While issues surrounding sterility, mutagenicity, stability and carcinogenicity, and the attendant GLP and GMP issues, are much the same for gene and orthodox therapies in principle, there is often greater complexity associated with the former. These complexities include a triple effort on preclinical toxicology and the potential for germ cell line incorporation.
First, the toxicology of any gene therapy needs to be considered as a combination of three products: the construct; non-genetic elements in the construct (e.g. pharmaceutical adjuvant stabilizing materials); and the vector.
Second, there is a need to test in animals the possibility of incorporation of the therapeutic gene into the germ cell line. Many constructs contain multiple genes: not only is the therapeutic gene present, but also genes to assist in manufacturing, e.g. those conferring antibiotic resistance to the microorganism that is being used for production, or a gene for a marker enzyme. All of these genes require toxicological assurance that they do not incorporate into the germ cell line, and thus will not be replicated in the offspring of the treated patient. This is a special field of toxicology that is in its infancy; in some cases clinical trials have to be restricted to surgically sterile patients in the absence of this information.
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