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Gene Therapy

Gene Therapy

Gene therapy is a rapidly growing field of medicine in which genes are introduced into the body to treat diseases. Genes control heredity and provide the basic biological code for determining a cell's specific functions. Gene therapy seeks to provide genes that correct or supplant the disease-controlling functions of cells that are not, in essence, doing their job. Somatic gene therapy introduces therapeutic genes at the tissue or cellular level to treat a specific individual. Germ-line gene therapy inserts genes into reproductive cells or possibly into embryos to correct genetic defects that could be passed on to future generations. Initially conceived as an approach for treating inherited diseases, like cystic fibrosis and Huntington's disease, the scope of potential gene therapies has grown to include treatments for cancers, arthritis, and infectious diseases. Although gene therapy testing in humans has advanced rapidly, many questions surround its use. For example, some scientists are concerned that the therapeutic genes themselves may cause disease. Others fear that germ-line gene therapy may be used to control human development in ways not connected with disease, like intelligence or appearance.

The biological basis of gene therapy

Gene therapy has grown out of the science of genetics or how heredity works. Scientists know that life begins in a cell, the basic building block of all multicellular organisms. Humans, for instance, are made up of trillions of cells, each performing a specific function. Within the cell's nucleus (the center part of a cell that regulates its chemical functions) are pairs of chromosomes. These threadlike structures are made up of a single molecule of DNA (deoxyribonucleic acid), which carries the blueprint of life in the form of codes, or genes, that determine inherited characteristics.

A DNA molecule looks like two ladders with one of the sides taken off both and then twisted around each other. The rungs of these ladders meet (resulting in a spiral staircase-like structure) and are called base pairs. Base pairs are made up of nitrogen molecules and arranged in specific sequences. Millions of these base pairs, or sequences, can make up a single gene, specifically defined as a segment of the chromosome and DNA that contains certain hereditary information. The gene, or combination of genes formed by these base pairs ultimately direct an organism's growth and characteristics through the production of certain chemicals, primarily proteins, which carry out most of the body's chemical functions and biological reactions.

Scientists have long known that alterations in genes present within cells can cause inherited diseases like cystic fibrosis, sickle-cell anemia, and hemophilia. Similarly, errors in the total number of chromosomes can cause conditions such as Down syndrome or Turner's syndrome. As the study of genetics advanced, however, scientists learned that an altered genetic sequence also can make people more susceptible to diseases, like atherosclerosis, cancer, and even schizophrenia. These diseases have a genetic component, but also are influenced by environmental factors (like diet and lifestyle). The objective of gene therapy is to treat diseases by introducing functional genes into the body to alter the cells involved in the disease process by either replacing missing genes or providing copies of functioning genes to replace nonfunctioning ones. The inserted genes can be naturally-occurring genes that produce the desired effect or may be genetically engineered (or altered) genes.

Scientists have known how to manipulate a gene's structure in the laboratory since the early 1970s through a process called gene splicing. The process involves removing a fragment of DNA containing the specific genetic sequence desired, then inserting it into the DNA of another gene. The resultant product is called recombinant DNA and the process is genetic engineering.

There are basically two types of gene therapy. Germ-line gene therapy introduces genes into reproductive cells (sperm and eggs) or someday possibly into embryos in hopes of correcting genetic abnormalities that could be passed on to future generations. Most of the current work in applying gene therapy, however, has been in the realm of somatic gene therapy. In this type of gene therapy, therapeutic genes are inserted into tissue or cells to produce a naturally occurring protein or substance that is lacking or not functioning correctly in an individual patient.

Viral vectors

In both types of therapy, scientists need something to transport either the entire gene or a recombinant DNA to the cell's nucleus, where the chromosomes and DNA reside. In essence, vectors are molecular delivery trucks. One of the first and most popular vectors developed were viruses because they invade cells as part of the natural infection process. Viruses have the potential to be excellent vectors because they have a specific relationship with the host in that they colonize certain cell types and tissues in specific organs. As a result, vectors are chosen according to their attraction to certain cells and areas of the body.

One of the first vectors used was retroviruses. Because these viruses are easily cloned (artificially reproduced) in the laboratory, scientists have studied them extensively and learned a great deal about their biological action. They also have learned how to remove the genetic information that governs viral replication, thus reducing the chances of infection.

Retroviruses work best in actively dividing cells, but cells in the body are relatively stable and do not divide often. As a result, these cells are used primarily for ex vivo (outside the body) manipulation. First, the cells are removed from the patient's body, and the virus, or vector, carrying the gene is inserted into them. Next, the cells are placed into a nutrient culture where they grow and replicate. Once enough cells are gathered, they are returned to the body, usually by injection into the blood stream. Theoretically, as long as these cells survive, they will provide the desired therapy.

Another class of viruses, called the adenoviruses, also may prove to be good gene vectors. These viruses can effectively infect nondividing cells in the body, where the desired gene product then is expressed naturally. In addition to being a more efficient approach to gene transportation, these viruses, which cause respiratory infections, are more easily purified and made stable than retroviruses, resulting in less chance of an unwanted viral infection. However, these viruses live for several days in the body, and some concern surrounds the possibility of infecting others with the viruses through sneezing or coughing. Other viral vectors include influenza viruses, Sindbis virus, and a herpes virus that infects nerve cells.

Scientists also have delved into nonviral vectors. These vectors rely on the natural biological process in which cells uptake (or gather) macromolecules. One approach is to use liposomes, globules of fat produced by the body and taken up by cells. Scientists also are investigating the introduction of raw recombinant DNA by injecting it into the bloodstream or placing it on microscopic beads of gold shot into the skin with a "gene-gun." Another possible vector under development is based on dendrimer molecules. A class of polymers (naturally occurring or artificial substances that have a high molecular weight and formed by smaller molecules of the same or similar substances), is "constructed" in the laboratory by combining these smaller molecules. They have been used in manufacturing Styrofoam, polyethylene cartons, and Plexiglass. In the laboratory, dendrimers have shown the ability to transport genetic material into human cells. They also can be designed to form an affinity for particular cell membranes by attaching to certain sugars and protein groups.

The history of gene therapy

In the early 1970s, scientists proposed "gene surgery" for treating inherited diseases caused by faulty genes. The idea was to take out the disease-causing gene and surgically implant a gene that functioned properly. Although sound in theory, scientists, then and now, lack the biological knowledge or technical expertise needed to perform such a precise surgery in the human body.

However, in 1983, a group of scientists from Baylor College of Medicine in Houston, Texas, proposed that gene therapy could one day be a viable approach for treating Lesch-Nyhan disease, a rare neurological disorder. The scientists conducted experiments in which an enzyme-producing gene (a specific type of protein) for correcting the disease was injected into a group of cells for replication. The scientists theorized the cells could then be injected into people with Lesch-Nyhan disease, thus correcting the genetic defect that caused the disease.

As the science of genetics advanced throughout the 1980s, gene therapy gained an established foothold in the minds of medical scientists as a promising approach to treatments for specific diseases. One of the major reasons for the growth of gene therapy was scientists' increasing ability to identify the specific genetic malfunctions that caused inherited diseases. Interest grew as further studies of DNA and chromosomes (where genes reside) showed that specific genetic abnormalities in one or more genes occurred in successive generations of certain family members who suffered from diseases like intestinal cancer, bipolar disorder, Alzheimer's disease, heart disease, diabetes, and many more. Although the genes may not be the only cause of the disease in all cases, they may make certain individuals more susceptible to developing the disease because of environmental influences, like smoking, pollution, and stress. In fact, some scientists theorize that all diseases may have a genetic component.

