ABSTRACT
The study of human disease can be improved by the introduction of disease-linked mutations into hES cells followed by in vitro differentiation and subsequent analysis of the affected cell type. The majority of disease models studied using transgenic mouse ES cells have involved the production of transgenic mice (e.g. see 12) an approach neither possible nor desirable in humans. However in vitro mouse disease models have been employed to explore both the phenotype of genetic diseases (e.g. see 13) and potential therapies (e.g. see 14). Moreover, it may be possible to alleviate genetic disease by targeted correction of disease genes. Controversially, therapeutic cloning could provide blastocysts genetically identical to the patient from which hES cells could be derived. Genetic modification of the disease allele would allow the corrected hES cells to be differentiated to a normal version of the affected cell type for transplant. Proof of principle has been achieved in an experimental system where a healthy immune system was restored to immune-deficient Rag2 mutant mice (15). However, in the face of the ethical and practical problems associated with therapeutic cloning and subsequent gene correction in humans, it seems likely that a transplant derived from normal, but allogeneic, hES cells will be less problematic.
