Cell and gene therapy
Tuesday, June 21, 2005, 09:30 - 10:00
Cell therapy in Parkinson's disease
O. Lindvall (Lund, S)
to be presented at ENS next week..
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Parkinson’s disease (PD) is characterized by tremor, rigidity, and hypokinesia. Levodopa teatment is effective in the initial phase, but within 5 to 10 years, most patients develop fluctuating therapeutic responses and involuntary movements (dyskinesias). The main pathology underlying disease symptoms is a rather selective loss of dopamine (DA)-producing neurons in the substantia nigra leading to severe DA depletion in striatum. Implantation of DA-producing cells in denervated striatum seems to be a rational restorative approach to treat PD. The clinical trials in PD patients using intrastriatal transplantation of human fetal mesencephalic tissue, rich in post-mitotic DA neurons, have provided proof-of-principle that neuronal replacement can work in the human brain. However, it is unlikely that transplantation of human fetal mesencephalic tissue will become routine treatment for PD due to problems with tissue availability and too much variation in functional outcome.
For the development of an effective cell replacement therapy for PD, the work should now be focused on four major scientific issues:
(i) Generation of large numbers of DA neurons from stem cells. Stem cells could be useful as an unlimited source of specific neuron types, e.g., DA neurons. Hypothetically, DA neurons could be generated from stem cells of four different sources: embryonic stem cells from the fertilized egg, neural stem cells from the embryonic/fetal or adult brain, or from stem cells in other tissues. So far, neurons with characteristics of DA neurons have been generated from embryonic stem cells and from stem cells taken from the embryonic/fetal brain. However, the survival of these neurons after grafting has in many cases been poor and it is also unclear if they function as normal nigral DA neurons.
(ii) Improved patient selection. It is important to emphasize that just the availability of virtually unlimited numbers of DA neurons will not mean that we have a clinically competitive treatment for PD. We must define better criteria for patient selection with respect to stage and type of disease, and we must know the preoperative degeneration pattern so that we can define what should be repaired. Dopaminergic cell therapy will most likely be successful only in those patients who exhibit marked benefit in response to DA agonists, and in whom the main pathology is a rather selective degeneration of DA neurons. Debilitating symptoms in PD and related disorders are also caused by pathological changes in non-dopaminergic systems.
(iii) Improved functional efficacy of grafts. The transplantation procedure needs to be tailor-made with respect to the dose and location of grafted cells based on preoperative imaging so that the repair of the DA system will be as complete as possible in each patient’s brain. It seems unlikely that DA neurons, predifferentiated from stem cells in vitro, will be able to induce a more pronounced improvement as compared to primary DA neurons in fetal grafts. Two major advantages with stem cells are, first, that the DA cells derived from stem cells can be standardized and generated in large numbers and, secondly, that they allow for controlled genetic modification which, hypothetically, could be used to increase, e.g., survival, migration, and function of their progeny. For a more complete reversal of PD symptoms, it may be necessary to develop tools to stimulate regrowth of axons from DA neuron grafts in the substantia nigra to the striatum, which probably will require modulation of host growth inhibitory mechanisms. It is currently unknown if immunosuppressive treatment would be needed in a clinical setting when the stem cells are of human origin.
(iv) Strategies to avoid adverse effects. New animal models are needed to reveal the pathophysiological mechanisms of graft-induced dyskinesias. The risk for teratoma from embryonic stem cells, and consequences of the introduction of new genes in stem cell-derived neurons should also be carefully evaluated.
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