Gene Therapy - The Future Is Here!
Medical Author: Frederick Hecht, MD, FAAP, FACMG
Gene therapy is the treatment of disease by replacing, altering, or supplementing a gene that is absent or abnormal and whose
absence or abnormality is responsible for the disease. Gene therapy may use the genetic material, DNA, itself as the means of
treatment.
DNA or deoxyribonucleic acid is the very long molecule that encodes the genetic information. A gene is a stretch of DNA required to make a functional product such as part or all of a protein. People have about 100,000 to 150,000 genes. During gene therapy, DNA that codes for specific genes is delivered to individual cells in the body. Most, if not all, diseases have a genetic factor. The genetic factor can be wholly or partially responsible for the disease. For example, in disorders such as cystic fibrosis, hemophilia, and muscular
dystrophy, changes in a gene directly result in the condition. In other conditions such as high cholesterol and high blood pressure, genetic and environmental factors interact to cause disease.
Disorders associated with aging often involve the loss of gene activity in specific types of cells. Even infections can be related to genes. In fact, they have two sets of genetic determinants: the genes of the infective agent and the genes of the person with the infection.
Uses of gene therapy
Gene therapy is being used in many ways. For example, to: Replace missing or defective genes;
Deliver genes that speed the destruction of cancer cells;
Supply genes that cause cancer cells to revert back to normal cells;
Deliver bacterial or viral genes as a form of vaccination;
Provide genes that promote or impede the growth of new tissue; and;
Deliver genes that stimulate the healing of damaged tissue. A large variety of genes are now being tested for use in gene therapy. Examples include: a gene for the treatment of cystic fibrosis (a gene called CFTR that regulates chloride); genes for factors VIII and IX, deficiency of which is responsible for classic hemophilia (hemophilia A) and another form of hemophilia
heart failure; and VEGF, a gene that induces the growth of new blood vessels (angiogenesis) of use in blood vessel disease.
A short synthetic piece of DNA (called an oligonucleotide) is being used by researchers to "pre-treat" veins used as grafts for heart bypass surgery. The piece of DNA seems to switch off certain genes in the grafted veins to prevent their cells from dividing and thereby prevent atherosclerosis.
Delivery of genes into cells
Gene delivery can be used in cells that have been removed from the body (ex vivo gene therapy) or in cells that are still in the body (in vivo gene therapy). Genes can be delivered into cells in different ways. The selection of a gene delivery system depends on the
target cell, the duration of gene expression required for therapeutic effect, and the size of the piece of DNA to be used in the gene
therapy.
Genes can be carried into cells by viruses. Viral vectors or carriers take advantage of the natural ability of a virus to enter a cell and deliver genetic material to the nucleus of the cell that contains its DNA. In developing virus carriers, the DNA coding for some or all of the normal genes of the virus to be used as a carrier are removed and replaced with a treatment gene. Most of these virus carriers are engineered so that they are able to enter cells, but they cannot reproduce themselves and so are innocuous.
Genes can also be delivered within tiny synthetic "envelopes" of fat molecules. Cell membranes contain a very high concentration of fat molecules. The fat molecule "envelope" can carry the therapeutic gene into the cell by being admitted through the cell membrane as if it were one of its own molecules.
Genes can also gain entrance into cells when an electrical charge is applied to the cell to create tiny openings in the membrane that surrounds a cells. This technique is called electroporation.
A "bionic chip"
A new "bionic chip" has been developed to help gene therapists using electroporation to slip fragments of DNA into cells.
Electroporation was originally a hit-or-miss technique because there was no way to determine how much of an electrical jolt it took to
Gene Therapy:
Revolutionizing
Medicine
Brandi Rocholl
Copyright 1996
Introduction
"We used to think that our fate was in our stars, but now we know that, in large measure, our fate is in our genes, "quotes James Watson. This fate that Watson is talking about is contained in our genes, and deals with a new technique, gene therapy. Gene therapy is revolutionizing the world of
medicine. Many physicians are predicting that in twenty years gene therapy may change the
practice of medicine from a treatment-based to a prevention-based practice. Our future is l ocked away inside of our genes. Gene therapy is
unlocking these doors. Researchers are starting to move away from developing new drugs, and
need.
What is Gene Therapy?
