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At present, there are still no approved cell therapies for any brain disorders in any country. There are, however, several therapies in ongoing clinical trials, for example for multiple sclerosis, motor neuron disease, stroke, and other conditions. Interesting to speculate, therefore, which disorder will be the first to have a licensed cell therapy—assuming any succeed at all.
Predicting such outcomes is unwise, but there would be a certain symmetry if the first success were to be in Parkinson’s Disease, since in an important sense, cell therapy in the brain began with Parkinson’s Disease.
By cell therapy, we mean the treatment of disease or disability by the injection into the patient of a preparation of cells. Neuroscientists now know that cells can have multiple therapeutic effects in the damaged brain, but in the early days, the focus was almost entirely on cell replacement. Most neurodegenerative disease is the result of cell loss. Sometimes it is fast, as in ischaemic stroke, where a blocked blood vessel suddenly robs a whole area of brain tissue of its blood supply. Sometimes it is slow, as with Alzheimer’s disease, where for reasons still unclear, individual cells are gradually lost over a period of years. In each case, it has been proposed that if the lost cells could be replaced, then perhaps function could be recovered.
The reason Parkinson’s looked a good bet was that the most troubling pathology for patients—the loss of control of movement—seems to be associated with the loss of a specific population of nerve cells, the dopamine cells of the midbrain. So, if this specific population of cells could be replaced, perhaps patients could regain the lost function. And indeed, this is what happens in experimental animals. When these dopamine cells are killed experimentally in rats, the animals acquire a movement disorder. This can be rectified in part by the injection of replacement cells.
Where do the researchers get the replacement cells from? They are the baby versions of those dopamine cells, taken from a rat embryo. These young nerve cells are injected into the lesioned rat, and sure enough, they replace the cells the rat has lost, and the animal’s parkinsonian behaviour recovers.
Could this work in human patients? During the 1980s this was tried extensively, and while it (sort of) worked, there were problems. The equivalent cells could only come from aborted human fetuses, and needless to say, some people would never be comfortable with that. But beyond the ethical concerns lay serious clinical and logistical issues. Getting a consistent cell preparation from aborted human fetal remains was almost impossible. Unsurprisingly, when proper controlled clinical trials were finally staged, the results were inconsistent: some patients seemed to prosper, but for others, the condition seemed worse.
So, where has the current optimism come from? Simply, we now have much better cells, namely pluripotent cells. ‘Pluripotency’ represents a key concept in stem cell biology. It means the potential to make everything. A pluripotent cell can generate every cell type in the body. A full description of what these cells are and where they come from will have to wait for another blog post, but suffice it to say, by the turn of the millennium, scientists had discovered how to generate them from human embryos, and within a decade of that discovery, they had worked out to make them from scratch, starting from essentially any cell in the body.
This has been a game-changer for Parkinson’s Disease therapy and much else. Since the pluripotent cells could make anything, this included dopamine nerve cells. Armed with the experience already gained, a method for making human baby dopamine cells has emerged quite quickly, and these artificially generated human nerve cells are now close to clinical trials in Japan, the U.S., and Europe.
The clinical trials may succeed or fail, but the cell product now compared with the 1980s is vastly improved. Let’s consider just one example of this. The 1980s cells were simply dissected from an aborted fetus, dissociated, pooled, and injected into the patient’s brain. In that cell soup were dopamine cells, but also cells from neighbouring bits of brain, blood cells, meninges, plus anything else that happened to get scooped up in the messy dissection. One complication would be that some immune cells were likely to be included, exacerbating the problem of immune rejection that always follows when cells from one individual (the fetus) are injected into another (the patient). Similarly, if some of the wrong type of nerve cells were included in the mix, they could exacerbate the movement disorder.
In the interim, biologists have worked out precisely the genetic pathway that generates this specific type of dopamine cell from fetal brain. This means we now understand what genes to turn on, and in what sequence, in order to generate midbrain dopamine nerve cells starting from a pluripotent cell. Finally, we can start to think of the generation of these cells as a defined manufacturing process, one that could be repeated precisely and accurately. Now, proper controlled studies become a real possibility. We can ask, how many cells are optimum, where precisely should they go, and how many injections per treatment?
Stem cell therapy has fallen flat on its face more than once, and it may do so again. But there is a real hope that progress with Parkinson’s Disease is now a possibility.
