Gene therapy is an experimental method using healthy genes to repair or modify cells. It is being developed to treat diabetes, cancer, heart disease and other conditions.
Genes are the basic unit of heredity. Humans have tens of thousands of genes, each of which contains a strand of DNA. DNA provides instructions to various parts of the body and controls everything from hair color to the creation of vital organs.
Gene therapy uses a modified virus or other carrier to transport genetic material into cells that have defective or missing DNA. This technology may have wide-ranging implications for the treatment of diabetes. For example, it is being studied as a way to produce insulin and to treat complications such as diabetic neuropathy, foot ulcers, high blood pressure and sexual dysfunction.
Although gene therapy has shown promise, several risks have already been identified. For example, the modified viruses that are sometimes used may cause an exaggerated immune reaction. Research on diabetic gene therapy is still in its early stages, but several trials on human volunteers have taken place, with more being planned.
About gene therapy
Gene therapy, also called gene transfer, is an experimental treatment being researched for a variety of medical conditions, including diabetes. It involves the introduction of normal genes to alter, replace or supplement genes that are not functioning properly.
To understand gene therapy and how it can be used for diabetes treatment, several terms should be explained. These include:
- Chromosome. Rod-shaped element in the nucleus (center) of each cell. Chromosomes contain the hereditary information that guides all cell actions. Most human cells have 46 chromosomes, with a set of 23 inherited from each parent. Twenty-two of these pairs are common to males and females and are called autosomes. The 23rd pair, known as the sex chromosomes, determine a person’s sex (XY in males, XX in females).
- Gene. The basic unit of hereditary. Each gene is located in a specific site on a chromosome. Each human cell has about 20,000 to 25,000 genes. A person inherits two copies of each gene, one from each parent. They determine physical characteristics such as eye color and skin color, and genetic diseases such as maturity-onset diabetes of the young (MODY). Genes also contribute to other characteristics in which environment and behavior play a role, such as body weight, intelligence and the risk of multifactorial diseases (e.g., type 2 diabetes).
- Genome. All of the genetic material of a species. The human genome has about 20,000 to 25,000 genes.
- DNA (deoxyribonucleic acid). A complex substance in genes that contains genetic information needed to make the body’s proteins. These proteins allow the body to function and grow.
- Allele. Variations of a single gene. Differences in alleles are one factor involved in differences among people in physical characteristics and susceptibility to disease. Some alleles, traits and genetic diseases are dominant, others recessive. For instance, a person who has inherited a brown-eye gene from one parent and a blue-eye gene from the other parent will have brown eyes. Blue eyes are a recessive trait, meaning a person must have inherited that allele from each parent. MODY is an example of an autosomal dominant condition – a person who inherits a MODY gene from only one parent will have the disease.
- Vector. A substance, such as a virus or protein, used to supply genetic material to target cells. A gutless viral vector is a carrier from which the harmful genes have been removed.
Each chromosome contains long, tightly wound strands of DNA, 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 result would be more than 5 feet long (1.5 meters) but only a tiny fraction of an inch in width, according to the Human Genome Project, an international research project that mapped all human genes.
A strand of DNA is composed of only four types of chemicals called bases: adenine (A), cytosine (C), guanine (G) and thymine (T). The strands determine traits such as hair color or height. Segments of the DNA strand that have been identified as having specific effects on the body are called genes.
Strands of DNA are linked together at specific points along their length so that the base (A, C, G or T) on one strand is paired with a complementary base on the other strand. A pairs only with T, and G pairs only with C. When the bases are paired, they form base pairs. The human genome is estimated to contain 3 billion base pairs. Scientists once thought that humans had about 100,000 genes, but the Human Genome Project has reduced that estimate to less than 25,000.
The Human Genome Project finished mapping the human genome in 2003, but analysis of the data on this complete DNA blueprint will continue for years. The potential benefits are enormous. Mapping the human genome not only allows scientists to interpret genetic information, but also gives them a chance to potentially change the genetic information through gene therapy. These treatments could have revolutionary effects on the diagnosis and treatment of many diseases. People could have the opportunity to have certain genetic elements altered, which might offer cures or prevention for certain diseases.
Scientists have identified specific defective genes that cause some diabetic conditions, such as MODY and Wolfram syndrome. Researchers have also linked certain genes to risk of type 2 diabetes, type 1 diabetes and gestational diabetes but understand these connections less clearly.
Gene therapy holds the greatest promise for diseases caused by one defective gene, according to the U.S. National Institutes of Health. Examples include sickle cell anemia, cystic fibrosis (a disease that can lead to secondary diabetes), hemophilia, MODY and Wolfram syndrome. Gene therapy may also offer hope for conditions involving multiple factors, such as type 1 diabetes, type 2 diabetes, heart disease and cancer, and possibly infectious diseases such as AIDS.
