On September 14, 1990, the first approved gene therapy procedure was performed on four-year old patient. Born with a rare genetic disease called (SCID), she lacked a healthy immune system, and was vulnerable to every passing germ or infection. Children with this illness usually develop overwhelming infections and rarely survive to adulthood; a common childhood illness is life-threatening. She led a cloistered existence; avoiding contact with people outside her family, remaining in the sterile environment of her home, and battling frequent illnesses with massive amounts of antibiotics.

In her gene therapy procedure, doctors removed white blood cells from the child's body, let the cells grow in the lab, inserted the missing gene into the cells, and then infused the genetically modified blood cells back into the patient's bloodstream. Laboratory tests have shown that the therapy strengthened her immune system by 40%; she no longer has recurrent colds, she has been allowed to attend school, and she was immunized against whooping cough. This procedure was not a cure; the white blood cells treated genetically only work for a few months, after which, the process must be repeated. As of early 2007, she was still in good health, and she was attending college.

The reasons for selecting this disease for the first approved human clinical gene therapy trial is that the disease is caused by a defect in a single gene, which increases the likelihood that gene therapy will succeed. In addition, the gene is regulated in a simple, “always-on” fashion, unlike many genes whose regulation is complex, and the amount of ADA present does not need to be precisely regulated. Even small amounts of the enzyme are known to be beneficial, while larger amounts are also tolerated well.

Although this simplified explanation of a gene therapy procedure sounds like a happy ending, it is little more than an optimistic first chapter in a long story; the road to the first approved gene therapy procedure was rocky and fraught with controversy. Gene therapy actually started around 1984 when Gluzman, Carter & Muzyczka developed a gene delivery system derived from adenoviruses and adeno-associated viruses. Soon it became clear that the biology of human gene therapy is very complex, and there are many techniques that still need to be developed and diseases that need to be understood more fully before gene therapy can be used appropriately. A major drawback came in 1999 with the first gene therapy death.

In 2001, the 500th gene therapy clinical trial was submitted to the FDA/NIH for approval. Whereas in 2003, the first commercial gene therapy medicine (Gendicine ) was available on the market in China (China approves first gene therapy and Controversial Chinese gene-therapy drug entering unfamiliar territory ). Gendicine is produced by SiBiono GeneTech Co., Ltd. and is registered for the treatment of head and neck cancers.

Gene Therapy was initially meant to introduce genes straight into human cells, focusing on diseases caused by single-gene defects, such as cystic fibrosis, hemophilia, muscular dystrophy and sickle cell anemia (see also Wiley database on indications addressed by gene therapy clinical trials). Three types of diseases for gene therapy can be distinguished:

• Monogenic disorders,  single locus (gene) is defective and responsible for the disease, 100% heritable. Examples: Sickle cell anemia, Severe Combined Immunodeficiency (ADA-SCID / X-SCID), Cystic fibrosis, Hemophilia, Duchenne muscular dystrophy, Huntington’s  disease,  Parkinson’s, Hypercholesterolemia, Alpha-1 antitrypsin, Chronic granulomatous disease, Fanconi Anemia and Gaucher Disease.
• Polygenic disorders, multiple genes involved, disease may be dependent on environmental factors and lifestyle. Examples: Heart disease, Cancer, Diabetes, Schizophrenia and Alzheimer’s disease.
• Infectious diseases, such as HIV.

Among the most notable advancements in gene therapy are the following. See also Major developments in gene therapy.

Severe Combined Immune Deficiency (ADA-SCID)
ADA-SCID is also known as the bubble boy disease. Affected children are born without an effective immune system and will succumb to infections outside of the bubble without bone marrow transplantation from matched donors. A landmark study representing a first case of gene therapy "cure," or at least a long-term correction, for patients with deadly genetic disorder was conducted by investigators in Italy. The therapeutic gene called ADA was introduced into the bone marrow cells of such patients in the laboratory, followed by transplantation of the genetically corrected cells back to the same patients. The immune system was reconstituted in all six treated patients without noticeable side effects, who now live normal lives with their families without the need for further treatment. (see also Description of ADA deficiency, in Online Mendelian Inheritance in Man, ADA: The First Gene Therapy Trial, from the National Institutes of Health and SCID.net)

Chronic Granulomatus Disorder (CGD)
CGD is a genetic disease in the immune system that leads to the patients' inability to fight off bacterial and fungal infections that can be fatal. Using similar technologies as in the ADA-SCID trial, investigators in Germany treated two patients with this disease, whose reconstituted immune systems have since been able to provide them with full protection against microbial infections for at least two years.

Hemophilia
Patients born with Hemophilia are not able to induce blood clots and suffer from external and internal bleeding that can be life threatening. In a clinical trial conducted in the United States, the therapeutic gene was introduced into the liver of patients, who then acquired the ability to have normal blood clotting time. The therapeutic effect however, was transient because the genetically corrected liver cells were recognized as foreign and rejected by the healthy immune system in the patients. This is the same problem faced by patients after organ transplantation, and curative outcome by gene therapy might be achievable with immune-suppression or alternative gene delivery strategies currently being tested in preclinical animal models of this disease.

Cancer
Multiple gene therapy strategies have been developed to treat a wide variety of cancers, including suicide gene therapy, oncolytic virotherapy, anti-angiogenesis and therapeutic gene vaccines. Two-thirds of all gene therapy trials are for cancer and many of these are entering the advanced stage, including a Phase III trial of Ad.p53 for head and neck cancer and two different Phase III gene vaccine trials for prostate cancer and pancreas cancer. Additionally, numerous Phase I and Phase II clinical trials for cancers in the brain, skin, liver, colon, breast and kidney among others, are being conducted in academic medical centers and biotechnology companies, using novel technologies and therapeutics developed on-site.