Parkinson's disease and transplants

Published on October 1, 2007 Updated on December 2, 2020   61 min

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In this talk, I'm going to discuss Parkinson's disease, possible repair of the brain in this condition, during neural transplant. In particular, I'm going to discuss which types of cells are best considered as a reparative therapy, where they should be transplanted in the Parkinsonian brain, and in whom. However, before discussing these issues, it is important to remind ourselves about Parkinson's disease.
Parkinson's disease is classically thought of as a disorder of the basal ganglia, which is fundamentally characterized by the loss of dopamine in the nigrostriatal pathway and the formation of Alpha-synuclein Lewy bodies within the substantia nigra. This loss of dopaminergic tone within the network leads to the classical motor triad of arresting pill roll tremor, bradykinesia or slowness of movement, and rigidity.
Knowing that this was the core pathological event in Parkinson's disease, leads to the obvious therapeutic manipulation of replacing it through drug therapies. In the late 1950s, it was discovered that this was the major pathological deficit in Parkinson's disease, which led to the use of levodopa in the 1960s. This therapy continues to be the mainstay of treatment, and is converted and works by being converted into dopamine in the Parkinsonian brain. Alternative strategies using drugs have also being pursued, including the use of selective dopamine receptor agonist, as well as anticholinergic drugs. Indeed, in the more advanced stages of disease, there are a number of other manipulations that can be done to enhance the efficacy of these drugs, including the use of various COMT and monoamine oxidase inhibitors, as well as amantadine, which can deal with the drug-induced dyskinesias. Indeed, drug-induced dyskinesias are one of the major complications of drug therapy, with about 10 percent of patients per treatment year developing this phenomenon. This involves involuntary dyskinetic movements, typically at the peak dose of levodopa when the patients have taken their drugs. As a result of this, alternative strategies are being pursued to help patients as they move towards the more advanced stages of disease. This is including the continuous stimulation of dopamine receptors using apomorphine infusions, as well as various neurosurgical interventions. Initially, this took the form of lesioning either of the internal part of the globus pallidus or the subthalamic nucleus. But of late has been superseded by the use of deep brain stimulation bilaterally to the subthalamic nucleus. Whilst all of these therapies are effective symptomatically, none of them are curative, as a result of which, other approaches have been taken, which are designed to actually repair the Parkinsonian brain. Of late great interest has been shown in the use of GDNF infusions. This factor, glial cell line-derived neurotrophic factor, is a growth factor for dopaminergic cells. In a pilot study done by Steven Gill and colleagues down in Bristol, it was shown that the direct intraputaminal, so directly into the basal ganglion, infusion this growth factor produced a clinical improvement in five patients, which correlated with an increase in dopamine on fluorodopa PET scanning. Indeed, one of these patients who subsequently died from unrelated causes, was found at post-mortem to have sprouting of dopaminergic fibers around the site of GDNF infusion. Whilst this therapy looks extremely effective, a recent double-blind placebo-controlled trial sponsored by the company that make GDNF, namely Amgen, has produced less significant results. There have also been a number of reports of side effects and pathological complications in experimental animals, which is lead currently to this factor not being used widely in Parkinson's disease. As a result of which other approaches have been used adopting a similar strategy, but in this case, linking the growth factor to viral vectors. It is yet to be seen whether this approach prove to be successful without side effects. The final approach to treating the Parkinsonian brain is that which involves replacing the cells through cell transplantation and it is this that will form the mainstay of my talk. In particular, I'm going to start by discussing what has been achieved with this approach to date experimentally and then clinically. If we are to use cell therapists to repair the Parkinsonian brain,