Gene Counseling and Gene Therapy

Genetic counseling and gene therapy

Prospective or current parents learn about diagnosing and treating inherited diseases and whether their children may inherit such diseases. /

There are two tools which are usually used in gene counseling and gene therapy. They are genetic analysis and DNA analysis.

Gene analysis

Studying how traits and genes for traits are passed from generation to generation and how genes and the environment interact to result in traits.

DNA analysis

Polymerase chain reaction (PCR) makes copies of a DNA segment. RFLP mapping (restriction fragment length polymorphism) detects patterns in DNA that can indicate the presence of a gene for a trait.
Both PCR and RFLP analysis can be used in "DNA fingerprinting" for genealogical studies and forensics.

Genetic counseling

Unaffected members of a family with a history of genetic defect can consult a genetic counselor for advice on the risk of having an affected child. Genetic counseling may also be sought by parents with an affected child who wish to know the likelihood that any future child they conceive may be affected. Advice is based on knowledge of the family’s pedigree and the frequency of the faulty gene in the national population, and on whether the parents are closely related. For some conditions it is possible to check whether they carry a faulty gene (for example, for cystic fibrosis).

Genetic counselors may also advise on the actual genetic status of the fetus, knowledge of which is obtained using techniques such as chorionic villus sampling. Typically this advice is sought by or offered to parents at particular risk.

What is the role of genetic counseling?

In the sophisticated programs that are pioneering predictive genetic tests for cancer, genetic counseling plays a vital role. Persons considering genetic testing meet with specially trained health professionals before testing begins, when they receive the test results, and in the weeks and months afterwards.

Before testing, the counselors try to make sure that the person is psychologically prepared to cope with the possibility of a positive test, and that he or she has enough balanced information to be able to formulate a truly informed consent. If the person decides to proceed with testing, counselors help the individual and the family adjusts to the test results, and they help them arrange whatever prevention and screening measures are appropriate.

What Happens During A Genetic Counseling Session?

Some genetic counseling sessions are simple, and require only one visit. Other times, multiple sessions are needed to collect additional information, to keep the family updated or to deal with ongoing medical and/or psychosocial problems.

The first step in a genetic counseling session is to determine why the patient or family is seeking genetic counseling and to identify what information they wish to get out of the session. Usually only one or two family members attend a counseling session. Sometimes cousins, in-laws, siblings, and grandparents may come. For genetic counselors, the family is the patient, not just the person affected, or potentially affected, with a genetic disease.

An accurate pedigree is an important part of genetic counseling. A pedigree is used to help make a diagnosis of a genetic disease, to determine a person's risk of developing a genetic disease or to determine the risk of having a child with a genetic disease. At minimum, a pedigree includes first degree relatives (parents and siblings), second degree relatives (aunts and uncles) and third degree relatives (cousins and grandparents). The counselor may ask questions about more distant relatives like great-uncles or second cousins when necessary.

A figure of a human pedigree which shows first to third degree relatives.

Besides depicting familial relationships, a pedigree also contains vital medical information like birth date, age of death, cause of death, health problems, and results of genetic tests. Obtaining medical records on affected relatives can ensure the medical information is accurate.

Sometimes, a pedigree reveals confidential information that is not necessarily known to all family members, such as which relatives have genetic diseases or may suggest non-paternity (when the husband is not the father of the baby). Insurance companies may use information from the pedigree to deny health or life insurance to a person at risk to develop a genetic disease. Therefore, extreme care must be taken to maintain confidentiality.

After medical tests are completed and records are collected, the genetic counselor may be able to make a diagnosis, or just as importantly, determine that a person does not have or is not at risk for a genetic disease. The pedigree can also be used to estimate the risk relatives face to develop a genetic disease or have a child with a genetic disease.

Genetic counseling involves more than just communicating complex medical information to families. The biggest challenge of genetic counseling is helping families cope with the emotional, psychological, medical, social and economic consequences of genetic disease.

Patients can react in unexpected ways when they learn their genetic risk status. Some people take the information matter-of- factly. Others react with anger, shock, denial, grief, depression, confusion, and guilt. Treating and caring for people with genetic diseases can be expensive, yet some people may lose their jobs and health insurance because of their risk of developing a genetic disease. Someone diagnosed with a genetic disease may be avoided by other relatives because the relatives don't know what to say or because they don't want to face up to the possibility that they too may develop the same genetic disease. Other people may have a hard time understanding the meaning of risk - a risk of 10% may seem high to one relative but seem low to another relative.