On September 14, 1990, a four-year old girl suffering from a genetic disorder that prevented her body from producing a crucial enzyme became the first person to undergo gene therapy in the United States. Because her body could not produce adenosine deaminase (ADA), she had a weakened immune system, making her extremely susceptible to severe, life-threatening infections. W. French Anderson and colleagues at the National Institutes of Health's Clinical Center in Bethesda, Maryland, took white blood cells (which are crucial to proper immune system functioning) from the girl, inserted ADA producing genes into them, and then transfused the cells back into the patient. Although the young girl continued to show an increased ability to produce ADA, debate arose as to whether the improvement resulted from the gene therapy or from an additional drug treatment she received.

Nevertheless, a new era of gene therapy began as more and more scientists sought to conduct clinical trial (testing in humans) research in this area. In that same year, gene therapy was tested on patients suffering from melanoma (skin cancer). The goal was to help them produce antibodies (disease fighting substances in the immune system) to battle the cancer.

These experiments have spawned an ever growing number of attempts at gene therapies designed to perform a variety of functions in the body. For example, a gene therapy for cystic fibrosis aims to supply a gene that alters cells, enabling them to produce a specific protein to battle the disease. Another approach was used for brain cancer patients, in which the inserted gene was designed to make the cancer cells more likely to respond to drug treatment. Another gene therapy approach for patients suffering from artery blockage, which can lead to strokes, induces the growth of new blood vessels near clogged arteries, thus ensuring normal blood circulation.

Currently, there are a host of new gene therapy agents in clinical trials. In the United States, both nucleic acid based (in vivo ) treatments and cell-based (ex vivo ) treatments are being investigated. Nucleic acid based gene therapy uses vectors (like viruses) to deliver modified genes to target cells. Cell-based gene therapy techniques remove cells from the patient in order to genetically alter them then reintroduce them to the patient's body. Presently, gene therapies for the following diseases are being developed: cystic fibrosis (using adenoviral vector), HIV infection (cell-based), malignant melanoma (cell-based), Duchenne muscular dystrophy (cell-based), hemophilia B (cell-based), kidney cancer (cell-based), Gaucher's Disease (retroviral vector), breast cancer (retroviral vector), and lung cancer (retroviral vector). When a cell or individual is treated using gene therapy and successful incorporation of engineered genes has occurred, the cell or individual is said to be transgenic.

The medical establishment's contribution to transgenic research has been supported by increased government funding. In 1991, the U.S. government provided $58 million for gene therapy research, with increases in funding of $15-40 million dollars a year over the following four years. With fierce competition over the promise of societal benefit in addition to huge profits, large pharmaceutical corporations have moved to the forefront of transgenic research. In an effort to be first in developing new therapies, and armed with billions of dollars of research funds, such corporations are making impressive strides toward making gene therapy a viable reality in the treatment of once elusive diseases.

Diseases targeted for treatment by gene therapy

The potential scope of gene therapy is enormous. More than 4,200 diseases have been identified as resulting directly from abnormal genes, and countless others that may be partially influenced by a person's genetic makeup. Initial research has concentrated on developing gene therapies for diseases whose genetic origins have been established and for other diseases that can be cured or improved by substances genes produce.

The following are examples of potential gene therapies. People suffering from cystic fibrosis lack a gene needed to produce a salt-regulating protein. This protein regulates the flow of chloride into epithelial cells, (the cells that line the inner and outer skin layers) that cover the air passages of the nose and lungs. Without this regulation, patients with cystic fibrosis build up a thick mucus that makes them prone to lung infections. A gene therapy technique to correct this abnormality might employ an adenovirus to transfer a normal copy of what scientists call the cystic fibrosis transmembrane conductance regulator, or CTRF, gene. The gene is introduced into the patient by spraying it into the nose or lungs. Researchers announced in 2004 that they had, for the first time, treated a dominant neurogenerative disease called Spinocerebella ataxia type 1, with gene therapy. This could lead to treating similar diseases such as Huntingtons disease. They also announced a single intravenous injection could deliver therapy to all muscles, perhaps providing hope to people with muscular dystrophy.

Familial hypercholesterolemia (FH) also is an inherited disease, resulting in the inability to process cholesterol properly, which leads to high levels of artery-clogging fat in the blood stream. Patients with FH often suffer heart attacks and strokes because of blocked arteries. A gene therapy approach used to battle FH is much more intricate than most gene therapies because it involves partial surgical removal of patients' livers (ex vivo transgene therapy). Corrected copies of a gene that serve to reduce cholesterol build-up are inserted into the liver sections, which then are transplanted back into the patients.

Gene therapy also has been tested on patients with AIDS. AIDS is caused by the human immunodeficiency virus (HIV), which weakens the body's immune system to the point that sufferers are unable to fight off diseases like pneumonias and cancer. In one approach, genes that produce specific HIV proteins have been altered to stimulate immune system functioning without causing the negative effects that a complete HIV molecule has on the immune system. These genes are then injected in the patient's blood stream. Another approach to treating AIDS is to insert, via white blood cells, genes that have been genetically engineered to produce a receptor that would attract HIV and reduce its chances of replicating. In 2004, researchers reported that had developed a new vaccine concept for HIV, but the details were still in development.

Several cancers also have the potential to be treated with gene therapy. A therapy tested for melanoma, or skin cancer, involves introducing a gene with an anticancer protein called tumor necrosis factor (TNF) into test tube samples of the patient's own cancer cells, which are then reintroduced into the patient. In brain cancer, the approach is to insert a specific gene that increases the cancer cells' susceptibility to a common drug used in fighting the disease. In 2003, researchers reported that they had harnessed the cell killing properties of adenoviruses to treat prostate cancer. A 2004 report said that researchers had developed a new DNA vaccine that targeted the proteins expressed in cervical cancer cells.

Gaucher disease is an inherited disease caused by a mutant gene that inhibits the production of an enzyme called glucocerebrosidase. Patients with Gaucher disease have enlarged livers and spleens and eventually their bones deteriorate. Clinical gene therapy trials focus on inserting the gene for producing this enzyme.

Gene therapy also is being considered as an approach to solving a problem associated with a surgical procedure known as balloon angioplasty. In this procedure, a stent (in this case, a type of tubular scaffolding) is used to open the clogged artery. However, in response to the trauma of the stent insertion, the body initiates a natural healing process that produces too many cells in the artery and results in restenosis, or reclosing of the artery. The gene therapy approach to preventing this unwanted side effect is to cover the outside of the stents with a soluble gel. This gel contains vectors for genes that reduce this overactive healing response.

Regularly throughout the past decade, and no doubt over future years, scientists have and will come up with new possible ways for gene therapy to help treat human disease. Recent advancements include the possibility of reversing hearing loss in humans with experimental growing of new sensory cells in adult guinea pigs, and avoiding amputation in patients with severe circulatory problems in their legs with angiogenic growth factors.

The Human Genome Project

Although great strides have been made in gene therapy in a relatively short time, its potential usefulness has been limited by lack of scientific data concerning the multitude of functions that genes control in the human body. For instance, it is now known that the vast majority of genetic material does not store information for the creation of proteins, but rather is involved in the control and regulation of gene expression, and is, thus, much more difficult to interpret. Even so, each individual cell in the body carries thousands of genes coding for proteins, with some estimates as high as 150,000 genes. For gene therapy to advance to its full potential, scientists must discover the biological role of each of these individual genes and where the base pairs that make them up are located on DNA.

To address this issue, the National Institutes of Health initiated the Human Genome Project in 1990. Led by James D. Watson (one of the co-discoverers of the chemical makeup of DNA) the project's 15-year goal is to map the entire human genome (a combination of the words gene and chromosomes). A genome map would clearly identify the location of all genes as well as the more than three billion base pairs that make them up. With a precise knowledge of gene locations and functions, scientists may one day be able to conquer or control diseases that have plagued humanity for centuries.

