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Leukemia Drugs for Treating Neurodegenerative Disorders
Researchers at Georgetown University Medical Center plan to start a clinical trial with humans, furthering their finding related to applying small doses of a leukemia drug to mice brains. These small doses showed a possible ability to halt development of neurodegenerative disorders.
This study offers a unique and exciting new strategy to treat neurodegenerative diseases that develop due to abnormal buildups of proteins like Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), frontotemporal dementia, Huntington disease and Lewy body dementia, and many others.

"This drug, in very low doses, turns on the garbage disposal machinery inside neurons to clear toxic proteins from the cell. 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," stated the study's senior investigator, neuroscientist Charbel E-H Moussa, MB, PhD who heads the laboratory of dementia and Parkinsonism at Georgetown.

When the drug, nilotinib, is used to treat chronic myelogenous leukemia (CML), it forces cancer cells into autophagy, a biological process that leads the cells to essentially devour itself, whicj in turn 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 says. "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 has, for a while now, been working on a way to forcefully activate the self-meitenance mechanism of neurons, and force them to clean up their internal damaged and dysfunctional proteins, their ‘garbage’, and he came up with the idea of using cancer drugs that push autophagy, a version of internal clean-up, in tumors to help diseased brains.

"No one has tried anything like this before," he says.
Moussa, and his two co-authors -- graduate student Michaeline Hebron and Irina Lonskaya, PhD, a postdoctoral researcher in Moussa's lab searched for cancer drugs that can specifically cross the blood-brain barrier. They discovered two plausible candidates; nilotinib and bosutinib, which is also approved and used to treat CML. This study discusses experiments with nilotinib, but Moussa says that use of bosutinib is also beneficial.

The mice used for this experiment have been shown to over-express alpha-Synuclein, the very same protein that builds up in Lewy bodies in Parkinson's disease and dementia patients and which is found in many other neurodegenerative diseases in the form of intracellular protein buildup. The animals were given one milligram of nilotinib every two days, a dose much lower that the FDA approved dose for treting cancer, 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. 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." – says Moussa.

After applying the cancer drug and noting the cellular results the scientist also noted a markable increase in mobility and functionality for the mice, apparently reducing the symptoms of the neurodegenerative diseases.

Moussa hypothesizes that for the therapy to be most efficient, it would have to be applied early in the development of the neurodegenerative disorders, to initially prevent the harmful buildup of protein and prevent any serious damage from occurring to neurons. Using this therapy later in the disease progression may 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).

Results published online May 10 in Human Molecular Genetics
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