Gene
therapy is a novel approach to treating diseases based on modifying the
expression of a person's genes toward a therapeutic goal. Gene therapy is most
often been discussed in the context of treating lethal and disabling diseases
although it also has a potential for disease prevention. With an 11 year
history of clinical trials, there is some recent evidence that gene therapy may
be efficacious in the treatment of certain single gene deficiency diseases.
Nevertheless, gene therapy remains a highly experimental collection of
technologies whose full potential is yet to be realized.
The rationale for gene therapy lies in our understanding of the genetic basis
of human disease. It is probably safe to say that genes we inherit from our
parents influence virtually every human disease. Several years ago, an
international effort was launched to identify every single human gene. This
effort, called the Human Genome Project, is largely completed and the data
suggests that each individual human being may have on the order of 30,000
genes. Variation in the structure of a person's genes collectively helps define
us as individuals, influencing such factors as height and eye color.
Unfortunately, some of this genetic heterogeneity leads to the development of
disease. Many genetic diseases are passed from one generation to the next by
inheritance of a single gene. An example is Huntingdon's disease. Many other
diseases and traits are influenced by a collection of genes, and we have less
detailed information about these so-called polygenic diseases.
The premise of gene therapy is based on correcting disease at the level of DNA
molecules and thus compensating for the abnormal genes. There are essentially
two forms of gene therapy, one of which is called somatic gene therapy. Somatic
gene therapy involves the manipulation of gene expression in cells so as to be
corrective for the patient, but this correction is not inherited by the next
generation. This is the type of gene therapy that is currently being
investigated at the Institute for Human Gene Therapy, as well as at other
laboratories around the world. The other form of gene therapy is called
germline gene therapy; this involves the genetic modification of germ cells
that will pass the selected change on to the next generation. Research on
germline intervention is strictly limited to animal model systems, and there is
no intent to pursue this type of approach in humans at any time in the near
future; this is because of significant technical and ethical challenges.
The
fundamental task for gene therapy is to develop approaches for delivering
genetic material to the appropriate cells of the patient in a way that is
specific, efficient and safe. This problem of "drug delivery," where
the gene is a drug, is particularly challenging for genes that are large and
complex and require targeting to the nuclei of cells. If genes are optimally
delivered, they can persist for the life of the cell and potentially lead to a
cure.
The functioning of gene therapy is based on strategies for delivering genes. To
do this we have developed gene delivery vehicles called vectors, which
encapsulate therapeutic genes for delivery to cells. Many of the vectors
currently in use are based on attenuated or modified versions of viruses. Over
millions of years of evolution, viruses have developed extraordinarily
efficient ways of targeting cells and delivering their genetic machinery in
such a way that they can reproduce; frequently this process leads to the
development of disease. Our challenge is to remove the disease-causing
components of the virus and insert recombinant genes that will be therapeutic
to the patient. The modified viruses cannot replicate in the patient, but do retain
the ability to efficiently deliver genetic material. Another strategy is based
on non-viral vectors in which complexes of DNA, proteins, or lipids are
constructed as particles capable of efficiently transferring genes.
The first human gene therapy trials began in 1990, using an ex vivo
strategy. In this approach, the patient cells were harvested and cultivated in
the laboratory and then incubated with vectors to introduce the therapeutic
genes. The cells were then harvested and transplanted back into the patient
from whom they were derived. The first therapeutic trials utilizing this
approach attempted to treat two genetic disorders, including children with an
inherited form of immune deficiency as well as children and adults with
extremely high levels of serum cholesterol. The field moved quickly into more
practical approaches for delivering genes based on so-called in vivo
gene therapy in which the virus is directly administered to the patients. The
first model for in vivo gene therapy was dependent on an attenuated
version of adenovirus in the treatment of cystic fibrosis. Adenoviruses have a
natural tropism for the lungs in that they are associated with respiratory
diseases.
Based on the initial concepts for gene therapy, it was ideally designed for the
treatment of single gene deficiency diseases in which the defects in the gene
are associated with a specific constellation of symptoms and organ defects. It
is most encouraging to note that gene therapy has evolved into an enabling
technology and is being used to develop treatments for such diverse diseases as
cancer, cardiovascular disease, and AIDS. In fact, the most common disease
target represented in the approved clinical research protocols is cancer; this
accounts for approximately 60% of all the trials being conducted.