Genetic counselors try to help families cope with the many ramifications of genetic testing. Patients who are having severe psychosocial problems may be referred to psychiatrists, social workers, or counselors. Genetic counselors can also help families who are having problems with insurance companies or employers who may not understand the medical implications of genetic testing.

Genetic screening

Part of the counselor’s job is to discuss the results of genetic screening with the person who has been tested. Genetic screening is testing for genetic disorders. Most commonly, prospective parents or a fetus is tested when a specific genetic disorder is suspected (e.g., Tay-Sachs or sickle cell disease ). In such a case, genetic screening begins with a complete medical history of both parents. If the parents decide to conceive or have already conceived, diagnostic tests, such as chorionic villus samplingand amniocentesis , can be performed on the fetus to detect various genetic disorders. In the case of a positive finding, the parents can elect to abort the fetus. Embryo biopsy , another diagnostic test, can be used on an embryo conceived by in vitro fertilizationto determine if the embryo is free of certain genetic diseases before it is implanted in the uterus. As researchers identify more genetic markers for diseases and develop blood tests for them, concern has arisen over the use of such tests to deny people health and life insurance, employment, and the like. A 1993 National Academy of Sciences report called for the establishment of ethical guidelines on the use of genetic screening, and in 1995 the Equal Employment Opportunity Commission said that the use of genetic screening to deny employment could violate the Americans with Disabilities Act.

Gene therapy

Gene therapy is the use of genesand the techniques of genetic engineering in the treatment of a genetic disorder or chronic disease. The two basic methods are called in vivo and ex vivo gene therapy. The in vivo method inserts genetically altered genes directly into the patient; the ex vivo method removes tissue from the patient, extracts the cells in question, and genetically alters them before returning them to the patient. The challenge of gene therapy lies in development of a means to deliver the genetic material into the nuclei of the appropriate cells, so that it will be reproduced in the normal course of cell division and have a lasting effect. One technique involves removing cells from a patient, fortifying them with healthy copies of the defective gene, and reinjecting them into the patient. Another involves inserting a gene into an inactivated or nonvirulent virus and using the virus's infective capabilities to carry the desired gene into the patient's cells. A liposome, a tiny fat-encased pouch that can traverse cell membranes, is also sometimes used to transport a gene into a body cell. Another approach employing liposomes, called chimeraplasty, involves the insertion of manufactured nucleic acid molecules (chimeraplasts) instead of entire genes to correct disease-causing gene mutations. Once inserted, the gene may produce an essential chemical that the patient's body cannot, remove or render harmless a substance or gene causing disease, or expose certain cells, especially cancerous cells, to attack by conventional drugs.
Gene therapy was first used in humans in 1990 to treat a child with adenosine deaminase deficiency (ADA), a rare hereditary immune disorder (see immunity ). It is hoped that gene therapy can be used to treat cancer, genetic diseases, and AIDS, but there are concerns that the immune system may attack cells treated by gene therapy, that the viral vectors could mutate and become virulent, or that altered genes might be passed to succeeding generations.
In the United States, gene therapy techniques must be approved by the federal government. The Recombinant DNA Advisory Committee of the National Institutes of Health oversees gene therapy experiments. Like drugs, products must pass the requirements of the Food and Drug Administration . Gene therapy is a competitive and potentially lucrative field, and patents have been awarded for certain techniques.

The aim of gene therapy is to treat genetic disease by replacing defective genes in the patient’s body with copies of the healthy gene. As a branch of applied molecular biology it is a very recent development. Whilst the ultimate goal of gene therapy is to cure all genetic disease, this eagerly awaited outcome is still a long way off.

Theoretically at least, genes may be added into germ cells (eggs or sperms) or into body cells (somatic cells). Adding genes to germ cells would mean that the genome of future individuals was being changed. Tampering with the genes of human sex cells is outlawed, in fact.

The available technologies for getting genes into cells are the approaches the genetic engineer seeks to adapt foe human gene therapy. The therapist concentrates on disorders caused by a single gene, since these present the best chances of success. The healthy gene has to be located, isolated and cloned to make it available for “transplantation”. Target cells in the body need to be robust enough to survive while a sample is withdrawn, cultured, modified genetically, and then returned for a substantial period(whist the healthy gene is expressed ). Molecular biologists have concentrated on bone marrow cells, liver cells and skin cells, so far. Ideally, the transplanted cells ought to divide in situ, replicating the implanted, healthy gene in the patient’s body.

Some human diseases are caused by a defective gene. An example is cystic fibrosis,a disease of mucous glands throughout the body that usually develops during childhood and makes breathing increasingly difficult. If a child receives two copies of the defective gene call the CF gene -- one copy from each parent -- then the child will develop the disease. Biotechnology is used in several ways in detecting, diagnosing and treating cystic fibrosis.

