gene therapy

gene therapy the use of genes and the techniques of genetic engineering in the treatment of a genetic disorder or chronic disease. There are many techniques of gene therapy, all of them still in experimental stages. The two basic methods are called in vivo and ex vivo gene therapy. The in vivo method inserts genetically altered genes directly into the patient; the ex vivo method removes tissue from the patient, extracts the cells in question, and genetically alters them before returning them to the patient.

The challenge of gene therapy lies in development of a means to deliver the genetic material into the nuclei of the appropriate cells, so that it will be reproduced in the normal course of cell division and have a lasting effect. One technique involves removing cells from a patient, fortifying them with healthy copies of the defective gene, and reinjecting them into the patient. Another involves inserting a gene into an inactivated or nonvirulent virus and using the virus's infective capabilities to carry the desired gene into the patient's cells. A liposome , a tiny fat-encased pouch that can traverse cell membranes, is also sometimes used to transport a gene into a body cell. Another approach employing liposomes, called chimeraplasty, involves the insertion of manufactured nucleic acid molecules (chimeraplasts) instead of entire genes to correct disease-causing gene mutations. Once inserted, the gene may produce an essential chemical that the patient's body cannot, remove or render harmless a substance or gene causing disease, or expose certain cells, especially cancerous cells, to attack by conventional drugs.

Gene therapy was first used in humans in 1990 to treat a child with adenosine deaminase deficiency (ADA), a rare hereditary immune disorder (see immunity ). It is hoped that gene therapy can be used to treat cancer, genetic diseases, and AIDS, but there are concerns that the immune system may attack cells treated by gene therapy, that the viral vectors could mutate and become virulent, or that altered genes might be passed to succeeding generations.

In the United States, gene therapy techniques must be approved by the federal government. The Recombinant DNA Advisory Committee of the National Institutes of Health oversees gene therapy experiments. Like drugs, products must pass the requirements of the Food and Drug Administration . Gene therapy is a competitive and potentially lucrative field, and patents have been awarded for certain techniques.

Bibliography: See J. Lyon and P. Gorner, Altered Fates: Gene Therapy and the Retooling of Human Life (1995).

gene therapy is the treatment of human disease by gene transfer. Many, or maybe most, diseases have a genetic component — asthma, cancer, Alzheimer's disease, for example. However, most diseases are polygenic, i.e. a subtle interplay of many genes determines the likelihood of developing a disease condition, whereas, so far, gene therapy can only be contemplated for monogenic diseases, in which there is a single gene defect. Even in these cases only treatment of recessive diseases can be considered, where the correct gene is added in the continued presence of the faulty one. Dominant mutations cannot be approached in this way, as it would be necessary to knock out the existing faulty genes in the cells where they are expressed (i.e. where their presence shows an effect), as well as adding the correct genetic information.

Gene therapy for recessive monogenic diseases involves introducing correct genetic material into the patient. This can be approached in two different ways. Cells can be taken from the patient, modified in the laboratory (‘in vitro’), and then re-introduced, or a carrier (‘vector’) of the correct genetic material can be delivered directly into the patient. Examples are adenosine deaminase (ADA) deficiency and cystic fibrosis, respectively.

ADA deficiency is a lethal monogenic disease in which adenosine is not normally metabolized, leading to high levels of 2′-deoxyadenosine, which is selectively toxic to cells of the immune system (T and B cells) and leads to immunodeficiency. The gene therapy for this disease is to isolate T cells from patients and treat these cells in vitro with a retroviral vector — a virus, normally capable of causing disease, which has been modified to carry the required genetic information. Cells that have incorporated the new genetic information into their genomes are selected and reinfused back into the patient, allowing the appropriate metabolism of adenosine to occur.

Cystic fibrosis (CF) is also a lethal disease resulting from a single gene mutation. It disables normal cell membrane function. The gene codes for a protein, the cystic fibrosis ‘transmembrane conductance regulator’ (CFTR), which acts as a chloride ion channel in the epithelia of the airways, alimentary canal, and numerous other hollow organs. The correct genetic sequence can be incorporated into a type of virus which ordinarily can infect the respiratory tract (adenoviruses), or into genetic particles (plasmids) linked to lipids to form lipocomplexes. Either of these can be delivered directly into the patient's lungs.

Both the examples given must still be regarded as at the experimental stage. In ADA deficiency the transformed T cells persist for only 6 months, while in CF the new genetic material is not incorporated into the genome and is expressed outside of it (episomally) for only a few weeks. The major problems with gene therapy relate to the delivery of new genetic instructions to the appropriate body targets. Ideally, delivery should be to stem cells — the progenitor cells which give rise to replacement cells as adult, mature cells die. Furthermore, the material should be incorporated into the genome so that all future generations of cells carry the correct instructions. Retroviral vectors (viruses carrying the genetic material) are incorporated in the genome, but this can only be used in the in vitro type of procedure, when the treated cells are outside the body. Incorporation of the new material into an inappropriate position may switch on an oncogene which can lead to tumour formation. Thus it is very necessary to be sure that cells transformed in vitro behave normally before reintroducing them to the patient. These problems do not occur with adenoviral vectors, but expression persists for only a short time, thus requiring repeated administration, leading to immune reactions. Use of lipoplexes avoids this latter problem, but the efficiency of gene delivery by this route is very low.

Gene therapy will undoubtedly have much to offer for the future. Unlike many conventional therapies, it aims to cure disease rather than simply treat the symptoms. The principles of gene therapy are established, but technical problems, primarily related to efficient and safe ways of delivery, have still to be overcome.

Alan W. Cuthbert

gene therapy n. treatment directed to curing genetic disease by introducing normal genes into patients to overcome the effects of defective genes, using techniques of genetic engineering. At present, gene therapy is most feasible for treating disorders caused by a defect in a single recessive gene, such as adenosine deaminase (ADA) deficiency, severe combined immune deficiency, and cystic fibrosis. Gene therapy for certain types of cancer is also undergoing clinical trials.