Gene therapy trial

Retrovirus- and lentivims-detived vectors are used in approximately one quarter of all gene-therapy trials (Table 1). The gene-therapy trial in patients suffering... 

Presently, 1,260 gene-therapy trials are underway worldwide (Tables 1 and 2). For details see http // www.wiley.co.uk/genetherapy/clinical/. Almost three fourths of all trials are based on viral vectors. The vast majority of nonviral gene-therapy trials use naked/ plasmid DNA (18% of all gene-therapy trials). 

At the present time, almost two thirds of all gene-therapy trials target immunological and oncological diseases (Table 2). 

Gene-therapy Vectors. Table 2 List of most common therapeutic genes used in gene-therapy trials (viral and non viral vectors)... 

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],... 

Figure 14.2 Vectors used thus far in gene therapy trials. Others are mainly viral-based and include the use of pox, vaccinia and adeno-associated viruses, as well as herpes simplex virus. Data adapted from www.wiley. co.uk/genemed/clinical...

As potential vectors for gene therapy, adenoviruses display a number of both advantages and disadvantages (Table 14.3), and they have been used in over 300 gene therapy trials to date. Their major advantage relates to their ability to infect non-dividing cells efficiently and the usually... 

To date, the majority of gene therapy trials undertaken aim to cure not inherited genetic defects, but cancer. The average annual incidence of cancer reported in the USA alone stands at approximately 1.4 million cases. Survival rates attained by pursuit of conventional therapeutic strategies (surgery, chemo/radiotherapy) stand at about 50 per cent. 

Table 14.6 Some specific cancer types for which human gene therapy trials have been initiated3...

Stephenson, J. (2001). Studies Illuminate Cause of Total Reaction in Gene-Therapy Trial. JAMA 285 2570-2571. 

A number of experimental in vivo gene therapy trials on animals using PAMAM dendrimers are in their preliminary stages. Numerous in vivo experiments are currently being conducted in order to optimize the dendrimer generation, concentration, and complex charge ratio to obtain optimal transfection efficiency. 

You can also search for clinical trials online. QmicalTrials.gov, a service of the National Institutes of Health, provides easy access to information on clinical trials. You can search for specific trials or browse by condition or trial sponsor. You may wish to refer to a list of gene therapy trials that are accepting (or will accept) patients. 

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. 

These are the successes there are many failures as well. More than 400 gene therapy clinical trials have been conducted, mainly on cancer, but not many cases worked. In 1999, an 18-year-old boy in Pennsylvania unexpectedly died from a reaction to gene therapy when he was treated for a metabolic disease. This trial raised many issues, and many trials with discrepancies and unreported adverse events were suspended by the FDA. The FDA has since introduced tighter controls for gene therapy trials. 

Mandavilli A. Gene-therapy trials for hemophiha make comeback, BioMedNet, October 1,2002. http //news.bmn.com/news/story day=021001 story=l [accessed November 27, 2002]. 

Exhibit 11.6 describes a recent gene therapy trial that resulted in unexpected outcomes, which the regulatory authorities have to consider. A recent report of gene therapy for treatment of Alzheimer s disease is also included. 

Gene therapy offers another potential avenue to fix the defective gene. The therapy itself is by no means straightforward. In a French gene therapy trial, three boys with SCID were treated using retrovirus-based gene therapy. They later developed cancer and one died of leukemia. Reviews showed that the retrovirus inserted near oncogenes and promoted development of cancer. 

Adenosine deaminase (ADA) deficiency, an autosomal recessive disorder, produces severe combined immunodeficiency (SCID). Lacking both B-cell and T-cell function, children are multiply infected with many organisms Pneumocystis carinii, Candida) and do not survive without treatment. Enzyme replacement therapy and bone marrow transplantation may be used. Experimental gene therapy trials have not yet yielded completely successfiil cures. 

Gene therapy trials and xenogenic cell therapy. 

Two types of DNA viruses have also been used in human gene therapy trials. Adenoviruses, double-stranded DNA viruses, can efficiently carry a larger gene into cells even if they are not dividing, but the genetic information does not become inserted into the cell s genetic material and the information may rapidly be lost. Adeno-associated virus vectors, made from small single-stranded... 

What would you want to know before you took part in a gene therapy trial ... 

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