Gene Therapy: A Brief History

More than a decade after the first approved gene therapy experiment, much uncertainly still exists about gene therapy's ability to treat critically ill patients.

In 1990, four year-old Ashanti DeSilva began treatment for a disease that severely weakened her immune system. In the first successful use of gene therapy, doctors inserted genetically altered white blood cells into her body to strengthen her immune system. What made this different from her past treatments was that the doctors genetically altered the structure of her DNA. Now a healthy teenager, Ashanti’s experience with gene therapy has a happy ending. Sadly, not all efforts to use this technology have a similar conclusion. After thousands of gene therapy attempts, many have failed to correct the disease being treated, some have caused other diseases, and tragically, some have resulted in patient deaths.

Gene therapy is a method of correcting a genetic disease in an individual without the traditional use of medication and surgery. According to the U.S. Food and Drug Administration, human gene therapy is the replacement of a person’s faulty genetic material with normal genetic material to treat or cure a disease or abnormal medical condition.¹ The terms gene transfer and genetic modification are also used to describe gene therapy.

Currently, there are two types of gene therapy: germline and somatic. Somatic gene therapy allows scientists to insert a vector (an agent that contains a modified gene) into a person’s body to correct a genetic abnormality. This type of therapy only changes the genetic composition of the person being treated – it has no affect on his or her future offspring because it only alters non-reproductive (somatic) cells. Somatic gene therapy usually targets one type of tissue within the body (blood cells, brain cells, etc.). For example, Ashanti had genetically altered white blood cells introduced into her body. Currently, somatic cell gene therapy has been done on a larger scale than germline gene therapy because there are less ethical and social concerns associated with it.

Somatic gene therapy can be performed in two ways: ex vivo (out of the body) and in vivo (in the body). Ex vivo somatic gene therapy, the first to be practiced, genetically alters the cells outside the patient’s body and then reintroduces them into the body. In vivo somatic gene therapy targets cells within the body to be genetically altered. It necessitates that the vectors are able to deliver the genes to the correct area of the body, deliver enough altered genetic material to the cells to ensure effectiveness, and remain otherwise undetected by the body’s immune system.

Germline gene therapy, also called inheritable genetic modification, alters the reproductive cells of a person’s body. Unlike somatic gene therapy, germline therapy corrects genetic defects in the person being treated, as well as in their future children. Although there is the potential to completely eliminate a genetic disease in a family using germline gene therapy, there is considerable apprehension about the use of this type of therapy. These concerns will be addressed later under ethical issues.

History of Gene Therapy

In the last couple decades there have been tremendous strides in the area of gene therapy. This timeline provides some highlights.

First unapproved/unauthorized attempt at gene therapy – In 1980, Dr. Martin Cline conducted a rDNA transfer into the bone marrow cells of two patients with hereditary blood disorders. . He did so in direct opposition to National Institute of Health gene therapy guidelines and without the approval of the Institutional Review Board at the University of California Los Angeles (UCLA), where his research was conducted. The ethical concerns that were generated prompted a call for review by a number of organizations – including the National Council of Churches, Synagogue Council of America, and the United States Catholic Conference. Consequently, Dr. Cline was forced to resign his department chairmanship at UCLA and lost several research grants.

First disease approved for gene therapy treatment – In 1990, adenosine deaminase (ADA) deficiency was the first disease approved for gene therapy treatment by the federal government. Lacking the ADA enzyme, patients with this disorder have a severely weakened immune system. Using traditional medicine, it can be treated with an expensive drug called PEG-ADA (costing more than $60,000 a year) that requires regular injections throughout the patient’s life. ADA deficiency was chosen for gene therapy because it is a single gene deficiency, regulated in a simple manner, and (compared to many other genetic disorders) involves a relatively simple experiment.

First human somatic gene therapy – On September 14, 1990, the first human gene therapy experiment was conducted on four year-old Ashanti Desilva who suffered from ADA deficiency. Dr. W. French Anderson performed the experimental therapy by infusing white blood cells (with the correct genetic composition) into Ashanti to correct her immunodeficiency. While the therapy did not yield a complete cure, it did help correct the deficiency so that Ashanti only takes small, weekly doses of the traditional PEG-ADA drug.

First gene therapy death – In September 1999, 18 year-old Jesse Gelsinger was the first reported death to be directly caused by gene therapy treatment. Jesse suffered from OTC disease (ornithine transcarboxylase deficiency), a liver disorder that results in poisonous levels of ammonia build-up in the body. His disorder was being controlled through diet and medication. Although he was healthy and full of life, he chose to participate in the gene therapy study because of his desire to help others with same disease. Four days after starting treatment, he died of multiple organ failure. His death is thought to be a result of a severe immune response to the adenovirus carrier (the vector used to carry the altered genes to his liver).

First germline gene transfer – As of 2001, there were 30 children born as a result of ooplasmic transfer. Ooplasmic transfer (also referred to as ooplasmic or cytoplasmic transplantation) can be performed on women who cannot conceive because of defects in their ooplasm – their eggs’ cytoplasm. The procedure is performed by inserting healthy ooplasm from donor eggs into the eggs with defective ooplasm. By inserting healthy ooplasm from the donor eggs into the mother’s defective eggs, a small amount of mitochondrial DNA is transferred into the egg. Unlike the majority of our DNA which is contained in the nucleus of the cell, mitochondrial DNA is contained in another cellular structure, the mitochondria. Since babies born as a result of this ooplasmic transfer have DNA from their mother, father, and the ooplasm donor (in the form of mitochondrial DNA), they are considered to have three genetic parents. This is considered germline gene transfer because the DNA of these children, and of their offspring, will always contain genetic material from three parents.

First complete gene therapy cures – In 2000, French doctors successfully used gene therapy to treat 10 children with X-linked severe combined immunodeficiency disease (X-SCID), sometimes known as ‘Bubble Boy’ syndrome. This unprecedented result differed from previous gene therapy treatments (like Ashanti Desilva’s) in that it completely cured the children of the disease without requiring additional and/or supplemental medication. Unfortunately, two of the 10 cured children developed leukemia after the treatment.



Measures taken by the government in response to concerns over gene therapy:

• After Jesse’s tragic death in 1999, the FDA began an investigation into gene therapy and the Pennsylvania State University researchers responsible for Jesse’s treatment halted all further experiments.

• Another repercussion of Jesse’s death was the FDA’s termination of Dr. Jeffrey Isnar’s research work on gene therapy. His experimentation was stopped because alleged conflicts of interest as well as the death of two of his gene therapy patients. These two deaths, unlike that of Jesse’s, are said to be unrelated to the gene therapy treatment received.

• In July 2001, the researchers who performed ooplasmic transfer on thirty women received a letter from the FDA explaining that human ooplasm transfer would require the submission of an investigational new drug (IND) application, since the product would be a “genetically manipulated cell.”

• In January 2003, the FDA placed a temporary halt on all gene therapy trials using retroviral vectors in blood stem cells after learning that two children in France had developed leukemia following their successful gene therapy treatment of X-SCID.

Dawn Vargo is a research assistant in the Public Policy Division of Focus on the Family.

If you enjoy reading stories like this one, sign up for the free CitizenLink Daily Update e-mail. You'll get news and commentary from Focus on the Family Action delivered right to your computer.