Scientists participating in the Human Genome Project identified an average of one new gene a day, but many expected this rate of discovery to increase. By the year 2005, their goal was to determine the exact location of all the genes on human DNA and the exact sequence of the base pairs that make them up. Some of the genes identified through this project include a gene that predisposes people to obesity, one associated with programmed cell death (apoptosis), a gene that guides HIV viral reproduction, and the genes of inherited disorders like Huntington's disease, Lou Gehrig's disease, and some colon and breast cancers. In April 2003, the finished sequence was announced, with 99% of the human genome's gene-containing regions mapped to an accuracy of 99.9%.

The future of gene therapy

Gene therapy seems elegantly simple in its concept: supply the human body with a gene that can correct a biological malfunction that causes a disease. However, there are many obstacles and some distinct questions concerning the viability of gene therapy. For example, viral vectors must be carefully controlled lest they infect the patient with a viral disease. Some vectors, like retroviruses, also can enter cells functioning properly and interfere with the natural biological processes, possibly leading to other diseases. Other viral vectors, like the adenoviruses, often are recognized and destroyed by the immune system so their therapeutic effects are short-lived. Maintaining gene expression so it performs its role properly after vector delivery is difficult. As a result, some therapies need to be repeated often to provide long-lasting benefits.

One of the most pressing issues, however, is gene regulation. Genes work in concert to regulate their functioning. In other words, several genes may play a part in turning other genes on and off. For example, certain genes work together to stimulate cell division and growth, but if these are not regulated, the inserted genes could cause tumor formation and cancer. Another difficulty is learning how to make the gene go into action only when needed. For the best and safest therapeutic effort, a specific gene should turn on, for example, when certain levels of a protein or enzyme are low and must be replaced. But the gene also should remain dormant when not needed to ensure it doesn't oversupply a substance and disturb the body's delicate chemical makeup.

One approach to gene regulation is to attach other genes that detect certain biological activities and then react as a type of automatic off-and-on switch that regulates the activity of the other genes according to biological cues. Although still in the rudimentary stages, researchers are making headway in inhibiting some gene functioning by using a synthetic DNA to block gene transcriptions (the copying of genetic information). This approach may have implications for gene therapy.

The ethics of gene therapy

While gene therapy holds promise as a revolutionary approach to treating disease, ethical concerns over its use and ramifications have been expressed by scientists and lay people alike. For example, since much needs to be learned about how these genes actually work and their long-term effect, is it ethical to test these therapies on humans, where they could have a disastrous result? As with most clinical trials concerning new therapies, including many drugs, the patients participating in these studies usually have not responded to more established therapies and often are so ill the novel therapy is their only hope for long-term survival.

Another questionable outgrowth of gene therapy is that scientists could possibly manipulate genes to genetically control traits in human offspring that are not health related. For example, perhaps a gene could be inserted to ensure that a child would not be bald, a seemingly harmless goal. However, what if genetic manipulation was used to alter skin color, prevent homosexuality, or ensure good looks? If a gene is found that can enhance intelligence of children who are not yet born, will everyone in society, the rich and the poor, have access to the technology or will it be so expensive only the elite can afford it?

The Human Genome Project, which plays such an integral role for the future of gene therapy, also has social repercussions. If individual genetic codes can be determined, will such information be used against people? For example, will someone more susceptible to a disease have to pay higher insurance premiums or be denied health insurance altogether? Will employers discriminate between two potential employees, one with a "healthy" genome and the other with genetic abnormalities?

Some of these concerns can be traced back to the eugenics movement popular in the first half of the twentieth century. This genetic "philosophy" was a societal movement that encouraged people with "positive" traits to reproduce while those with less desirable traits were sanctioned from having children. Eugenics was used to pass strict immigration laws in the United States, barring less suitable people from entering the country lest they reduce the quality of the country's collective gene pool. Probably the most notorious example of eugenics in action was the rise of Nazism in Germany, which resulted in the Eugenic Sterilization Law of 1933. The law required sterilization for those suffering from certain disabilities and even for some who were simply deemed "ugly." To ensure that this novel science is not abused, many governments have established organizations specifically for overseeing the development of gene therapy. In the United States, the Food and Drug Administration (FDA) and the National Institutes of Health require scientists to take a precise series of steps and meet stringent requirements before proceeding with clinical trials. As of mid-2004, more than 300 companies were carrying out gene medicine developments and 500 clinical trials were underway. How to deliver the therapy is the key to unlocking many of the researchers discoveries.

In fact, gene therapy has been immersed in more controversy and surrounded by more scrutiny in both the health and ethical arena than most other technologies (except, perhaps, for cloning) that promise to substantially change society. Despite the health and ethical questions surrounding gene therapy, the field will continue to grow and is likely to change medicine faster than any previous medical advancement.


Cell The smallest living unit of the body that groups together to form tissues and help the body perform specific functions.

Chromosome A microscopic thread-like structure found within each cell of the body, consisting of a complex of proteins and DNA. Humans have 46 chromosomes arranged into 23 pairs. Changes in either the total number of chromosomes or their shape and size (structure) may lead to physical or mental abnormalities.

Clinical trial The testing of a drug or some other type of therapy in a specific population of patients.

Clone A cell or organism derived through asexual (without sex) reproduction containing the identical genetic information of the parent cell or organism.

Deoxyribonucleic acid (DNA) The genetic material in cells that holds the inherited instructions for growth, development, and cellular functioning.

Embryo The earliest stage of development of a human infant, usually used to refer to the first eight weeks of pregnancy. The term fetus is used from roughly the third month of pregnancy until delivery.

Enzyme A protein that causes a biochemical reaction or change without changing its own structure or function.

Eugenics A social movement in which the population of a society, country, or the world is to be improved by controlling the passing on of hereditary information through mating.

Gene A building block of inheritance, which contains the instructions for the production of a particular protein, and is made up of a molecular sequence found on a section of DNA. Each gene is found on a precise location on a chromosome.

Gene transcription The process by which genetic information is copied from DNA to RNA, resulting in a specific protein formation.

Genetic engineering The manipulation of genetic material to produce specific results in an organism.

Genetics The study of hereditary traits passed on through the genes.

Germ-line gene therapy The introduction of genes into reproductive cells or embryos to correct inherited genetic defects that can cause disease.

Liposome Fat molecule made up of layers of lipids.

Macromolecules A large molecule composed of thousands of atoms.

Nitrogen A gaseous element that makes up the base pairs in DNA.

Nucleus The central part of a cell that contains most of its genetic material, including chromosomes and DNA.

Protein Important building blocks of the body, composed of amino acids, involved in the formation of body structures and controlling the basic functions of the human body.

Somatic gene therapy The introduction of genes into tissue or cells to treat a genetic related disease in an individual.

Vectors Something used to transport genetic information to a cell.



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National Human Genome Research Institute. The National Institutes of Health. 9000 Rockville Pike, Bethesda, MD 20892. (301) 496-2433.


Online Mendelian Inheritance in Man. Online genetic testing information sponsored by National Center for Biotechnology Information.

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Gene Therapy

Gene Therapy

Gene therapy is a new and largely experimental branch of medicine that uses genetic material (DNA) to treat patients. Researchers hope one day to use this therapy to treat several different kinds of diseases. While rapid progress has been made in this field in recent years, very few patients have been successfully treated by gene therapy, and a great deal of additional research remains to be done to bring these techniques into common use.

Disease Targets

Humans possess two copies of most of their genes. In a recessive genetic disease, both copies of a given gene are defective. Many such illnesses are called loss-of-function genetic diseases, and they represent the most straightforward application of gene therapy: If a functional copy of the defective gene can be delivered to the correct tissue and if it makes ("expresses") its normal protein there, the patient could be cured. Other patients suffer from dominant genetic diseases. In this case, the patient has one defective copy and one normal copy of a given gene. Some of these disorders are called gain-of-function diseases because the defective gene actively disrupts the normal functioning of their cells and tissues (some recessive diseases are also gain-of-function diseases). This defective copy would have to be removed or inactivated in order to cure these patients.

