Gene therapy is an experimental treatment for a variety of different medical conditions, including heart disease. The technique uses harmless viruses to transport healthy genes into human cells that contain defective or missing DNA. Today, researchers are actively studying and testing this noninvasive technique that could offer hope to heart patients around the world. Gene therapy for heart disease has one of three goals:

By identifying the genes that place people at greater risk of heart attack or other cardiovascular conditions, diagnostic tests may become available to help identify people who are at high risk and give them a chance to change their diet, exercise habits or even some of their genes.

Although this type of treatment offers great hope, it is important to remember that much more research will be necessary before gene therapy is as specific as possible, such that a specific gene can target a specific site, with no other effects, with fully safe and highly effective results. There is a long way to go before gene therapy will be offered as a cure for heart disease or a guaranteed vaccine against atherosclerosis (hardening of the arteries).

Gene therapy is an experimental treatment for a variety of medical conditions, including heart disease. The American Heart Association has listed gene therapy as one of the most important areas of research, and it continues to be pursued by researchers from around the world.

Gene therapy focuses on repairing or replacing malfunctioning genes. In the center of most human cells are 46 chromosomes. They are arranged in 23 pairs, with one chromosome in each pair from each biological parent. Twenty-two of these pairs are called autosomes and are common to both males and females. The 23^rd pair is known as the sex chromosomes, which are responsible for determining gender (XY in males, XX in females).

Each chromosome contains long, tightly wound strands of DNA (deoxyribonucleic acid), which is the genetic blueprint for how the body is constructed and maintained. If the DNA strands within each chromosome were uncoiled and connected, the resulting strand of DNA would be over five feet long but only a tiny fraction of an inch in width.

A strand of DNA is composed of four types of chemicals called bases: adenine (A), cytosine (C), guanine (G) and thymine (T). Strands of DNA are linked together at specific points along their length. They are linked together such that the base (A, C, G or T) on one strand is paired with a matching base on the other strand. For example, A only pairs with T, and G only pairs with C. Segments of the DNA base pairs that have been identified as having specific effects on the body (e.g., manufacturing a protein) are called genes. Each gene forms the basis for some piece of genetic information, such as hair color, eye color or the presence of some disease.

The number of base pairs possessed by a living thing determines the size of its genome (the sum total of all its genetic information). The human genome is estimated to contain about three billion (3,000,000,000) base pairs and about 20,000 to 25,000 genes.

Identification of specific genes and their associated proteins has made gene therapy possible. Certain conditions are caused by a single defective gene. Scientists hypothesized that if they could replace a given defective gene with a functioning one, the disease or condition could be cured. In addition, they might also be able to treat certain defective genes of conditions where multiple genes were malfunctioning, possibly alleviating symptoms or lessening the severity of a condition.

A healthy gene is inserted into a cell to produce an enzyme or protein that is missing or defective. Scientists use certain types of viruses to transport genes. The disease-causing part of the virus is removed and the healthy gene is inserted. Different types of viruses have different advantages and disadvantages for gene transport and researchers continue to study their uses.

Gene therapy is still experimental. Researchers are conducting studies with animals and have some clinical trials underway with humans. Some trials have had problems by only getting short-term results from gene therapy. In addition, both the introduced gene and virus can trigger the body’s immune response, which tries to kill any invading cells. Recent research has focused on developing non-viral methods of gene introduction, which may reduce the risk of unwanted immune responses.

For decades, researchers suspected that genes played a role in the development of cardiovascular conditions such as heart disease. Heart-related conditions tend to run in families, which suggests a genetic component is being passed from generation to generation. In combination with one’s environment (e.g., eating a high-fat diet, genetics appeared to play an important role in the development of high blood pressure (hypertension), high cholesterol and other conditions. However, the necessary technology to test this idea was not available.

A major advance in gene therapy occurred in the 1980s, when researchers learned how to transport healthy genes into human cells. They did this by grafting the healthy genes onto a weakened virus (an adenovirus), which was then injected into cells. The weakened virus then “infected” the cells with the healthy genes, causing the cells to follow the healthy new blueprint instead of the old harmful blueprint. The weakened virus was then easily destroyed by the body’s immune system.