Gene therapy is being developed at universities, research centers, corporations and medical centers around the world. Most of the studies are in early stages, and the research materials are not used in standard treatments. Several thousand people have taken part in trials of gene therapy in the United States, most for cancer but a small number for diabetes. The U.S. Food and Drug Administration (FDA) has not yet approved the sale of any gene therapy products.
Role of gene therapy in treating diabetes
Gene therapy might once day play numerous roles in the treatment and prevention of diabetes and its complications. Most diabetes research on gene therapy has involved animal subjects, but some early studies on humans have taken place. For example:
- Scientists injected English and American diabetic volunteers with a DNA-binding protein called ZFP TFTM that produces a nerve growth factor. Preliminary results in 2006 suggested a potential method of preventing diabetic neuropathy. Results of phase II clinical trials (controlled studies that evaluate effectiveness) are awaited.
- Clinical trials are assessing the effectiveness of gene therapy to treat diabetic ulcers. Scientists have developed a topical application of a gene that is designed to stimulate repair cells in and around the wound.
- In diabetic patients at risk for foot or leg amputation, some participants in a gene therapy project in 2007 at Ohio State University reported resolution of chronic pain and healing of chronic wounds.
- The first human trial of gene therapy for erectile dysfunction, a common complication in diabetic men, yielded some encouraging preliminary results in late 2006 in New York. Research on diabetic rodents has also suggested that gene therapy might one day play a role in treating erectile dysfunction.
Much of the research in diabetic gene therapy has focused on the stimulation of insulin and the insulin-producing beta cells of the pancreas. Laboratory researchers are exploring gene therapy to extend the life of human beta cells, lower glucose (blood sugar) by delivering insulin genes to the pancreas, extend the life of pancreatic islet cell transplants and prevent problems such as tumors.
Gene therapy research is also focusing on bypassing the beta cells in insulin production. Studies are testing whether elements of the insulin-producing mechanism of beta cells could be introduced to non-beta cells. The hope is that the autoimmune disorder that causes the destruction of beta cells in type 1 diabetes would bypass these new non-beta insulin-producing cells. However, the future potential success of insulin gene therapy is dependant on many factors, including the ability to regulate glucose levels. Related areas of gene therapy research include stimulating insulin production in the liver and developing protected cells that are engineered to secrete insulin.
Researchers have also used gene therapy in the laboratory to:
- Prevent the onset of hyperglycemia in normal-weight diabetes-prone mice, a potential advance in preventing type 1 diabetes
- Increase beta cells and lower blood glucose levels in mice with a condition similar to type 2 diabetes
- Restore the growth of rodent nerves and blood vessels that were damaged by diabetes
Gene therapy is also being investigated to address diabetic complications and risk factors including high blood pressure, unhealthy levels of cholesterol, atherosclerosis, peripheral arterial disease, heart attack, stroke and diabetic nephropathy.
Potential benefits and risks of gene therapy
The goal of gene therapy research is to prevent, treat, relieve the symptoms of or cure diseases such as diabetes. The potential benefits are great. Gene therapy in the future may be able to control the production of insulin, thus freeing patients from the need for injections, pumps and other methods of insulin administration. It might also be used to treat complications ranging from foot ulcers to kidney disease.
However, there are also certain risks associated with gene therapy. One of the major risks is the potential for infection or an immune system reaction. Vectors, the means of delivering gene therapy to a cell, have traditionally used viruses that were rendered harmless. In a few cases, however, viral vectors have been involved in causing disease or sparking a reaction in people during trials of gene therapy, sometimes fatally.
Scientists have reported progress with gutless viral vectors, which have been tested for safety on animals after the removal of harmful genes. They are also experimenting with nonviral vectors such as proteins.
Another risk involved with gene therapy for diabetes patients is hypoglycemia, low levels of glucose (blood sugar). Researchers who use gene therapy to produce insulin, particularly outside the pancreas, must avoid creating too much insulin. Excess insulin (hyperinsulinemia) leads to hypoglycemia, which can result in unconsciousness, coma and even death. Research scientists are trying to resolve this factor by adding genetic material that helps to regulate glucose levels.
Many gene therapy treatments rely on immune suppression for success. People with type 1 diabetes have an autoimmune disorder that makes the immune system destroy the insulin-producing beta cells. A primary focus of research is correcting the function of the immune system to protect the cells produced by gene therapy. However, scientists need to create a balance between reducing unwanted immune function and hindering the normal disease-fighting function of the immune system.
