where a new or existing drug may have a previously
unexpected positive effect.
Scientists expect the long, laborious and unpredictable
process of discovering new drugs to become more stream-lined
and efficient as experience with and cost-effectiveness
of new genetic and genomic technologies increase.
There should be fewer "misses" in the initial
selection of possible targets for new medicines and
increased accuracy about which drugs are most likely
to be safe and effective in humans.
Safety
and Effectiveness
An important goal in applying genetics research at GlaxoSmithKline is to improve
the development and delivery of medicines —
getting the right medicine to the right patient.
It is possible to determine the safety
and efficacy of a drug for a group of people,
but it's more difficult to determine if a medicine
is safe and effective for a specific person.
We know that people can respond differently
to medicines based on their genetic makeup. Some individuals
are especially responsive to the beneficial effects
of a particular medicine, while others may not respond
at all. A safe dose in one person may be unsafe in
another.
When you take medicine by mouth, it is absorbed from
the stomach and intestines into the body, distributed
throughout the body, and then eliminated.
Genes are involved in every step of this process.
One person's body may perform these steps differently
from another's because everyone's genes (and therefore
their enzymes) are different.
Scientists already know about several important gene
variants that affect the breakdown of many common
medicines; some of these variants occur more often
in specific ethnic groups, for example. They can screen
new compounds to see what breakdown pathways will
be used. If a new compound uses a pathway that is
affected by a common gene variant, they may try to
change the compound or develop another one so that
another, less variable, pathway is used.
Applying genetics and genomics to drug discovery
should help make the process faster and more efficient,
resulting in more safe and effective new medicines
for the people who need them.
Pharmacogenetics
The field of
involves examining the genetic basis of patients'
responses to medicines — understanding why some
medicines work better for some people than others
and why some people are more likely than others to
experience serious side effects.
The knowledge that scientists gain from this research
will result in the delivery of safer, more effective
"personalized" medicines.
In order to achieve this goal of correlating patients'
with their responses to medicines, GSK is incorporating
pharmacogenetic research into many clinical studies.
This pharmacogenetic research is a separate part of
the study for which volunteers give separate informed
consent. All clinical studies are approved by an International
Ethics Committee/Institutional Review Board and follow
strict ethical guidelines.
Patients who participate in a study of a GSK medicine
may have the opportunity, after giving specific informed
consent, to provide a sample (e.g., blood or saliva) for
analysis by GSK scientists.
These samples are coded so that patient confidentiality
is protected. Evaluation of the DNA samples, along
with analysis of clinical data regarding drug safety
and efficacy, will make it possible to correlate patient
response to medication with specific genetic profiles,
often using SNP markers.
SNPs
SNPs are single-base differences in the DNA sequence
that can be observed among different individuals in
the population. They are the simplest and most common
form of DNA .
SNPs are present throughout the human
with an average frequency of 1 per 1,000 base pairs.
The frequency, stability and relatively even distribution
of SNPs in the genome make them particularly valuable
as genetic markers.
By comparing the genetic profiles of patients who
have a serious side effect with those who don't, scientists
may be able to detect one or more SNPs that differ
between the two groups. By examining just a small
area of the genome where this difference is found,
we will be able to predict how likely a person is
to experience the side effect.
Medicine Response Tests (MRTs)
A medicine response test is any genetic or laboratory
test that is used to predict a patient's response
(positive or negative) to a specific medicine or group
of medicines.
Eventually, medicines may be marketed with test kits
that will allow health care providers to assess a
patient's likely response to a medicine before prescribing
it, thus saving the expense and risk of long periods
of trial and error before finding the best medicine
for a specific patient.
Some medicine response tests may be based on SNPs
or patterns of SNPs that are associated with the response,
but do not cause it (i.e., they are near the unidentified
gene that causes the response). Other MRTs may be
based on genetic differences that are known to cause
changes in the enzymes that process drugs in the body.
Still others may be based on RNA, proteins, or techniques
used to measure the amount of DNA being produced by
specific cells.
Genetic Testing
It is important to distinguish between medicine response
tests and genetic testing that predicts or confirms
the presence of a disease. Many existing gene-specific
tests detect single gene (monogenic) disorders such
as Huntington disease and cystic fibrosis, for which
few, if any, effective treatments exist. There are
major ethical, legal and social implications associated
with the use of single gene diagnostic tests, including:
- the potential for discrimination against people
who carry the disease-associated gene
- the psychological and healthcare impact on the
patient and family
- the need for pre- and post-test genetic counseling.
Medicine response tests, in contrast, will be used
to collect limited genetic information related to
a patient's response to a specific medicine; it is
unlikely that any information about disease genes
will be gathered. These tests are similar to routine
laboratory tests such as blood typing and blood chemistry
analyses.
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