In the 1990s, this strategy of gene therapy successfully treated a young woman’s case of hypercholesterolemia (extremely high cholesterol due to a genetic defect). Other human gene experiments followed. 

The advances of gene therapy and its potential have been greatly helped by the Human Genome Project. This scientific collaboration of government research bodies and some private companies created a blueprint to map all the genes contained in the human genome. The Human Genome Project started as a result of conferences held in the late 1980s and coordinated work in the United States began in 1990. The project was completed in 2003. In 2001 and 2003, drafts of the sequencing of the human genome were published by the government consortium and also by Celera Genomics, a private biotechnology company also working on the human genome.

In April 2003, the (U.S.) National Institute of Environmental Health Sciences announced that it had catalogued 200 genes identified with such diseases as cancer, vascular disease, heart disease and asthma.

Gene therapy on heart disease has one of three goals:

• To change or fix an abnormal gene so that it is normal.
• To inject healthy genes into the body to compensate for an absent or weakly functioning gene.
• To replace an abnormal gene with a normal one.

Research on gene therapy as a treatment for cardiovascular conditions includes:

• ADD2 and SLC9A2 have been identified as “blood pressure genes.” Further study may enable the detection of individuals with either of these genes. This, in turn, can help researchers assess the risk for developing high blood pressure and propose the best treatment strategies. Both genes have been associated with increased performance of some heart medications, including beta blockers and diuretics.
• Akt1 is a gene shown to prevent death of transplanted cells. Scientists have added this gene to bone marrow cells that, when injected into animal heart muscle damaged by a heart attack, resulted in an 80 to 90 percent increase in the heart’s pumping ability.
• Gene therapy for peripheral arterial disease led to the growth of new blood vessels in the legs, which delivered much-needed blood to the oxygen-deprived tissues near the blockages.
• An endothelial lipase gene is shown to control HDL (so-called “good”) cholesterol levels. Further studies may be directed to drugs to interfere with the gene’s HDL-lowering effects.
• Certain molecules (matrix metalloproteinases) cause the rapid growth of cells after bypass surgery, which can eventually close the newly opened bypass grafts and make another surgery necessary. However, this build-up was prevented with the use of gene therapy, by which the tissue inhibitor of metalloproteinase (TIMP-3) effectively blocked new cell growth in both human and animal laboratory studies.
  
  
• Gene therapy, using S16EPLN, was found to strengthen the functioning of weakened heart muscle cells in laboratory studies. If this effect is also produced in human beings who have been diagnosed with heart failure, it may help to reverse the condition.
  
  
• A gene for a protein called S1001A1 was shown to improve heart failure among lab rats when injected. Researchers injected the gene into rats 12 weeks after simulating a heart attack. After about a week, the rats’ hearts began to function normally.
  
  
• Mutations (changes) in the gene GATA4 have been associated with congenital heart disease, specifically damage to the muscular wall (septum) that divides the heart’s chambers.
  
  
• Mutations found in the gene PRKAG2, located on chromosome number 7, have been linked to Wolff-Parkinson-White syndrome. This is a condition in which the normal electrical signals in the heart are traveling along an extra, abnormal electrical pathway, which can cause an abnormal heart rhythm (arrhythmia). These genetic abnormalities are also associated with cardiomyopathy that is caused by Wolff-Parkinson-White and other diseases of the heart’s electrical conduction system.
  
  
• Some ethnic/racial groups may have a higher number of variations within genes that can influence a number of cardiovascular conditions. Among black Americans, for example, changes in two genes – alpha2c and beta 1 – may raise blood pressure, constrict blood vessels and increase the risk for heart failure.

Other research is investigating the roles played by the following genes:

• AC6 gene. Strengthens the heartbeat and may be helpful in cases of heart failure.
  
  
• ACE (angiotensin-converting enzyme) I/D gene. May be associated with increased risk of both heart attack and stroke, and could have implications for which people would be most likely to benefit from taking ACE inhibitors. The ACE gene has also been linked to a higher risk of high blood pressure in men, although no link has been found in women, as well as the type and distribution of body fat among obese people.
  
