Joann Boughman, PhD,
Executive Vice President, American Society of Human Genetics (ASHG)

Gene therapy refers to the treatment of human disease by transfer of genetic materials (DNA or RNA) into a patient to replace a deficient or non-functional gene. In most medical treatments, a drug is used to either replace a missing or defective molecule (for example, thyroid hormone), to increase or stimulate production of a molecule, or to counteract or inhibit an adverse bodily production or condition (for example, cholesterol reducing pills, an antibiotic to fight an infection, or medications to lower blood pressure). In gene therapy, the concept is that a gene is introduced to produce the substance needed or to reduce a substance that is overproduced. While gene therapy holds great promise for the treatment of genetic diseases in the future, several challenges remain to be resolved through scientific research and clinical trials.

Because the control of expression of genes is not completely understood, targeting the gene to the right cells in the body and into the DNA of those cells is extremely difficult, leaving in question the safety and efficacy of gene therapy. To begin with, gene therapy can target two types of cells, germline cells or somatic cells. Germline gene therapy introduces genetic material into all cells of the body or a subset of cells, including the germ cells (reproductive cells, e.g., eggs or sperm). As a result, the genetic modification can be passed on to offspring, thereby permanently altering the genetic material. This type of gene therapy is not permitted in the United States. In contrast, in somatic gene therapy, genes are introduced into cells of various parts of the body (e.g., muscle, heart, bone marrow) but not the germ cells. This form of treatment affects only the patient and does not result in transmission of the genetic modification to future generations.

For gene therapy to be successful, several things must occur: 1) the gene must be known; 2) the gene must be able to be expressed (turned on); and 3) the gene must be introduced into the appropriate host tissue. Thanks to many years of genetic research and most recently the Human Genome Project, the genes responsible for many genetic diseases have been identified and studied extensively. However, introducing the gene into the target host cell and making sure it is expressed has proved to be more difficult. The most common approach to transmitting a gene into a cell involves using a virus as a transporter. The gene of interest is packaged into the virus, which has been rendered harmless. The virus carrying the gene of interest is then injected into the body and targeted to specific cells. Sometimes naked DNA (without a carrier) can be taken up by host cells such as muscle cells, but often times the DNA is degraded or does not efficiently integrate into the DNA of the host cell. Other carrier molecules or packages are also being examined.

Next, the DNA (gene) of interest must integrate into the DNA of the host cell and be activated. But sometimes the DNA can integrate at an important site in the genome, disrupting other important cellular functions and possibly resulting in serious adverse responses or even another disease. In addition, even if the gene is successfully integrated and expressed, the time of expression may be brief and require additional gene therapy treatment.

Gene therapy strategies may vary depending on the disease being treated and the type of vector used. In ex vivo gene therapy, cells are first removed from the patient and then mixed with the viral vector carrying the corrected gene. This type of gene therapy occurs "outside" of the patient. Once the cells have taken up the virus and the new gene, the cells are inserted back into the patient. Another strategy would take place "inside" the patient, known as in vivo gene therapy. In this approach, the viral vector is given to the patient and targeted to the affected tissue.

While the concept of gene therapy seemed straightforward when it was first tested in 1990, subsequent studies have revealed just how complicated the process is, requiring an exquisite understanding of the gene, the control of its expression, and the delivery of material that will not be rejected to the precise site of needed action. As many genetic disorders are the result of very early developmental alterations that result in long-term problems, not every genetic disorder can be treated through gene therapy.

Nonetheless, there are hundreds of gene therapy studies ongoing, and gene therapy trials are underway in many places across the world. Serious adverse effects remain a major safety concern for all gene therapy trials. Although the widespread use of gene therapy for many genetic disorders is years away, with each new understanding and study on gene therapy, scientists are advancing to the day when gene therapy can be used as a successful treatment.

Additional information regarding gene therapy trials registered with the NIH may be found by accessing the Genetic Modification Clinical Research Information System (GeMCRIS).