Gene therapy may also be effective in treating cancer or viral infections such as HIV-AIDS. It can even be used to modify the body's responses to injury. These approaches could be used to reduce scarring after surgery or to reduce restenosis, which is the reclosure of coronary arteries after balloon angioplasty. Each of these cases will be discussed in more detail below, but first we will deal with two technical issues of gene transfer: gene delivery and longevity of gene expression.

Gene Delivery

Whether given as pills or injections, most conventional drugs simply need to reach a minimal level in the bloodstream in order to be effective. In gene therapy, the drug (DNA) must be delivered to the nucleus of a cell in order to function, and a huge number of individual cells must each receive the DNA in order for the treatment to be effective. The situation is further complicated by the fact that a given gene may normally function in only a small portion of the cells in the body, and ectopic expression may be toxic. Thus, successful gene therapy often requires highly efficient delivery of DNA to a very restricted population of cells within the body.

To achieve these goals, many researchers have turned to viruses. Viruses are parasites that normally reproduce by infecting individual cells in the human body, delivering their DNA to the nucleus of those cells. Once there, the viral DNA takes over the cell, converting it to a factory to make more viruses. The cell eventually dies, releasing more viruses to continue the cycle. Scientists can remove or disable some of the genetic material of the virus, making it unable to reproduce outside of the laboratory. This genetic material can then be replaced by the gene needed to treat a patient. The modified (or recombinant) virus can then be administered to the patient, where it will carry the therapeutic gene into the target cells. In this way, scientists can take advantage of the virus's ability, gained over millions of years of evolution, to deliver DNA to cells with tremendous efficiency. One of the most commonly used is a cold virus called adenovirus. Recombinant adenoviruses have been used in experimental gene therapy for muscle diseases, and can deliver genes to almost all of the cells in a small region surrounding the site of injection. Unfortunately, while adenoviruses excel at gene delivery, evolution is a double-edged sword, and the many mechanisms our own bodies have evolved to combat harmful viral infections are also used against therapeutic viruses, as will be discussed in more detail below.

Recombinant adenoviruses cannot be used to transfer DNA to all cell types, because they cannot reproduce themselves outside of the laboratory. When a cell with a recombinant adenovirus in it divides, only one of the two resulting cells contains the virus and the therapeutic gene it bears. The treatment of some diseases requires gene transfer to a stem cell, a cell that actively divides to create many new cells. For example, white blood cells live for only a short time, and must be constantly replenished by the division of precursor cells called hematopoietic stem cells. Gene therapy to treat an immune disease affecting white blood cells would thus require targeting these rapidly dividing cells. Researchers use a different kind of virus to accomplish this: retroviruses, so called because they contain RNA (a different kind of genetic material) rather than DNA.

When a retrovirus infects a cell, it converts its RNA to DNA and inserts it into the chromosome of the target cell. As the cell subsequently copies its own DNA during cell division, it copies the viral DNA as well, so that all of the progeny cells contain the retroviral DNA. At some later time, the viral DNA can liberate itself from the chromosome, direct the manufacture of many new viruses, and go on to repeat its life cycle. Recombinant retro-viruses are engineered so that they can enter the target cell's chromosome, but become trapped there, unable to liberate themselves and continue their life cycle. Because all progeny cells still carry the recombinant retrovirus, they will also carry the therapeutic gene.

This is a great advantage over adenoviruses as a tool for gene delivery to dividing cells, but retroviruses have some drawbacks as well. They can only infect cells that are dividing quickly, and in most cases this infection must be carried out in the laboratory. Cells must be removed from the patient, infected with the recombinant retrovirus, grown for several weeks in the lab, and then reintroduced to the patient's body. This process, called ex vivo gene transfer, is extremely expensive and labor intensive. Nonetheless, this form of gene therapy has been used in one of the most successful clinical applications to date, the treatment of two patients with severe combined immune deficiency (SCID) caused by a defect in the adenosine deaminase gene.

Before treatment, these patients had essentially no immune system at all, and would have been required to live as "bubble children," completely isolated in a sterile environment. While their treatment did not completely cure their genetic disorder, it restored their immune systems enough to allow them to leave their sterile isolation chambers and live essentially normal lives. Many other viruses are being engineered for application to gene delivery, including adeno-associated virus, herpes simplex virus, and even extensively modified forms of the human immunodeficiency virus (HIV), to name just a few.

Many researchers are also exploring nonviral methods for gene delivery. One of the most successful of these methods consists of coating the therapeutic DNA with specialized fat molecules called lipids. The resulting small fatty drops called vesicles can then be injected or inhaled to deliver the DNA to the target tissue. Many different lipid formulations have been tested and different formulations work better in different tissues. These approaches have the great advantage that they do not stimulate the serious immune response that some viral vectors do. However, in general, these nonviral methods are not as efficient as viruses at transferring DNA to the target cells. No clearly superior method for gene delivery has yet emerged, and scientists are still actively developing both viral and nonviral methods. It is likely that many different methods will eventually be used, with each method specifically tailored to work best in a specific tissue or organ of the body.

Longevity of Gene Expression

One of the most challenging problems in gene therapy is to achieve long-lasting expression of the therapeutic gene, also called the transgene. Often the virus used to deliver the transgene causes the patient's body to produce an immune response that destroys the very cells that have been treated. This is especially true when an adenovirus is used to deliver genes. The human body raises a potent immune response to prevent or limit infections by adenovirus, completely clearing it from the body within several weeks. This immune response is frequently directed at proteins made by the adenovirus itself.

To combat this problem, researchers have deleted more and more of the virus's own genetic material. These modifications make the viruses safer and less likely to raise an immune response, but also make them more and more difficult to grow in the quantities necessary for use in the clinic. Expression of therapeutic transgenes can also be lost when the regulatory sequences that control a gene and turn it on and off (called promoters and enhancers) are shut down. Although inflammation has been found to play a role in this process, it is not well understood, and much additional research remains to be done.

Examples of Gene Therapy Applications

There are many conditions that must be met in order to allow gene therapy to be possible. First, the details of the disease process must be understood. Of course, scientists must know exactly what gene is defective, but also when and at what level that gene would normally be expressed, how it functions, and what the regenerative possibilities are for the affected tissue. Not all diseases can be treated by gene therapy. It must be clear that replacement of the defective gene would benefit the patient. For example, a mutation that leads to a birth defect might be impossible to treat, because irreversible damage will have already occurred by the time the patient is identified. Similarly, diseases that cause death of brain cells are not well suited to gene therapy: Although gene therapy might be able to halt further progression of disease, existing damage cannot be reversed because brain cells cannot regenerate. Additionally, the cells to which DNA needs to be delivered must be accessible. Finally, great caution is warranted as gene therapy is pursued, as the body's response to high doses of viral vectors can be unpredictable. On September 12, 1999, Jesse Gelsinger, an eighteen-yearold participant in a clinical trial in Philadelphia, became unexpectedly ill and died from side effects of liver administration of adenovirus. This tragedy illustrates the importance of careful attention to safety regulations and extensive experiments in animal model systems before moving to human clinical trials.

Muscular Dystrophies.

Duchenne and other recessive muscular dystrophies are well suited in many ways for gene therapy. These are loss-of-function recessive genetic diseases caused by mutations in the dystrophin gene or in genes for other structural muscle proteins. The normal levels of these proteins are known, as are many of the ways that they function in the muscle cell. There is ample evidence in animal model systems that these diseases can be cured by delivery of functional copies of the gene. This is true in large part because muscle tissue has a tremendous capacity for repair and regeneration, so one could imagine that the heavily damaged muscle could repair itself after successful gene transfer. Muscle tissue is also an excellent target for gene transfer.