So what is this mystical new wonder called gene therapy? Gene therapy is the introduction of genes into existing cells to prevent or cure a wide range of diseases. For example, suppose a brain tumor is forming by rapidly dividing cancer cells. The reason this tumor is forming is due to some defective or mutated gene. The therapy chosen for this case would be to use a herpes virus that has had its virulence removed, rendering it harmless. The virus is still abl e to insert its genetic material into the target cells. The virus is then taken and
injected into mouse cells, where it makes
additional copies of itself. These mouse cells, now containing the virus, are then injected into the brain containing the tumor . Once inside the brain, the virus seeks out the target tumor cells and
invades them. The tumor will now start to produce herpes enzymes because the virus has inserted its genetic material into the tumor cells. Now a
physician can treat the patient wit h a herpes
curing drug that will destroy the tumor cells along with the mouse cells that are producing the herpes enzyme. The other target of some of the various retroviruses used include: bone marrow, skin, and liver cells. Genetic alteration of bone marrow cells aims to correct the mutated part of the cell or its progeny. Skin cells work in a different manner. Geneticists found that these cells synthesize and secrete proteins, but these are then transported through the blood to be utilized by other cells. Researchers are trying to use skin cells to
make. They then hope that it will take that enzyme to some other cell. That cell may not be able to make that enzyme, but the skin cell transports an ess ential enzyme that will help that new cell
function properly. Research with liver cells is still in the beginning stages.
Keys to the Kingdom, Time Magazine
Examples of Gene therapy
This new therapy appears to work quite well in the lab setting, or theoretically in some scientist's
mind, but it still had not been proven in a human subject. The first human to receive gene therapy treatment wa s a 4 year old girl with severe
immune-deficiency disease. This disease is caused by a faulty gene that fails to produce a vital
enzyme. In the therapy procedure, they extracted some of the girl's white blood cells. Then, they exposed them to a geneti cally engineered virus that had lost its virulence but still carried normal versions of the gene that was not functioning correctly in the girl. The virus invaded the white blood cells, and then these cells were transfused back into the girl. Once back i nside the girl's
bloodstream, the cells began producing the proper enzyme. Although the girl still needs follow-up
treatments, she now leads a relatively normal life following the gene therapy. This is one of the
success stories of gene therapy.
A Success Story
With the success of this first gene therapy
treatment, the public's expectations began to rise. They assumed that permanent cures would be
achieved for many diseases. The problem with this over assumption is t hat along with this miracle technique comes a host of technological problems. The main problem that geneticists are
encountering is the viruses may target the wrong cells. These viruses often do not seek out the target cells, and sometimes they insert t
hemselves into the wrong place in the DNA. The area that the virus targets may trigger
uncontrollable growth. This may lead to the development of a tumor, or a preexisting tumor may become larger due to either a mutated virus or insertion in the wrong p lace. This would be a huge disadvantage if the virus was inserted into a cancer cell, and instead of inserting its DNA into the cell, it causes uncontrollable growth of the tumor. They have also found that even if the virus invades the target cell and i nserts the new gene, sometimes that new gene fails to express itself. For example, a virus used in cystic fibrosis produced an inflammatory response. These is an example of the virus not producing the desired response. The trials with that virus had to than be halted, and other virus vectors had to be developed. Another problem researchers are encountering, is
delivering the viruses into bone-marrow stem cells. These cells divide infrequently, and the viruses used in gene therapy only insert genes in to cells that are dividing. Despite some of these
hnological obstacles and hurdles that they are encountering in their research.
Possible Pitfalls
Encountering Problems in Research
The other problem that researchers are encountering is in the research itself. Many
skeptics say that not enough is known about this procedure, and so it should be confined to lab animals until more is k nown. The researchers do not believe in this because human patients are vital to their research. The researchers need the public to understand that this technique is a new idea, and it will take time to work out all the
details. The potential of the th erapy appears to be limitless if the researchers are allowed to perform their lab work.
