Gene Therapy Clinical Trial

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],... 

Gene-therapy Vectors. Table 1 Gene therapy - clinical trials... 

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). 

Pharmacogenomic studies are often carried out in the context of clinical trials which, by virtue of having both a treatment and placebo group, are able to assess the association between a gene and disease progression independent of therapy as well as interactive effects of genotypes and therapy on disease. Several of the phar-... 

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...

Some 24 per cent of all gene therapy clinical trials undertaken to date have employed retroviral vectors as gene delivery systems. Retroviruses are enveloped viruses. Their genome consists of ssRNA of approximately 5-8 kb. Upon entry into sensitive cells, the viral RNA is reverse transcribed and eventually yields double-stranded DNA. This subsequently integrates into the host cell genome (Box 14.1). The basic retroviral genome contains a minimum of three structural genes ... 

The theoretical complications posed by random chromosomal integration became a medical reality in 2002, when two children who had received retroviral-based gene therapy 2 years previously developed a leukaemic-like condition. The initial clinical trial aimed to treat X-linked severe combined immunodeficiency (SCID-X1), a hereditary disorder in which T-lymphocytes and NK cells in particular do not develop, due to a mutation in the gene coding for the yc cytokine receptor subunit. The clinical consequence is near abolition of a functional immune system. 

The trial entailed retroviral-mediated ex vivo transduction of haematopoietic stem cells from 10 young SCID-X1 sufferers, with subsequent re-infusion of the treated cells. A marked and prolonged clinical response in which the condition was essentially reversed was observed in 9 out of the 10 patients. The prolonged response was likely due to the transduction of pluripotent progenitor cells with self-renewal capacity (Chapter 10). However, the two youngest patients (1 and 3 months old at the time of treatment) developed uncontrolled proliferation of mature T-lymphocytes 30 months and 34 months after gene therapy respectively. 

Edelstein, M.L., Abedi, M.R., Wixon, 1, and Edelstein, R.M. 2004. Gene therapy clinical trials worldwide 1989-2004 - an overview. Journal of Gene Medicine 6(6), 597-602. 

Palmer, D.H., Young, L.S., and Mautner, V. 2006. Cancer gene therapy clinical trials. Trends in Biotechnology 24(2), 76-82. 

In models of MND, therapeutic manipulations, manipulation of expression of selected genes in specific cell populations [15, 16], creation of chimeric animals to test whether abnormalities are cell autonomous [17], administration of trophic factors to prevent trophic cell death [18-20] and testing of a variety of drug therapies [21-24] have been used to try to ameliorate phenotypes and thus provide insights into disease mechanisms and potential treatment strategies [1, 3, 4, 15, 25, 26]. Results of these studies are being used to design novel therapies to be tested in clinical trials in humans. 

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