Several different approaches have been used to transfer DNA to muscle. The most straightforward approach is the direct intramuscular injection of DNA in a circular form called a plasmid . The advantage to this approach is that it induces little to no immune response, although the overall number of cells expressing the gene is fairly low. In contrast, recombinant adenoviruses are extremely efficient at transferring genes to muscle, but give rise to a potent immune response that results in only short-term expression of the transferred genes. Because the efficiency of adenoviral transfer is so great, huge efforts are underway to reduce the immunogenicity of these vectors. These efforts have produced some significantly improved vectors, and research is now focusing on developing methods to prepare the large quantities necessary for clinical use. Adeno-associated virus combines the extremely high efficiency of adenoviral transfer with the very low immunogenicity of direct DNA transfer. However, this virus has a rather small capacity to carry DNA, so small that it cannot carry the dystrophin gene (one of the largest genes known), which is needed to treat Duchenne muscular dystrophy.

From these examples, it should be clear that many different approaches to gene therapy for muscular dystrophy have been tried, but that each approach suffers from one or more key shortcomings. In addition, all of these approaches to treat muscular dystrophy face one common problem: Although it is easy to transfer genes to a small part of a single muscle, simultaneously delivering a gene to all parts of all the muscles of the body is impossible with today's technology.

Hemophilia and Sickle Cell Disease.

Because of the difficulty in treating diseases such as muscular dystrophy, many researchers have chosen to focus on genetic diseases that may be easier to treat, particularly those resulting from the lack of proteins freely dissolved in the bloodstream. Hemophilia is one such disorder, caused by a lack of blood-clotting proteins. Such patients have long been treated by the infusion of the missing clotting proteins, but this treatment is extremely expensive and requires almost daily injections. Gene therapy holds great promise for these patients, because replacement of the gene that makes the missing protein could permanently eliminate the need for protein injections. It really does not matter what tissue produces these clotting factors as long as the protein is delivered to the bloodstream, so researchers have tried to deliver these genes to muscle and to the liver using several different vectors. Approaches using recombinant adenoviruses to deliver the clotting factor gene to the liver are especially promising, and tests have shown significant clinical improvement in a dog model of hemophilia.

Gain-of-function genetic diseases present a very different sort of challenge because the mutant gene or genes create a new biological activity that actively interferes with the normal functioning of the cell. An example of such a disorder is sickle cell disease. Patients suffering from this disease have a defective hemoglobin protein in their red blood cells. This defective protein can cause their red blood cells to be misshapen, clogging their blood vessels and causing extremely painful and dangerous blood clots. Most of our genes make an RNA transcript, which is then used as a blueprint to make protein. In sickle cell disease, the transcript of the mutant gene needs to be destroyed or repaired in order to prevent the synthesis of mutant hemoglobin.

The molecular repair of these transcripts is possible using special RNA molecules called ribozymes . There are several different kinds of ribozymes: some that destroy their targets, and others that modify and repair their target transcripts. The repair approach was tested in the laboratory on cells containing the sickle cell mutation, and was quite successful, repairing a significant fraction of the mutant transcripts. While patients cannot yet be treated using this technique, the approach illustrates how biologically damaging molecules can be inactivated. Similar approaches are being developed to treat HIV-AIDS infections, and these may one day be used along with other antiviral therapies to treat this dreaded disease.


Very different strategies of gene therapy are used to treat cancer. When treating diseases such as muscular dystrophy, researchers try to deliver genes without detection by the patient's immune system. When treating cancer, the object is often precisely the opposite: to stimulate a patient's immune reaction to the tumor tissue and improve its ability to fight the disease. For this reason, tumor tissue is often transformed by the new gene to produce specific activators of the immune system, such as interleukins or GM-CSF (granulocyte monocyte colony stimulating factor).

Usually, cancer cells are not recognized by the immune system because they are in many ways identical to the patient's normal cells. These stimulating factors activate the immune system and help it recognize and attack the tumor tissue. In another approach, called "suicide therapy," a gene such as the herpes simplex virus thymidine kinase gene (HSV-TK ) is transferred to the tumor. This gene normally does not occur in the human body, and it is not metabolically active. After several rounds of gene therapy have built up high levels of TK activity in the tumor, a drug called ganciclovir is given to the patient. This drug is inactive in normal cells, but the TK gene converts it into a potent toxin, killing the tumor cells. Even nearby tumor cells that do not have the TK gene can be killed by a phenomenon called the "bystander effect." This approach not only kills tumor cells directly, but also activates the immune system to further attack the tumor.

Anticancer gene therapy is a powerful adjunct to other more traditional forms of cancer treatment. Its advantages are that it can be beneficial even if only a portion of the tumor cells receive the transferred gene, there is no need for long-term gene expression, and it works with the immune system, rather than trying to defeat it. Anticancer gene therapy is already in significant use in the clinic, and is likely to become even more commonplace in the near future.

In summary, gene therapy covers several related areas of research and clinical treatment, all using the genetic material DNA as a drug. Gene therapy is currently being used, along with other techniques, to treat cancer. One day, gene therapy may also be used to treat a variety of hereditary and nonhereditary diseases, ranging from loss-of-function disorders such as muscular dystrophy and hemophilia, to gain-of-function disorders such as sickle cell disease, to viral diseases such as HIV-AIDS. Active areas of research include improvements in the methods of gene delivery to the individual tissues and cells of the body and the modulation of the immune response to gene delivery. Many challenges remain to the successful maturation of gene therapy from the laboratory to the clinical setting.

see also Cancer; Cystic Fibrosis; Disease, Genetics of; Embryonic Stem Cells; Gene Discovery; Gene Therapy: Ethical Issues; Hemophilia; Muscular Dystrophy; Retrovirus; Ribozyme; Severe Combined Immune Deficiency; Virus.

Michael A. Hauser


Beardsley, T. "Working under Pressure." Scientific American 282 (2000): 34.

Clark, William R. The New Healers: The Promise and Problems of Molecular Medicine in the Twenty-first Century. New York: Oxford University Press, 1999.

Vogel, G. "Gene Therapy: FDA Moves against Penn Scientist." Science 290 (2000):2049-2051.

Internet Resource

Institute for Human Gene Therapy. <>.

In April 2002 researchers announced that ex vivo gene therapy for severe combined immunodeficiency had been successful in five boys for up to 2.5 years.

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Gene Therapy

Gene therapy


Classic gene therapy is the direct use of genetic material in the treatment of disease. This usually involves inserting a functional gene or DNA fragment into key cells to mitigate, or cure, a disease. A broader definition of gene therapy includes all applications of DNA technology to treat disease. For people with certain neurological conditions such as Parkinson's disease and Canavan disease , initial gene therapy trials have shown promise. Developing gene therapies for treating disorders of the nervous system poses unique challenges, such as how to introduce the therapeutic gene across the blood-brain barrier or how to target the therapeutic gene to one specific area of the brain.


Genes play a role in every function of the human body. Defects or mutations within a gene can lead to malfunction or disease of cells, tissues, and/or organs. Although standard drug therapy is usually effective in treating the symptoms of a disorder, a patient may be required to take the drugs for an extended time and there may be serious or unpleasant side effects. However, a patient may be cured with few negative consequences if treatment can be targeted directly at the specific cause of the disease (the gene defect), or if that cause can be neutralized or reversed. Therefore, gene therapy provides an attractive alternative to drug therapy as it seeks to provide treatment strategies that will be more complete and less toxic to the patient. Furthermore, gene therapy may provide a way of treating diseases that cannot be managed by standard therapies.


There are many diverse approaches to gene therapy since the biological basis of each disease is unique, presenting a different set of parameters and challenges. However, in each case, a basic set of criteria must be met. First, it is essential to fully understand the disease to be treated. The cells or tissues associated with the disease must be well defined and accessible. The gene and the specific mutation or mutations causing the disease must be known, and it must be possible to isolate or synthesize a normal, functional copy of that gene and to incorporate it into a vector. The vector then transfers the new gene to the target cells where, hopefully, the gene will become fully active. The most common roles for the expressed gene include replacing a defective gene, inhibiting or degrading a deleterious DNA, RNA, or protein, or directly or indirectly killing the cell.