1. Genetic testing or "screening" enables healthy people to know whether they carry one copy of the CF gene. If both potential parents have one copy each of the CF gene, then the genetic counselor can provide information and help assess whether the couple may have a child who will develop cystic fibrosis.
2. Genetic testing can alert parents their child has two copies of the CF gene, permitting diagnosis even before the disease develops in the child.
3. Children with cystic fibrosis can enjoy some relief from the mucus buildup in their lungs by breathing in a mucus-breaking drug made with recombinant DNA technology. The drug contains a protein that chews up the DNA so the mucus is easier to remove from the lungs by coughing.
4. An experimental approach to curing cystic fibrosis uses a genetically engineered cold virus that delivers to the patient's lung cells a working version of the defective gene. The new gene enables lung cells to make the protein that is lacking in cystic fibrosis patients.

Gene therapy for cystic fibrosis

Here the approach has been to “wrap” cloned healthy genes in microscopic lipid envelops (forming liposomes) and periodically to spray these on to the surface of the lungs of a diseased animal where mucus production is failing due to a defective gene. Application is by means of an aerosol spray. The expectation is that many of the tiny liposome packages will be taken into the cells of the lung surface (by membrane merger), and the genes may enter the chromosomes and be expressed. In trails using laboratory mice with induced cystic fibrosis, this technique has appeared to be largely successful. It is now to be tried out with human sufferers.

Gene therapy for familial hypercholesterolemia (FH)

The surface membranes of liver cells carry receptors for low-density lipo-proteins (LDL). LDLs circulate in the blood and are normally taken into cells and metabolized. The membrane receptors in FH suffers are defective, and consequently LDLs accumulate in the blood circulation. In FH, the lipids are laid down in arteries as cholesterol (leading to atherosclerosis and coronary heart disease), and under the skin.

Samples of liver tissue may be removed and the cells genetically modified and returned. The human body quickly regenerates missing liver tissue. Liver cells are relatively easy to handle and many genetic diseases may eventually be corrected by modifying liver cell function.

Gene therapy for arthritis

The patient, who has rheumatoid arthritis, received injections of her own cells into the knuckles of one hand. These cells were cultured and modified to carry a gene that blocks both joint erosion and inflammation caused by interleukin-1 (IL-1). IL-1, a biological response modifier, is active in many biological processes within tissues.

The patient's synovial cells were removed from her thumb joint in an operation to stabilize that joint. Some of the synovial cells were cultured and then exposed to the gene, whereas others were grown but did not receive the gene. After testing the cultures for any microbial contaminants, cells were injected into the four knuckle joints on one hand. Two of the joints received injections with gene-containing cells. Two joints received injections of cultured cells without the gene. Neither the patient nor the surgeon knew which knuckles were being treated with the gene.

One week later the patient then underwent surgery to replace her own arthritic joints with artificial ones. The tissues and diseased joints removed during surgery will be evaluated. Preliminary results from this study, which includes nine women, are not anticipated until later this fall. This type of therapy would eventually reduce the amount or complexity of surgery required by many patients with rheumatoid arthritis and other chronic joint disorders.

Normally, IL-1 is involved in provoking inflammation to ward off infection or disease. In the case of rheumatoid arthritis, the immune system attacks a person's own tissues in what is called autoimmunity. Once released inside a joint, IL-1 causes both inflammation and erosion of joint tissues, as well as limited mobility and chronic pain associated with rheumatoid arthritis.

The gene being delivered in this protocol makes interleukin-1 receptor antagonist (IL-1Ra). IL-1Ra attaches to receptors on the surface of synovial cells. IL-1 normally binds to these receptors, but IL-1Ra prevents this process from occurring.

It is important to inject the genetically manipulated cells into the affected joint. If the blocking agent IL-1Ra were injected into the bloodstream, it might cause severe side effects in other parts of the body that are unaffected by rheumatoid arthritis but which are in some way regulated by IL-1. Moreover, IL-1Ra would break down more easily in the blood, so the patients would need to deliver much greater quantities of it to reach therapeutic levels in the affected joints

However, current therapies reduce pain and inflammation, but they do not stop the progress of rheumatoid arthritis.

Ethical issues in gene therapy

While gene therapy is looked upon with excitement by many people, there are also those that are particularly opposed to it. One of the main reasons for this is the ethical considerations which come into play. Unlike conventional methods of treatment, gene therapy attempts to permanently alter our genetic make-up, changing the way we are forever. The diagram above asks some of the moral questions associated with gene therapy.