Diagnosing and Treating Genetic Diseases
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Gene therapy attempts to treat genetic diseases at the molecular level by correcting what is wrong with defective genes. Clinical research into gene therapy’s safety and effectiveness has just begun. No one knows if gene therapy will work, or for what diseases. If gene therapy is successful, it could work by preventing a protein from doing something that causes harm, restoring the normal function of a protein, giving proteins new functions, or enhancing the existing functions of proteins. How Do You Do It? Gene therapy relies on finding a dependable delivery system to carry the correct gene to the affected cells. The gene must be delivered inside the target cells and work properly without causing adverse effects. Delivering genes that will work correctly for the long term is the greatest challenge of gene therapy.

This photograph is of an adenovirus. Viruses are often used by researchers to deliver the correct gene to cells. Viruses deposit their own genetic material into host cells to instruct those cells to make more viruses. In gene therapy, the DNA for the desired gene is inserted into the genetic material of the virus. The virus is engineered so that it cannot reproduce, but it does deliver its new genetic material which contains the desired DNA.
Adenovirus. Courtesy of Child Health and Human Development

  Gene therapy researchers are investigating ways other than viruses to deliver the correct gene to cells. Fatty molecules known as liposomes may also be used as can micropipettes, sometimes called "gene guns" to insert genes into cells physically.
Liposome.  Courtesy of Liposome Technology, Inc.


ADA: The First Gene Therapy Trial

A four-year old girl became the first gene therapy patient on September 14, 1990 at the NIH Clinical Center. She has adenosine deaminase (ADA) deficiency, a genetic disease which leaves her defenseless against infections. White blood cells were taken from her, and the normal genes for making adenosine deaminase were inserted into them. The corrected cells were reinjected into her. Dr. W. French Anderson helped develop this landmark clinical trial when he worked at the National Heart, Lung, and Blood Institute.

Human ex vivo Gene Therapy

Below is a Timeline Telling the Story of Developing the First Human Gene Therapy:

  Culver, Anderson, and Blaese with gene therapy patients. Courtesy of Dr. Kenneth Culver, Novarti Pharmaceuticals Corporation
    The laboratories of Drs. W. French Anderson and Michael Blaese in the National Heart, Lung, and Blood Institute and the National Cancer Institute worked together to show that cells from patients with ADA deficiency can be corrected in tissue culture. They used a retrovirus to carry the correct human ADA gene to the cells. Here, Drs. Kenneth Culver (then of the NHLBI), W. French Anderson, and Michael Blaese pose with gene therapy patients.


  The team studied how safely and efficiently the correct genes were transfered into bone marrow cells in animals. The process wasn’t harmful, but the number of cells that received the correct gene was too small to be a useful treatment.

  White Blood Cell. Courtesy of Dr. Kenneth Culver, Novarti Pharmaceuticals Corporation.
    The researchers decided to use white blood cells (T cells), pictured here in tissue culture, instead of bone marrow cells. This switch greatly increased the number of correct genes taken up by the cells in the animal experiments -- the experiments were so successful that the team began to look for ways to test the delivery system in people.


  The team worked with Dr. Steven Rosenberg to test the safety and effectiveness of the gene therapy process in cancer patients. The team grew tumor infiltrating lymphocytes (TIL cells) from people with the deadly cancer malignant melanoma, and then they engineered a virus to put a DNA marker into those cells. These "marked TIL cells" helped the researchers learn two things: which TIL cells work best for cancer treatment; and that the engineered virus can be used safely in humans.

  Drawing of infusion procedure by patient. Courtesy of the National Museum of American History
    Drs. Anderson, Blaese, and Kenneth Culver used a virus to deliver the correct ADA gene to a four-year old girl and a nine-year old girl with ADA deficiency. Each girl was given repeated treatments over a period of two years. The nine-year old girl drew several pictures of her treatment -- here she is receiving an infusion of her own corrected cells.


  Researchers used gene therapy to treat newborn babies with ADA deficiency. The normal ADA genes were delivered to immature blood cells isolated from the babies’ umbilical cords. It is hoped these special cells will provide longer-lasting benefits.


  The two original ADA patients attend school and are leading normal lives. The newborn patients have shown steady increases in ADA in their immune cells following a single gene therapy treatment. But although the promise of gene therapy is great, many scientific obstacles remain before it becomes a practical form of therapy.
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Revolution in Progress: Human Genetics and Medical Research/
National Institutes of Health