Single gene disorders resulting in a loss of gene function in one specific target tissue provide the easiest options for gene therapy, though strategies for many types of mutations have been investigated. A broad spectrum of diseases has been considered for gene therapy, including:

  • neurological disorders, e.g., Parkinson disease, Huntington disease
  • muscular dystrophies
  • immunological disorders, e.g., severe combined immunodeficiency syndrome (SCIDS)
  • blood abnormalities, e.g., thalassemias, hemophilia
  • cancer

Unfortunately, many of the more commonly occurring disorders, including heart disease, diabetes, and high blood pressure, result from defects in multiple genes making them unlikely candidates for gene therapy using existing technologies.

For each disease, it must be determined if ex vivo or in vitro technology is the best approach. In ex vivo technology, patient cell samples are collected and cultured in the laboratory. The new gene is incorporated into the growing cells, and these are subsequently transferred back into the patient. Not all of the cultured cells will include the new gene, and not all will survive the transfer. The hope is that a sufficient number of the modified cells will be functional in the patient such that the therapy will reverse the disease. In vitro therapy involves injecting the new gene directly into the target tissue where the individual cells must pick it up. Of the two, this method is technically easier and cheaper, but it is harder to determine how many of the target cells actually acquire the new gene. Ex vivo therapy is more expensive and time consuming, but allows greater control of the conditions.

Both processes require the use of a vector to get the new gene across the cell membrane and into a cell. Viruses have proven to be highly effective as vectors since these are biological entities with a natural function of infecting host cells. DNA technology allows viruses to be manipulated to replace the normal payload of disease-causing genetic material with therapeutic genes. The virus will retain its ability to infect a host cell but, instead of causing a disease, it will deposit the new gene into the cell.

Other mechanisms of gene transfer have also been investigated. Artificial chromosomes have been developed, but these are often too large to move across cell membranes. Liposomes, structures with lipid membranes, that encompass genetic material can be successfully used as vectors if the liposome is absorbed by the cell or if its membrane fuses with the cell membrane releasing the new gene inside the cell.

Once the gene enters the cell, one of two things occurs. It may be degraded and lost, which is an unfavorable outcome. Preferably, the gene will stably incorporate into the DNA of the target cell so that it can be processed as a normal part of that genome. If the gene therapy is designed to replace a defective gene, the best-case scenario is for the new gene to integrate into a completely renewable cell such as a stem cell. Theoretically, in this situation, the gene will be permanently incorporated into the patient's body and no further therapy will be required. Alternatively, if the gene integrates into a genome of a cell with a finite lifespan, the beneficial effects of the gene will only exist while that cell lives, requiring the gene therapy to be repeated at a later time.

One of the early successes of gene therapy was for a four-year-old girl with adenine deaminase (ADA) deficiency. This is a form of SCIDS that results in malfunction of the immune system and can lead to death as a result of severe infection. Conventional treatment had failed for this patient, making her a candidate for gene therapy. A normal ADA gene was incorporated into a retroviral vector that transferred the gene into the patient's lymphocytes in vitro. The modified cells were returned to her circulation by transfusion. After five months, her levels of ADA activity had risen from less than 1% to 50%. With additional therapies over the next two years, her health improved as the enzyme activity stabilized, and she was able to begin a normal life. Twelve years later, she still demonstrates reasonable levels of ADA activity, but the gene therapy was not a cure as she must continue to receive the standard enzyme replacement therapy to maintain her health.

Acquired diseases can also be treated with gene therapy as demonstrated by a novel strategy for treating brain cancer. The thymidine kinase (TK) gene from the herpes simplex virus (HSV) has an enzymatic property that converts the drug ganciclovir into a toxic substance that can kill human cells. It was postulated that this could be used as a targeted killing tool. To investigate, cloned HSV TK genes were injected into brain tumors. In the brain, only the tumor cells are dividing, so these are the only cells that will be infected by the viral vector, and are thus the only cells that will receive the HSV TK gene. When the patient is subsequently treated with ganciclovir, the tumor cells that have incorporated the HSV TK gene will be selectively killed. Clinical trials proved that tumor cells could be selectively eliminated by demonstrating a reduction in the size of the brain tumors in seven of nine patients.

A completely different set of therapies is possible if the idea of gene therapy includes the use of DNA for patient treatment in ways other than inserting new genes into cells. One example is the drug Gleevec that was approved in 2001 for use in patients with chronic myelogenous leukemia (CML). Gleevec is a substance that binds to the defective protein produced in CML, blocking that protein's activity and alleviating the symptoms of the disease. This is a targeted therapy that affects only the cells with the CML mutation, so there are very few side effects. Recombinant DNA technology has also been utilized to generate genetically engineered copies of vaccines (Recombivax HB), antibodies, and normal gene products (insulin).


If the new DNA can be stably incorporated into the proper regenerative target cells, the patient may be cured of disease. No additional care should be required, although periodic monitoring of the patient is appropriate.

For gene therapies in which the new DNA is inserted into cells with a finite lifespan, the therapeutic effect will be lost when those cells die. In these situations, the patient will require continuing treatments. Monitoring of patients who receive drugs and substances arising from recombinant DNA technology is the same as standard drug therapy.


Currently classic gene therapy is still experimental. Although many patients have shown significant improvement following their treatment, at least two individuals have died as a result of this type of therapy. Therefore, experts carefully review all protocols before any studies are undertaken. Initial research is done in an animal model system, and any problems detected are carefully evaluated before the same treatments are attempted in humans.


A patient who is receiving gene therapy may face a number of potential problems. The viral vectors used may cause infection and/or inflammation of tissues, and artificial introduction of viruses into the body may initiate other disease processes. Functional gene therapy relies on stable incorporation of a new gene into an individual's own DNA. As the integration is random, occasionally the new gene may insert within another normally functioning gene, causing its damage or inactivation. This, in turn, could lead to cancer or other disease. It is also critical that the new gene have the proper regulatory controls so that the gene product is produced in the proper amount. Over-expression of certain genes can have deleterious results. Any of these problems could render the gene therapy ineffective, or, at worst, cause the death of the subject.

Normal results

Classic gene therapy seeks to treat or cure a defined disease by incorporating a functional gene or gene product into target cells of an affected individual.



George, Linda. Gene Therapy. Woodbridge, CT: Blackbirch Marketing, 2003.

Nussbaum, Robert L., Roderick R. McInnes, and Huntington F. Willard. Thompson and Thompson Genetics in Medicine, 6th edition. Philadelphia, PA: W. B. Saunders Company, 2001.

Strachan, T., and Andrew P. Read. Human Molecular Genetics, 2nd edition. New York, NY: John Wiley and Sons, 1999.


National Cancer Institute. Questions and Answers about Gene Therapy. Cited January 4, 2004 (March 23, 2004). <>.

Constance K. Stein

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Gene Therapy

Gene Therapy

Gene therapy refers to the repairing or replacing of malfunctioning genes that cause a deleterious illness or condition. There are two forms of gene therapy: somatic and germline.

Somatic and germline therapies

Somatic therapies are used to replace or repair malfunctioning genes that are expressed in such conditions as cystic fibrosis or sickle cell disease. Since these therapies attempt to remedy the causes rather than alleviate the effects of disease, they presumably will provide more effective and beneficial medical treatments. Although initial attempts to develop somatic gene therapies proved largely unsuccessful, experimental treatments since the mid 1990s of severe combined immunodeficiency disease (SCID) and sickle cell disease have renewed public optimism regarding its potential efficacy.

Like somatic therapies, germline therapies attempt to repair or replace malfunctioning genes. The principal difference is that the corrected gene, rather than the deleterious one, is passed-on to subsequent generations. Consequently, the potential benefits or effects of germline therapies could be much more widespread than those of somatic therapies. As of 2002, no experimental procedures employing human germline techniques had been undertaken.

