A new study suggests low doses of a leukemia drug may provide a new treatment strategy for neurodegenerative diseases.
Georgetown University Medical Center researchers discovered the drug prevented the accumulation of toxic proteins linked to Parkinson’s disease in the brains of mice. Researchers will now develop a clinical trial to study the effects of the drug on humans.
Investigators say their study, published online in Human Molecular Genetics, is a new strategy to treat neurodegenerative diseases that feature abnormal buildup of proteins.
Common diseases that develop in association with the abnormal buildup of proteins include Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), frontotemporal dementia, Huntington disease and Lewy body dementia, among others.
“This drug, in very low doses, turns on the garbage disposal machinery inside neurons to clear toxic proteins from the cell,” said the study’s senior investigator, neuroscientist Charbel E-H Moussa, M.B., Ph.D.
“By clearing intracellular proteins, the drug prevents their accumulation in pathological inclusions called Lewy bodies and/or tangles, and also prevents amyloid secretion into the extracellular space between neurons, so proteins do not form toxic clumps or plaques in the brain,” he said.
When the drug, nilotinib, is used to treat chronic myelogenous leukemia (CML), it forces cancer cells into autophagy — a biological process that leads to death of tumor cells in cancer.
“The doses used to treat CML are high enough that the drug pushes cells to chew up their own internal organelles, causing self-cannibalization and cell death,” Moussa said.
“We reasoned that small doses — for these mice, an equivalent to one percent of the dose used in humans — would turn on just enough autophagy in neurons that the cells would clear malfunctioning proteins, and nothing else.”
Moussa hypothesized that the cancer drugs could help to clean up diseased brains. “No one has tried anything like this before,” he said.
However, a unique characteristic of the brain is a membrane that separates circulating blood from the brain’s extracellular fluid (BECF) in the central nervous system (CNS).
This blood-brain barrier protects the brain from many common bacterial infections but also has historically limited the administration of medical and therapeutic agents.
To this end, Moussa and his team searched for cancer drugs that can cross the blood-brain barrier.
They discovered two candidates — nilotinib and bosutinib, which is also approved to treat CML. This study discusses experiments with nilotinib, but Moussa says that use of bosutinib is also beneficial.
The mice used in this study were genetically engineered to have the Lewy bodies that are found in Parkinson’s disease and dementia patients, and in many other neurodegenerative diseases.
The animals were given one milligram of nilotinib every two days. (By contrast, the FDA approved use of up to 1,000 milligrams of nilotinib once a day for CML patients.)
“We successfully tested this for several diseases models that have an accumulation of intracellular protein,” Moussa says. “It gets rid of alpha synuclein and tau in a number of movement disorders, such as Parkinson’s disease as well as Lewy body dementia.”
The team also showed that movement and functionality in the treated mice was greatly improved, compared with untreated mice.
In order for such a therapy to be as successful as possible in patients, the agent would need to be used early in neurodegenerative diseases, Moussa said. Later use might retard further extracellular plaque formation and accumulation of intracellular proteins in inclusions such as Lewy bodies.
Moussa is planning a phase II clinical trial in participants who have been diagnosed with disorders that feature build-up of alpha Synuclein, including Lewy body dementia, Parkinson’s disease, progressive supranuclear palsy (PSP) and multiple system atrophy (MSA).