Achondroplasia

Definition

In its narrowest meaning, gene therapy refers to replacing or fixing a defective gene. In a broader sense, the term is used to denote the use of genes to treat diseases.

Purpose

As of the late 1990s, the field of gene therapy is still considered to be in the experimental stages. There are relatively few cases where gene therapy has been tried on humans, and the vast majority of those have been seriously ill patients. The greatest potential for gene therapy is in the future.

There are at least 4,000 diseases known to be directly caused by a single, faulty gene. These range from sickle cell anemia and cystic fibrosis, to achondroplasia (a disorder in which normal growth of cartilage is disturbed, resulting in a form of dwarfism) and neurofibromatosis (a disorder characterized by tissue and bone deformities, brown spots on the skin, and tumors). Correcting illness by substituting a normal gene for an abnormal one is probably the most familiar concept of gene therapy. Yet, in 1995, less than one quarter of all clinical trials involving gene therapy funded by the National Institutes of Health were directed at this type of genetic disease.

Many disorders and conditions are caused by the interaction of several genes. Scientists believe that environmental agents such as viruses or chemicals may act on certain genes to produce these multifactorial diseases. Diabetes mellitus and multiple sclerosis are two conditions thought to be the result of an interaction between an individual's genes and outside factors. Cancer is the most well-known example of this type of illness. A large proportion of the clinical trials using gene therapy involve attempts to stop or at least slow the abnormal growth of cancer cells. This is one of the most promising areas for the use of gene therapy.

A number of ailments are attributed to polygenic causes. This means the interaction of two or more genes is responsible for the disease. Sometimes a whole group of genes may be the culprit, as in Down syndrome, where an entire extra chromosome 21 is present in the G group. There is little direct research on correcting the genes responsible for polygenic conditions, however, much has been done regarding detection of and testing for some of these disorders.

As more knowledge is acquired, the role of genes in many human maladies is becoming more apparent. For example, the development of schizophrenia and alcoholism is now thought to be due, in part, to an inherited predisposition toward these conditions. Direct gene therapy for these types of cases is not at the forefront of research, but may be investigated in the future.

Precautions

There are many valid concerns regarding the potential misuse of gene therapy and related technologies such as genetic testing. The potential for discrimination based on genetic makeup is an obvious example. Legislative guarantees regarding confidentiality are one way these issues are being addressed.

Perhaps even more complex issues surrounding gene therapy are not as publicly debated. There is concern among researchers that there is excessive pressure for quick results from genetic treatment. This may be encouraging some investigators to skip over the essentials of basic scientific experimentation. The drive for speed may be further exacerbated by the large numbers of private companies participating in genetic research. They have a primary interest in the business rather than scientific aspects of this field.

As information regarding human genetics grows, other questions will inevitably arise. Where is the line between curing disease and simply enhancing an individual's genetic potential? Should treatments be available to everyone, or just those able to afford them? If genes for intelligence are discovered, should anyone be able to get an "IQ lift," as individuals now are free to enhance their appearance with a face lift? The list is endless and illustrates the issues to be worked out as knowledge increases.

Description

Before discussing the current methods gene therapy employs, a brief review of very basic genetics will be helpful. A gene is the basic unit of heredity. Genes are the biologic substances that cause us to have specific traits, such as blue eyes, brown hair, and AB negative blood. It is most likely that groups of genes, in conjunction with environmental factors like nutrition, are responsible for our height, our skin color, and perhaps our hot temper or keen sense of humor. Genes are made up of segments of a chemical called deoxyribonucleic acid (DNA).

DNA has a unique structure, which allows it to act like a blueprint that instructs the cells to produce specific proteins. These proteins, in turn, direct all of the cell's functions. If the DNA of a particular gene is abnormal, it is as if the blueprint is blurry or unreadable. The protein it is supposed to make may not function properly, or may not be manufactured at all. The abnormal or absent protein then upsets the normal functioning of the cells, which produces the symptoms of disease.

Humans have approximately 100,000 genes. These genes are lined up on structures called chromosomes, somewhat like beads on a string. Every cell in the human body, except red blood cells, contains the same genetic information. But a brain cell will act very differently than a skin cell, because different genes will be used, or "expressed" in each.

In principle, gene therapy should be able to insert a normal gene so it can physically replace a flawed one. In practice, scientists are most often working to compensate in some way for the impaired gene. The therapy is more likely to deal with the protein produced by that gene rather than replacing the defective gene with a "normal" version.

The methods being explored to use gene therapy are varied. Approximately half of the experimental therapies involve cancer. Many investigations attempt to stimulate the natural immune system of the body to attack the cancer cells. Others seek to administer a gene which may affect the tumor cell directly. The gene will theoretically cause the tumor itself to secrete a substance which makes the cancer more vulnerable to treatment. In a similar experimental therapy, a gene causes the cancer to make something toxic to itself, virtually a "suicide gene."

Oncogenes are part of the body's normal mechanisms to regulate growth. These genes stimulate the production of proteins which encourage cells to grow. Some cancers are thought to be caused by oncogenes which don't "turn off." Humans also have tumor-suppressor genes. It is thought that these genes don't "turn on" appropriately, allowing cancers to grow unchecked. Manipulating these types of genes is a promising aspect of gene therapy.

Genetic therapies for many other conditions are also being actively investigated. These ailments include acquired immunodeficiency syndrome (AIDS), cystic fibrosis, and muscular dystrophy. Adenosine deaminase deficiency, the first condition treated with authorized human gene therapy in 1990 continues to be studied, as are several other rare diseases such as Gaucher disease.

One of the biggest obstacles to gene therapy is physically placing the therapeutic agent in the right place. Controlling its behavior is another hurdle. The structures involved are smaller than microscopic and not easy to manipulate. Finding an appropriate agent, called a vector, to get the beneficial gene or other material into the target cells at the desired location is a challenge. The body's defense systems cannot distinguish a healing intruder from a harmful one and may attempt to reject the potentially helpful agent. The most common vectors that have been tried are inactivated viruses.

Preparation

Unknown.

Aftercare

Unknown.

Risks

The risks of gene therapy are largely unknown. Some agents have produced undesired inflammatory or immune responses in patients during experimental trials.

Normal results

Successful gene therapy would cure the disease being treated.

Key Terms

Achondroplasia

A genetic disorder in which normal growth of cartilage is disturbed, resulting in a form of dwarfism.

Adenosine deaminase deficiency

A deficiency of an important enzyme that helps convert adenosine to inosine.

Deoxyribonucleic acid (DNA)

Often referred to as the "building block of life," DNA is a large, double-helixed molecule that carries genetic information.

Gaucher's disease

A rare metabolic disorder that runs in families and is caused by an enzyme deficiency.

Multifactorial

A condition or disorder resulting from the interaction of several genes, often influenced by environmental factors.

Neurofibromatosis

Also known as von Recklinghausen's disease, this congenital disorder is characterized by tissue and bone deformities, brown spots on the skin, and tumors of the nerves and skin.

Oncogenes

Genes that normally control the growth of cells and may become cancer spreaders when altered by a cancer-causing agent.

Polygenes

A number of genes that interact together to produce a resulting cumulative trait, such as skin color or height.

Tumor suppressor genes

A gene that is able to undo mutations in certain other genes.

Gale Encyclopedia of Medicine. Gale Research, 1999.