There has not been a new effective therapy for any neurodegenerative disease in decades. Recent trials of drugs for Alzheimer’s disease have been disappointments. Because of these very expensive failures, many of the big pharmaceutical companies have moved away from targeting brain diseases to more profitable areas like cancer. So is there any good news on the horizon for the millions who are suffering and will suffer from these devastating brain disorders?
This year there was news that a cancer drug showed remarkable benefits for patients with Parkinson’s disease. It was only one, nonrandomized, nonblinded, non–placebo-controlled study that looked at only a few patients. So it’s very early to know whether it really works. But it’s news to follow, and it’s big for three reasons.
First, unlike any other treatment, the drug appears to work close to the root cause of Parkinson’s disease. Parkinson’s is one of the few neurodegenerative disorders for which there is any effective treatment. In Parkinson’s, the neurons that supply the brain with the neurotransmitter, dopamine, degenerate. The mainstay of treatment for the disease has been to replace that missing dopamine with a pill that provides a chemical that is converted in the brain into dopamine. This "dopamine replacement therapy" treats the symptoms of Parkinson’s—the tremors, the stiffness, and the slowness of movements—but not its root cause. So the death of the dopamine-containing neurons continues unabated, and the pills only work well for around seven years.
The new drug, called nilotinib, was developed for leukemia and has the same action as the better known chemotherapeutic agent, Gleevec. But unlike other similar drugs, nilotinib gets across the blood-brain barrier, which prevents most drugs from working well in the brain. Although the cause of the neuronal degeneration of Parkinson’s is still not known, it is thought to involve the accumulation and misfolding of proteins inside the dying neurons, a process like the curdling of the proteins in milk. Nilotinib was predicted to suppress the accumulation of misfolded proteins inside neurons. After taking nilotinib, the patients not only did better clinically, but the amount of the misfolding proteins released into the patients’ cerebral spinal fluid went down—a sign that it was working on the degenerative process, itself.
Second, the target that nilotinib inhibits is a new one for a brain disease. Like Gleevec, nilotinib inhibits an enzyme inside the cell called a protein kinase. There are around 500 different kinds of protein kinases in cells, and nilotinib targets one of them. But whereas there are many kinases in a cell, there are far more biochemical functions that a cell has to do. So most kinases have many functions, some seemingly unrelated. Scientists focused on the kinase that nilotinib inhibits, because if it becomes overactive it can drive unchecked growth of white cells in the blood, causing leukemia. But they also found that it is involved in the accumulation of neuronal proteins that can get misfolded. Nilotinib is big news because drugs that target kinases are relatively easy to develop, and nilotinib provides the first example showing that if they work for one disease, they might be used for a second seemingly unrelated disease. At the bedside, leukemia and Parkinson’s seem as far apart as you can get.
Third, the timing with which the drug may work tells us something new and exciting about Parkinson’s itself, which might be relevant to other neurodegenerative diseases such as Alzheimer’s. Protein misfolding in neurons seems a very general process in many neurodegenerative disorders. But no one knows whether suppressing protein misfolding will result in the slowing or stopping of a disease, or even in recovering function. The effect of nilotinib seems relatively fast—the trial was only for a few months. If nilotinib’s beneficial action to patients is really on inhibiting the accumulation and misfolding of neuronal proteins (and not secondarily on increasing the release of dopamine), and if the patients really improved, this could mean that the misfolding is one side of an active and dynamic battle in neurons between "good" folding and "bad" folding. In that case, there would be processes in neurons that are actively trying to repair the cell. This gives us hope for a cure and restoration of lost function in many neurological diseases.