The use of foetal human brain tissue as brain implants: phenotype manipulation by genetic manipulation and biochemical induction.

The use of dopaminergic mesencephalic (VM) human foetal brain tissue as implants to neurosurgically treat Parkinson's disease has been in progress since the 1980's. A major limitation in the use of VM tissue is the amount of tissue available from each human embryo. Usually tissue from about 7 embryos is required to treat each patient unilaterally. To overcome this we have developed various strategies. One is to convert embryonic cerebral cortex in human embryos into dopaminergic tissue which is stable, and which will secrete dopamine in vivo once implanted. The cerebral cortex is about 500 times larger than the VM and can therefore provide a lot more tissue for transplantation. This can be achieved by genetic manipulation of the embryonic cerebral cortex tissue, involving the lipo-transfection of multiple copies of the human tyrosine hydroxylase gene into both neurones and glial cells. In another approach we have biochemically manipulated the development of the cerebral cortex to direct the neurotransmitter phenotype towards the dopaminergic type, and away from other phenotypes. This tissue, too, is stable and will synthesise and secrete dopamine when transplanted. Our third approach has been to manipulate pluripotential neural cells which are yet to develop into neurones and glial cells. These cells can be expanded in number many-fold before treatment to direct their development into stable dopaminergic neurones in large numbers (70%), which synthesise and release dopamine. When used as transplants in animal models of Parkinson's disease, these various types of artificially induced dopaminergic tissue are very effective at reducing the Parkinsonian syndrome.