Ethical and moral objections

In principle, somatic gene therapy has raised few ethical objections. Because these therapies treat the underlying causes of disease at the molecular level rather than concentrating on affected organs or compromised biological processes, somatic therapies have been largely perceived as more sophisticated and potentially more effective extensions of established medical procedures. So long as these therapies are safe, there is nothing inherently wrong in deploying them. The issue of safety, however, came to the forefront with the death in 1999 of a patient undergoing an experimental genetic treatment for ornithine transcarbamylase (OTC) deficiency, an incident that prompted calls for greater public oversight or regulation.

The prospect of germline therapy has proven much more controversial. The primary objection is that humans should not attempt to construct the genetic inheritance of future generations. This objection usually takes one of two forms. First, since so little is known about the complex relationship between genes and larger environmental factors, it would be imprudent to introduce genetic alterations that would be inherited by future generations. Although the goal would be to eliminate a severely debilitating disease or condition, there might be unintended or unforeseen consequences that would adversely affect subsequent generations. Individuals carrying a recessive deleterious gene, for example, might in the future incur certain survival advantages in response to changing environmental factors. Since the effects of germline therapy are so much more widespread than those of somatic therapies, large populations could be potentially devastated. The seemingly harmless or even beneficial intervention into the human germline could wreak havoc down the road.

The second form of this objection invokes a more sweeping moral imperative. Humans do not have a right to shape the genetic endowment of their descendants, and correspondingly, individuals have the right to be born with unaltered genomes. People must simply resist the temptation to play God in shaping the destiny of humans, both as individuals and as a species.

The principal defense against this objection, in both its forms, is that it does not sufficiently take into account the nature of evolutionary change, thereby imposing unwarranted responsibilities regarding the possible fate of future generations. Other than identical twins, there are no unique genomes that parents do not have a right to alter or that offspring have a right to inherit in an unaltered form. Human reproduction entails the creation of a unique genome, derived from the genes of parents but also including mutations. It is difficult to imagine what an unaltered genome might be in the future in evolutionary terms. If individuals have a right to inherit an unaltered genome, then presumably cloning should become the preferred method of human reproduction. In addition, many argue that the prudential claim that current ignorance should prohibit germline interventions is unwarranted. Every action entails unforeseen consequences, and it is not known whether failing to intervene will prove better or worse than intervening. It cannot be known in advance whether the consequences of germline therapies will be any more or less devastating than those of natural selection upon future generations.

Some religious and moral concerns have also been raised, not so much with the prospect of genetic therapy per se, but with the fear that their introduction might exacerbate some already troubling trends. For instance, it is argued that the growing knowledge of human genetics is not being used, at least initially, to develop more effective therapies, but to prevent the birth of offspring with debilitating or undesirable genetic traits. Some fear that parents will turn increasingly to embryonic testing and screening techniques, such as preimplantation genetic diagnosis, to prevent the implantation of embryos carrying certain genetic abnormalities, leading in turn to the destruction of embryos deemed to be undesirable.

The issue is further compounded because the same techniques being developed as therapies may also be applied to select, and perhaps someday enhance, certain genetic characteristics of offspring. The bar of parental expectation would then be raised dramatically regarding what constitutes a desirable or even healthy child. The prospect of so-called designer babies will exert social pressure on parents not only to prevent the birth of offspring with severely debilitating conditions, but to select or enhance their genetic endowment in the hope of giving their children the best possible start in life. Although the development of genetic therapy is motivated by a humane impulse, its advent could fuel parental anxieties and prejudicial attitudes toward individuals with physical and mental disabilities, thereby unwittingly supporting a new, implicit, and insidious form of eugenics.

Proponents of genetic therapy counter that these worries are both unfounded and inflammatory. Legal protections against discrimination can be enacted as needed. Moreover, the best way prevent the destruction of so-called undesirable embryos is to develop effective genetic therapies as quickly as possible. More importantly, the distinction between genetic therapy and genetic selection and enhancement is spurious. Any therapy is also an enhancement, because the restoration of health is presumably an improvement over illness. In addition, many non-genetic medical procedures are enhancing, rather than therapeutic, in character, and genetic therapies will make them more effective. Genetically enhancing an individual's immune system, for example, is merely a more effective form of inoculation. Despite the moral and religious objections, the development of effective gene therapies may alleviate the suffering of many people.

See also Biotechnology; DNA; Ethnicity; Eugenics; Evolution; Gene Therapy; Genetic Engineering; Genetic Testing; Genetically Modified Organisms; Genetics; Human Genome Project; Mutation; Nature versus Nurture; Playing God; Reproductive Technology


chapman, audrey r. unprecedented choices: religious ethics at the frontiers of genetic science. minneapolis, minn.: fortress press, 1999.

engelhardt, h. tristram, jr. the foundations of bioethics. new york and oxford: oxford university press, 1996.

fletcher, joseph. the ethics of genetic control: ending reproductive roulette. garden city, n.y.: anchor books, 1974.

parens, eric, ed. enhancing human traits: ethical and social implications. washington d.c.: georgetown university press, 1998.

peterson, james c. genetic turning points: the ethics of human genetic intervention. grand rapids, mich.: eerdmans, 2000.

ramsey, paul. fabricated man: the ethics of genetic control. london and new haven, conn.: yale university press. 1970.

walters, leroy, and palmer, julie page. the ethics of human gene therapy. new york: oxford university press, 1997.

brent waters

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Gene Therapy

Gene therapy

Gene therapy is a new field in which normal genes are given to patients to cure genetic disorders. Some successes have occurred, as well as some failures. But researchers believe that gene therapy shows promise, because this approach to disease treats the root of the disease instead of just its symptoms.

Three Types of Therapy

Three types of therapy currently exist. In gene replacement therapy, a mutant gene is replaced with a normal gene. In gene augmentation therapy, a normal gene is added but the mutant gene is not removed. And in gene inactivation therapy, a gene is added that will cancel the effects of the defective gene. Sometimes combined to produce the desired cure, the type or types of therapy selected depend on many factors, including whether the actual genetic defect can be pinpointed exactly.

Body Must Be Tricked to Accept Cloned Genes

The point of gene therapy is twofold. First, the gene must be cloned (created), or engineered. This process is also known as recombinant DNA technology (first performed in 1972). Secondly, the normal gene must be introduced into the patient's chromosomes. The body, hoever, actually regards the cloned "normal" gene as foreign, so the it must be tricked into accepting the cure.

Of the various methods tried, the most efficient technique uses an RNA virus called a retrovirus. The retrovirus infects the patient's cells, then copies its DNA into the patient's DNA.

The first human gene therapy was approved for clinical trial in the United States in May 1989. At the end of 1992, at least 37 gene therapy projects were completed, in progress, or approved in China, France, Italy, the Netherlands, and the United States. Each country has its own approval process, designed to protect the patient, the health workers, and the public. By mid-1995 the National Institutes of Health (NIH) and Pharmaceutical Research and Manufacturers of America reported increased efforts in this field. U.S. companies had 57 projects underway, 12 projects completed, and 18 pending, while drug companies had 17 therapies in development.

In the United States, each procedure must be approved by the director of the NIH, by the NIH Recombinant DNA Advisory Committee, and by the U.S. Food and Drug Administration (FDA).

Therapy Trials

Gene therapy trials have included severe combined immunodeficiency (SCID) and malignant melanoma. SCID is a rare disease that prevents the person's immune system from functioning. This well-publicized study concerned the teenager named David who lived for several years in a plastic bubble to protect him from infection.

Some cases of SCID result from ADA deficiency, a genetic mutation that prevents lymphocytes from producing the enzyme adenosine deaminase (ADA). Lymphocytes are white, or nearly colorless, cells in the blood and lymph systems produced either by the bone marrow (B cells) or by the thymus (T cells). T cell lymphocytes are the major players in the body's immune system, which does not develop normally without the enzyme ADA.

