Somatic Gene therapy is provided by introducing a new
therapeutic gene (transgene) into the diseased cells of a
patient. The modified cells express the introduced gene and their
new phenotype provides some advantage to the patient. For this
approach two prerequisites must be worked out:
1. a gene which will benefit the patient and
2. a mechanism or "vector" for introducing that gene
into the desired cell types.
The appropriate gene to introduce is obvious for some diseases.
For example, cystic fibrosis results from mutations which derange
the cftr gene and a logical course is to introduce normal copies
of that gene. Finding an appropriate gene for other diseases
requires more ingenuity. For example, AIDS researchers are
investigating half a dozen very diverse sorts of genes to make
cells resistant or inhospitable to HIV infection. The human
genome project will help enormously both by making it far easier
to identify mutated genes in patients and by revealing the total
repertoire of human genes which might be manipulated.
Most gene therapy uses viruses of one sort or another as the
vector. The therapeutic gene is inserted into the viral
chromosome in place of an essential viral gene. The virus then
carries this transgene into the cell it infects. The cell remains
viable and expresses the transgene. Of course, the virus must be
able to infect the cells to be modified. Some viruses infect only
a few cell types. This specificity has certain advantages for
genetic engineering. Other viruses infect a broader range of
cells and can act as a more general vector, which again is an
advantage for some purposes.
The cells easiest to infect are ones that line a surface of
tissue, internal or external. They can be directly exposed to
viruses. Cystic fibrosis is a good example. One of its major
problems is that cells lining the respiratory tract over-produce
mucus due to a defective cftr gene. Adenoviruses
infect these lining cells. Ideally, patients would merely need to
inhale an aerosol of engineered adenoviruses for therapy.
Unfortunately, it is not so simple in reality. The efficiency of
these vectors in transfering an expressed cftr gene
into the target cells leaves much to be desired.
Diseases of deeply buried tissues present an even more formidable challenge. Viruses might be injected into a mass of tissue or the tissue might be removed and its cells dispersed in a test tube, treated with the vector and then reinjected into the body. The latter procedure is called ex-vivo therapy as opposed to in-vivo therapy such as the cystic-fibrosis treatment mentioned.
The first approved somatic gene therapy was in 1990 to treat
ADA deficiency (an ex-vivo treatment of white blood cells), and
the technology has spread rapidly. In 1996, there were already
more than 1500 patients involved in some 230 approved protocols.
The original ADA treatment was relatively successful, but the
jury is still out on how effective these treatments will prove.
Early hype about how rapidly somatic therapy would become a major
new avenue to fight disease has led to some disillusionment over
the slow pace of its subsequent development. Yet in a few short
years much has been accomplished. It is now generally accepted
that the main limitations to widespread somatic gene therapy are
simply the technical ones of devising effective vectors and
transgenes. Most general reservations over safety and
philosophical issues have now been satisfied.