  
• Alu gene. Identified as a possible marker for heart attack.
  
  
• A variant of the Apolipoprotein E (apoE-4) gene. May be associated with increased risk of heart attack, regardless of cholesterol level. Variations in a particular gene may increase the risk of heart attack. Researchers have found variations specific to males and to females.
  
  
• Endothelial nitric oxide synthase (eNOS) gene. Mutations (abnormal changes) in this gene may be a cause of coronary artery spasm, as well as a contributing factor to the development of blood clots.
  
  
• P1^A2 polymorphism. People with this type of genetic variation may be more likely to benefit from a daily aspirin than people who do not have it.
  
  
• P21 gene. Linked with diseases commonly associated with aging, such as Alzheimer's and atherosclerosis (hardening of the arteries).
  
  
• Specific growth factors are being investigated for their therapeutic angiogenic effects, or the ability to stimulate the growth of new blood cells. Two are basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). There is also a genetically engineered version of bFGF called FGF-2. Growth factors have shown good results in animal studies and are now being tested in clinical trials with human volunteers. For example, infusions of FGF-2 have improved the weakness and pain associated with claudication. In stimulating the formation and growth of new blood vessels, VEGF may reduce certain types of chest pain (angina). VEGF may also enhance balloon angioplasty by reopening many narrowed blood vessels, as well as preventing re-narrowing (restenosis) after the procedure.

Stem cells are immature cells, meaning they have the ability to develop into a variety of mature cells, such as red or white blood cells, platelets, heart muscle cells, brain cells, etc.

Recent studies have reported encouraging findings after transplanting stem cells taken from patients’ own bone marrow into heart muscle following a heart attack. For heart failure patients, bone marrow cells have been injected into the heart’s left ventricle. Bone marrow cells are seen to enhance the formation of blood vessels and rebuilding of muscle. Early results have been promising. Some study patients responded so well that they were taken off waiting lists for heart transplantation. Other researchers are seeing that bone marrow implanted into the leg can impact against peripheral arterial disease.

Researchers are also encouraged by the use of muscle cells taken from other parts of the body (e.g., thigh) and injecting them into damaged areas of the heart. It is believed that such skeletal muscle helps to restore the contractile properties of affected heart muscle. Animal studies have found, for example, that vitamin C triggers the transformation of mouse embryonic stem cells to heart muscle cells.

Harvesting and implanting stem cells from a patient’s own bone marrow is known as autologous transplantation. Compared to embryonic stem cells, autologous stem cells are significantly more limited in their ability to develop into different cell types. Embryonic stem cells are more versatile in the cell types they can develop into, but their use in research is controversial and sometimes restricted.

Recent research has indicated that stem cells harvested from amniotic fluid (the liquid that surrounds fetus while it is in the womb) may have similar versatility to embryonic stem cells and are more readily attainable. Amniotic fluid is routinely extracted from the womb during pregnancy in a procedure called amniocentesis. The fluid is then analyzed to diagnose a variety of conditions in the fetus. Scientists have discovered that amniotic fluid-derived stem (AFS) cells – which represent roughly one percent of the cells in amniotic fluid – may be able to produce fat, bone, muscle, blood vessels and nerve cells, much like embryonic stem cells. However, research on AFS cells is still in its infancy and clinical trials have not yet taken place on humans.

Scientists continue to research uses for other, more readily attainable types of stem cells.

Preparing questions in advance can help patients have more meaningful discussions with their physicians about their conditions. Patients may wish to ask their doctors the following questions related to gene therapy:

1. What is gene therapy and when will it be available to treat heart disease?
   
   
2. How can I get in a clinical trial for gene therapy?
   
   
3. Are any of my heart problems being studied for gene therapy?
   
   
4. Will gene therapy replace surgery or lifestyle changes for heart disease?
   
   
5. Where can I get updated information about gene therapy advances?
   
   
6. What drawbacks have been observed in gene therapy clinical trials?
   
   
7. How is stem cell treatment related to gene therapy?
   
   
8. Is there an autologous stem cell treatment appropriate for me?