In September 1990 NIH researchers R. Michael Blaese and W. French Anderson performed the world's first gene therapy on a four-year-old child with SCID. A normal gene for ADA was inserted into a virus and allowed to "infect" lymphocytes that had been withdrawn from the child's body. Then the girl was injected with the altered cells. During the next 18 months, the patient had several series of injections, along with other treatment. A second patient, a nine-year-old girl, had similar treatments. The cells encouraged production of ADA in both children, who attended school, had only the normal number of infections, and reportedly experienced no side effects. Since then similar treatments have been used on children in other countries.

Many gene therapy studies have been completed or are underway for various cancers. In a study of the skin cancer melanoma, doctors withdrew a sample of the patient's own cells, inserted an altered gene, and returned the new cells to the patient. The purpose of this procedure is to introduce a protein that will kill the melanoma tumor.

Cystic Fibrosis Study Yields Few Results

A gene therapy study for the lung disease cystic fibrosis began in 1992. The therapy calls for inserting a needed gene into an engineered cold virus (the virus is altered so that it will not cause a cold), which the patients inhale. The gene enters the lung and improves cell function, preventing the production of the mucus (a slimy secretion) that blocks a patient's breathing.

The genes performed precisely under laboratory conditions, but in human studies, less than one percent of patients achieved the desired results. The results are not considered to be sufficient enough to be promising.

Further Research

Another study concerned familial hypercholesterolemia, a condition in which patients lack a gene for disposing of harmful low-density lipoprotein cholesterol (the so-called "bad" cholesterol). These patients develop a build-up of this low-density cholesterol in their bodies. People lacking both copies of the gene usually die from a heart attack in their early teens. Some-one with only one copy suffers from severe coronary (heart) disease. Scientists at several medical centers are studying insertion of the needed gene into cells from a patient's liver, then injecting the cells into the person's body.

Scientists in China are studying the bleeding disease hemophilia B, which occurs in people whose blood lacks clotting Factor IX. Researchers are attempting to engineer cells with this factor. Studies are also underway on gene therapy for AIDS, liver failure, leukemia, brain tumor, various cancers, rheumatoid arthritis, Gaucher's disease (a metabolic disorder), and various other inherited diseases.

[See also Cloning ; Enzyme ; Gene ; Genetic Engineering ]

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gene therapy

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

See also genetics, human; immune system.

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"gene therapy." The Oxford Companion to the Body. . 16 Jan. 2018 <>.

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Gene Therapy

Gene Therapy

Gene therapy is an experimental disease treatment in which a gene is delivered to cells in the body. The protein made by the new gene compensates for the absence of normal proteins or interacts with some abnormal protein already in the cell to interrupt its function. Gene therapy is not yet a routine treatment for any disease, but it may become so as researchers solve the many technical problems it presents.

Humans are prey to numerous diseases due to single-gene defects, such as adenosine deaminase deficiency (defective enzyme ), cystic fibrosis (defective ion channel), and Duchenne muscular dystrophy (defective muscle protein). Replacement of the defective gene is conceptually simple, but practically very difficult. Effective gene therapy requires delivering the gene to each cell in which it acts, integrating the gene with the thousands of others on the chromosomes and regulating the expression of the gene.

Gene delivery is a major hurdle. Viruses are the most commonly used vehicle, or vector , since they have been designed by evolution to deliver their own genes to our cells. Adenovirus (a type of cold virus) has been the most commonly used vector, since it can carry a very large gene and will infect most cell types. However, the immune system is designed to prevent this type of infection, and immune rejection has so far thwarted most gene therapy efforts. While most patients have not been harmed by this problem, one gene therapy patient has died from immune response to the adenovirus. Modifications of the virus, using fewer immunogenic viruses (such as adeno-associated virus, herpes virus, or retrovirus), immune-suppressive drugs, and nonviral delivery systems are all possible solutions. Curiously, the brain does not mount a strong immune response, and as such, represents a promising site for gene delivery in neurological diseases.

Getting the gene to enough target cells is also a significant challenge. Adenosine deaminase deficiency affects white blood cells and causes severe combined immune deficiency ("bubble boy" disease). This disease can be treated by removing white blood cells, inserting the adenosine deaminase gene into them, and returning the cells to the bone marrow. Cystic fibrosis presents a much bigger challenge, since it affects the airways and pancreas. Inhalation of the vector may treat the lungs, but the pancreas is more difficult to reach without injecting vector into the bloodstream. Duchenne muscular dystrophy is an even bigger challenge, since it affects all muscles, and muscles make up 45 percent of the body. The only realistic treatment option in this case is systemic delivery, which poses the added challenge of preventing delivery to nonmuscle tissue.

Once inside the target tissue, genes usually become active whether or not they are integrated into the host chromosome. However, long-term expression requires that the gene join the host chromosome. Directing the gene to do so, and to integrate in a way that doesn't disrupt other genes, is still a significant challenge. Regulating its expression, so that enough of the protein (but not too much) is made, is also a problem. Currently, most virally delivered genes do not integrate successfully, and stop making protein after several weeks to months.

While correction of gene defects was the original inspiration for gene therapy research, treatment of other diseases is now being explored. Cancers are an appealing target, and several strategies are possible. Currently the most promising is delivering a so-called "suicide gene," whose protein product renders a tumor more sensitive to cell-killing drugs, allowing lower doses of chemotherapy to be effective. This works well for solid tumors, which can be injected with the gene. Delivery to more diffuse locations is still problematic. Further research on cellular properties of cancer cells may broaden the reach of this and similar cancer-targeting strategies.

see also Chromosome, Eukaryotic; Crick, Francis; Gene; Genetic Diseases; Mendel, Gregor; Recombinant DNA

Richard Robinson


Lemoine, N. R. Understanding Gene Therapy. Oxford: BIOS Scientific Publishers, 1999.

Lewis, Ricki. Human Genetics: Concepts and Applications, 4th ed. New York: McGraw-Hill, 2001.

Stolberg, Sheryl Gay. "The Biotech Death of Jesse Gelsinger." New York Times Magazine (28 November 1999): 17.

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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, a rare hereditary immune disorder (see immunity). Gene therapy has since been used experimentally to treat a number of conditions, including advanced metastatic melanoma, a myeloid disorder, and a rare hereditary condition that leads to severely impaired vision. Despite the hope that gene therapy can be used to treat cancer, genetic diseases, and AIDS, 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 a few instances trials have been halted when a patient has died or developed disease after undergoing gene therapy.

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.

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

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"gene therapy." The Columbia Encyclopedia, 6th ed.. . 16 Jan. 2018 <>.

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gene therapy

gene therapy The application of genetic engineering techniques to alter or replace defective genes. A defective gene may result from an incorrect sequence of bases in the DNA molecule or an inability of the gene to code for the expression of a particular polypeptide. Techniques currently being investigated involve the transfer of normal genes into the genetic material of the cell to replace the defective gene and the use of antisense RNA to ‘knock out’ defective genes in certain tissues. Retroviruses are often used as vectors for transferring genes into cells as part of the natural retrovirus life cycle involves the insertion of their own genetic material into the chromosomes of their host. Alternatively liposomes may be used. Gene therapy is being developed in an attempt to cure and prevent such genetic diseases as cystic fibrosis.

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"gene therapy." A Dictionary of Biology. . 16 Jan. 2018 <>.

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gene therapy

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.

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"gene therapy." A Dictionary of Nursing. . 16 Jan. 2018 <>.

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gene therapy

gene ther·a·py • n. the transplantation of normal genes into cells in place of missing or defective ones in order to correct genetic disorders.

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"gene therapy." The Oxford Pocket Dictionary of Current English. . 16 Jan. 2018 <>.

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