Human trials on gene therapy are under way for conditions including diabetic neuropathy. The U.S. National Institutes of Health has current information on trials seeking volunteers (www.clinicaltrials.gov). Patients who are interested in participating are advised to consult their physician about the potential risks and benefits.
Alternatives and variations of gene therapy
One of the major variations in gene therapy is the choice of a vector. A vector is a carrier that brings the genetic material to the targeted cell. Vectors must conform to certain requirements in order to be effective in gene therapy. For example, they must be small enough to enter tissues and cells, and they must be able to deliver the genetic material to other parts of the body.
Vectors can be viral or non-viral. Viral vectors contain viruses, which are parasitic packages of genetic material encased in protein. Some viruses may be harmless to humans, but many cause infectious diseases, ranging from colds and flu to HIV/AIDS. Viruses used in gene therapy are “gutless,” which means that the harmful material has been removed. Viruses are used because they “infect” the body and are able to replicate whatever genetic material is placed inside them.
However, researchers have raised concerns about the safety of viral vectors, so scientists are working to create non-viral vectors. For example, fats (lipids) are being tested for potential effectiveness as a vector. There are numerous types of lipids available. Liposomes are synthetic fatty shells created to carry genetic material or medicine. They are not infectious but are small and unstable, which currently limits research potential. Additionally, lipoplexes are made of a liposome and DNA. They are larger and can carry more genetic material than a liposome. Scientists are also researching the use of proteins, transposons (segments of DNA that can transfer genetic material), plasmids (DNA molecules derived from bacteria) and ultrathin polymer films as nonviral vectors.
Another variation in gene therapy involves the way in which gene therapy is delivered. In some cases, treatment is in vivo (within the body). During in vivo treatment, the modified genes are introduced directly inside the body. Conversely, ex vivo treatment (outside the body) involves genetic cells being extracted from the body, modified in a laboratory and then re-introduced to the body. Both types have advantages and disadvantages: In vivo is an easier technological method, but ex vivo offers more control over undesirable factors that may develop before the gene is introduced into a person.
Ongoing research on gene therapy
The research surrounding gene therapy is still in early stages of development, and scientists are exploring many potential uses of gene therapy to treat diabetes and other conditions. It is important to emphasize that years of additional research will be required before these techniques might be used as medical treatments. The areas of study include:
- Stem cells. Stem cells are immature cells that have the ability to develop into a variety of mature cells. Stem cells may be used to create insulin-producing beta cells or islet cells.
- Vaccines. A priority of genetic diabetic research is stopping the autoimmune process that kills beta cells. Scientists are researching the possibility of using DNA-based vaccines to increase the immune system’s tolerance.
- Identification of all the genetic factors involved in type 1 diabetes, type 2 diabetes and other forms of the disease. Scientists have linked a number of genes to the various forms of diabetes. They hope one day to identify all the specific genes that may be responsible.
- Improvement of vector alternatives. Although many alternatives to viral vectors have been found, there are still several drawbacks to some variations. Researchers are attempting to resolve some of the issues related to the toxicity of viral vectors in addition to creating new and effective non-viral vectors.
- Delivery of insulin that can respond to glucose (blood sugar). Researchers are developing cellular depots to store insulin and secrete it in response to an increase in glucose.
Researchers have reported preliminary success in using gene therapy to treat diabetic rodents. Although these findings have been widely reported in the media, such advances might or might not translate to success in treating humans with diabetes. Scientists have cautioned, for example, that mice do not process glucose like humans do. Extensive testing is required before any studies completed on animals can be undertaken on human subjects.
Gene therapy is a growing field of research that will likely have many advances and setbacks before a cure for diabetes may be found. Although it offers promise, people with diabetes should understand that any research breakthrough reported in the media may take years to develop as a medical treatment and might never become feasible.
In the meantime, it is important that patients control their diabetes by exercising, eating healthily, performing glucose monitoring, taking medication and following the other steps in a physician’s treatment plan.
Questions for your doctor about gene therapy
Preparing questions in advance can help patients have more meaningful discussions with their physicians regarding their conditions. Patients may wish to ask their doctor or healthcare professional the following questions about gene therapy:
- Is gene therapy being used for my type of diabetes, diabetic complications or other conditions I have?
- Am I a candidate for gene therapy?
- Do you recommend that I consider participating in a clinical trial?
- What would my treatment options be with gene therapy?
- How does this therapy work?
- Are these treatments available to me only in clinical trials?
- Can you refer me to an appropriate clinical trial or tell me where to get more information?
- What are the benefits and risks of the treatments for me?
- How would I be monitored during and after gene therapy?
- What would my prognosis be with the treatment? How would this compare to my prognosis with standard treatments?