Gene therapy

Gene Therapy
More than 4,000 diseases are thought to be related to mutated genes that are inherited from one or both parents. But whether a gene actually triggers a disease can be dependent on a variety of factors, including lifestyle and the environment.

Genetic testing can determine if a person has a predisposition to a particular condition. Many doctors now offer genetic tests for cancers that run in families, including a test for the BRCA1 gene mutation that predisposes women to hereditary breast and ovarian cancer, as well as tests for colon cancer and a few rare cancers that affect children and young adults. Genetic testing also exists for conditions such as Lou Gehrig’s disease, Huntingtons disease and dangerously high cholesterol.

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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 has been discussed in the context of treating lethal and disabling diseases although it also has a potential for disease prevention. Gene therapy is in its formative stages, being investigated in basic research laboratories. A number of early human clinical trials have been initiated to test important concepts that have emerged in these laboratory studies.


The reasoning 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. A composite of approximately 150,000 individual genes constitutes a human being. Several years ago, an international effort was launched to identify every single human gene. This effort called the Human Genome Project, is well underway and should be completed soon after the turn of the century. Variation in the structure of a person’s genes collectively helps define us as individuals such as how tall we are to the color our eyes. Some of this genetic heterogenetics unfortunately leads to the development of disease. The genetics of many diseases are passed from one generation to the next by inheriting a single gene. An example is Huntingdon’s disease. Many other diseases and traits are influenced by a collection of genes.


The premise of gene therapy is based on correcting disease at its root – 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 that will be corrective to the patient but not inherited to 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 other laboratories across 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 change on to the next generation. Little, if any, research is currently being conducted in germline intervention largely for technical and ethical reasons
The basic challenge in 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 which are large and complex and require targeting to the nuclei of cells. If genes are appropriately delivered they can persist for the life of the cell and potentially lead to a cure.


The enabling technology 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 billions of years of evolution, viruses have developed extraordinarily efficient ways of targeting cells and delivering genome, which unfortunately leads to 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 synthetic vectors in which complexes of DNA, proteins, or lipids are formed in particles capable of efficiently transferring genes.


The first human trials of gene therapy began in 1990 using a strategy of ex vivo gene therapy. In this approach, the patient cells were harvested and refined in the laboratory and incubated with vectors to modify their genes. The cells were then harvested and transplanted back into the patient from whom they came. 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 has quickly moved 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 based on an attenuated version of the adenovirus in the treatment of cystic fibrosis. Adenoviruses have a natural tropism for lungs in that they are associated with respiratory diseases. Many other types of diseases are currently being investigated as candidates for gene therapy including cardiovascular diseases, infectious diseases such as AIDS, and cancer
A recent conference at the National Institutes of Health (NIH) began to address the questions surrounding the uses of gene transfer for purposes other than treating disease. The term applied to such an application of the technology is enhancement. Along with all the ethical and philosophical conundrums that have been raised, there is one fundamental reality about this issue. There will never be any consensus about priorities because different types of enhancement will have a different level of appeal to different people. This is in stark distinction to disease where a group of medical experts can convene and come to some definitive conclusions about malfunctions in the body. Furthermore, one can gradate diseases in a spectrum ranging from mild to serious to fatal. Absent the disease parameters, one can think of the market for enhancement as largely driven by desire.


Some of the common cosmetic enhancements that might be envisioned is the use of genes to correct pattern baldness, the use of genes that encode for growth factors to promote muscle development and the use of genes to affect skin color or hair color or physical appearance are among the most common types of physical enhancement that are mentioned. If one wants to stretch the boundaries of the imagination, the matter of improving intelligence immediately comes into play. However, it must be pointed out that intelligence undoubtedly is a multigenic function with hundreds or even thousands of genes potentially involved; obviously, such genes have not been identified, and even if they were identified, this would not be sufficient since one would need to know the interactions among such genes. It is not likely that the genetic definition of intelligence will be understood anytime in the near future.


Can genetic enhancement be prevented or should it be prevented? The regulatory agency that will be the first to face this issue is the Food and Drug Administration (FDA). Two main questions will have to be answered. (1) Does the product do what it is alleged to do? (2) Is the product safe? The second question can turn out to be a very complicated one because it involves a risk/benefit ratio. One can justify certain kinds of risks when treating a serious or fatal illness, particularly if there is a reasonable chance of benefit. The tolerance of risk for a “cosmetic” may be difficult to determine, particularly if there are potential genetic side effects that are impossible to predict. On the other hand, if the enhancement product is deemed to be safe by all the measures available, then the FDA may proceed to make approval. There is no obligation for the FDA to conduct an “ethical” review although the agency retains the right to convene public advisory conferences when it is deemed necessary; such a conference would guarantee press attention.


It is not unlikely that there will be sufficient progress in the refinement of gene therapy techniques so as to enable the development of products to be used for enhancement. There are many issues to be considered. However, until we have gained major new insights into the fields of cell biology, virology, and immunology, and until we have greatly improved the current, but primitive, techniques of human gene transfer, it will be difficult to improve or cure diseases using this approach. It is somewhat arrogant to worry about the non-medical uses of gene transfer until our current science has made quantum leaps forward.

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