Gene therapy first trial

Human gene transfer experiments in lymphocyte marking studies began in 1989. These early studies showed that gene transfer was feasible and could be well tolerated although there was no demonstrable therapeutic benefit. The first human gene therapy clinical trial was in 1990, in a patient with adenosine deaminase (ADA) deficiency initial responsiveness proved not to be uniform when the series of cases was extended, possibly due to the fact that the disease phenotype could be elicited by a variety of genotypes. 

Because of the potential to revolutionize treatment of a broad range of human diseases, including some of mankind s most-hated and currently intractable afflictions, gene therapy has been heavily investigated over the past decade. More than 17,000 papers containing the keywords gene therapy have appeared in the MEDLINE database since 1990. The first gene therapy clinical trial, for... 

First gene therapy clinical trial for heart failure. Molecular Therapy, 16, 1353-1353. 

The results of the first gene therapy clinical trial were published in 1995. This trial involved the ex vivo retroviral treatment of T-cells from patients suffering from adenosine deaminase deficiency with severe combined immuno-deficiency (ADA-SCID). Two patients with ADA-SCID were chosen who had not fully responded to conventional treatment (PEG-ADA)... 

First clinical human gene therapy trials with polyplexes were performed using cancer vaccines based on autologous patient tumor cells. These were modified ex vivo with interleukin-2 pDNA. To obtain high level transfection rates of patient s primary tumor cells, Tf-PLL/pDNA polyplexes linked with inactivated endosomolytic adenovirus particles were applied [221]. Polymer-based in vivo human gene transfer studies were performed with PEGylated PLL polyplexes, delivering CFTR pDNA to the airway epithelium of cystic fibrosis patients [222],... 

Comprehensive federal laws, regulations, and guidelines help protect people who participate in research studies (called clinical trials). The U.S. Food and Drug Administration (FDA) regulates all gene therapy products in the United States and oversees research in this area. Researchers who wish to test an approach in a clinical trial must first obtain permission from the FDA. The FDA has the authority to reject or suspend clinical trials that are suspected of being unsafe for participants. 

The first gene therapy trial was conducted in September 1990. A 4-year-old girl with SCID (an inherited immune disorder disease, otherwise known as the bubble boy syndrome) was treated in Cleveland, Ohio. She is doing well some 10 years after the treatment. A second girl with the same disorder underwent gene therapy and she too continues to do well. 

Muul, L. M L. M. Tuschong, S. L. Soenen, G. J. Jagadeesh, et al. Persistence and Expression of the Adenosine Deaminase Gene for 12 years and Immune Reaction to Gene Transfer Components Long-term Results of the First Clinical Gene Therapy Trial. Blood 101 no. 7 (2003) 2563-2569. 

A. OTC is a metabolic enzyme required to break down ammonia. Total lack of this enzyme leads to death shortly after birth owing to a buildup of ammonia. The partial presence of OTC also leads to accumulation of ammonia, which can be controlled by drugs and dietary intake. The genetic cause of this disease, its morbidity, and the need for rapid production of OTC by adenoviral vectors may extend the life span of OTC-deficient newborns to allow for drug treatment and dietary manipulation. Jesse Gelsinger, the 18-year-old patient who was the first patient to die on a phase I gene therapy trial, had OTC deficiency. 

Their proposal won FDA approval, the first gene therapy trial everto inject AAV. In June 1999 the clinical team injected the first patient with genetically altered AAV. The procedure was uneventful. Two more patients followed. As the team reported in the March 2000 issue of Nature Genetics, at the suboptimal dose used in the study, meant only to detect manifest safety problems, the first three patients showed no untoward effects and no detectable antibodies [6]. Within 12 weeks after the injec-(Continued on next page)... 

Clinical trials, also known as clinical studies, test potential treatments in human volunteers to see whether they should be approved for wider use in the general population. A treatment could be a drug, medical device, or biologic, such as a vaccine, blood product, or gene therapy. Potential treatments, however, must be studied in laboratory animals first to determine potential toxicity before they can be tried in people. Treatments having acceptable safety profiles and showing the most promise are then moved into clinical trials. 

Retrovirus vectors were subjected to the first clinical trial on human gene therapy to correct adenosine deaminase (ADA) deficiency (32). White-blood cells isolated from patients were infected ex vivo with an MLV-based vector expressing ADA and a neomycin marker gene. After selection with G418, neomycin-resistant cells were isolated and reintroduced into patients. The treatment improved the physical condition of the patients and the ADA-containing provirus was stable in the blood for several years. 

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