Problems with Gene Therapy
Disadvantages of Gene Therapy
positive test for a disease are now are faced with a dilemma. That dilemma is in finding adequate
insurance to cover the treatments, which could be gene t herapy, or living out their lives knowing that they carry a gene for a disease. This positive test has placed them in a high risk group that they may have not been in if they had not been tested. This high risk tag makes insurance coverage almost imposs ible to find. The insurance that will cover them may be extremely expensive. So, choosing to have the test may be a question of whether they think their current insurance will cover them or not. Many young couples may find out that they are carriers of a disease, and now must decide if they want to have a child that could be born with a
genetic disease. Still another problem is regulation of the uses of gene therapy. Our society is
obsessed with the idea of youth and beauty. If scientists could ide ntify the gene that contributes to youth or beauty, then the technique of gene therapy could be monopolized by the cosmetic industry to enhance beauty or to "turn back the clock." The problem with this is whether baldness, height, or beauty should be eno ugh of a reason to require gene therapy. Federal regulation will have to come into play in deciding whether a big nose is as important of a genetic problem as cystic fibrosis and which requires gene therapy.
Gene therapy at a Crossroads
Advantages of Gene Therapy
or who develops cancer the chance at a normal life. I thin k this is an advantage that far out weighs any of the disadvantages that have been
presented against gene therapy. Giving someone a chance at a normal life should be enough for many of the people that oppose this technique to change their minds. I bel ieve the reason that these people are opposed to gene therapy is because they see it as something foreign and scary. The reason people are scared is because they do not understand the technique. I think if scientists educate our society, many people wou ld change their minds. I believe that if the people that oppose this technique were ever faced with cancer or a child born with a
genetic disease, they would change their views. These skeptics would choose gene therapy,
especially if it would save a lo ved one's life. In the coming future, gene therapy will play an important part in many people's lives.
The Authors Opinions
I believe that gene therapy will revolutionize the practice of medicine. The role of doctors and
patients will be changing in the coming years, and it will all be due to gene therapy. This technique has the ability to cure many of the diseases that have effected our society for years. One of the reasons that I am such a supporter of this
technique is because I have a friend that suffers from cystic fibrosis. She is one of the success stories of this disease that has a very short life expectancy. She will be celebrating her 26th
gene that causes cystic fibrosis. I hope that in the coming years the technique of gene therapy will be perfected, and my friend will be given a chance at the normal life that she has been denied all these years. I believe gene therapy is going to be a great advancement for science. I hope that this
technique will not be abused by people for cosmetic reasons. I hope that the government regulates who can receive this treatment, and restricts it to people that have serious genetic
diseases. I believe that if the government does not mak e laws, people with money and power will
abuse this scientific wonder. The people who want to use gene therapy to enhance their lives because they suffer from a disease should not have to be on the same waiting lists with people that want to enhance thei r beauty or intelligence. The abuse of gene therapy would be a sad thing for the scientific world.
Conclusions
Gene therapy is an exciting new approach that is just making the news. In the future, this technique will be an everyday word used in our households. Gene therapy will change the field of medicine from what it is today. As s cientists discover more genes and their functions, the potential of this
How is gene therapy being used in cardiovascular disease?
To date, most gene therapy studies have been done in the laboratory and the earliest experiments seem promising for treatment of cardiovascular disease.
An example of these studies is the use of gene therapy to help increase blood flow to ischemic tissue. Ischemia is a condition in which the flow of blood, and thus oxygen, is restricted to a part of the body. Limb ischemia and myocardial ischemia refer to lack of blood flow and oxygen to the limb and heart muscle, respectively. The body’s first response to less blood flow to the heart is to grow tiny new “collateral” vessels to help blood flow around the
blockage. (This process is known as angiogenesis.) For unknown reasons, the process eventually switches off. Some proteins in the body can help trigger new blood vessel growth and so increase the oxygen supply to the ischemic tissue. Such angiogenic proteins include the endothelial growth factors, vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) and hepatocyte growth factor (HGF).
In gene therapy trials, scientists have used a variety of different ways to deliver the genes for VEGF-1, VEGF-2 and FGF4 into the hearts of patients with advanced myocardial ischemia. After gene therapy, patients had less severe angina (chest pain) and their hearts worked better. Similarly, after gene delivery of VEGF to patients with limb ischemia, the blood supply improved and leg sores healed better. Gene therapy has prevented below-knee amputation in some patients for whom amputation had been recommended.
Gene therapy has also been successful in preventing re-occlusion, or re-blockage, of coronary artery bypass grafts and in keeping arteries open after angioplasty surgery.