PD Psychosis Therapy Approved, alpha-Synuclein Antibodies Advance
By Karen Hales, Neurology Solutions Contributing Writer
This past year brought several exciting new developments in the treatment of Parkinson’s disease (PD) as researchers advance new medications for motor and secondary symptoms of the disease and gain greater understanding of and uncover potential therapies to slow disease process.
Potentially disease-modifying treatment for Parkinson’s deemed safe
A disease-modifying drug candidate that was shown to significantly reduce the levels of a protein linked to PD is being advanced to the next stage of development. PRX002 is an antibody against alpha-synuclein (α-synuclein), a protein found in nerve cells and considered a major factor in PD.
A collaboration between biotechnology company Prothena and Roche Holding, PRX002 binds to and blocks α-synuclein. During a six-month Phase I clinical trial of 64 healthy patients with PD, PRX002 was found to be safe and well tolerated and yielded a statistically significant reduction in α-synuclein levels. Levels of free serum α-synuclein were reduced by up to 97 percent after a single dose of PRX002.
In another important finding in this study, researchers observed PRX002 penetration in the central nervous system (CNS) that exceeded expectations based on preclinical experience. CNS penetration is hindered by a highly impermeable network of blood vessels called the blood-brain barrier that protects the CNS from viruses, bacteria and other damaging agents found in the circulatory blood system. This critical barrier is largely impenetrable to medicines that target the brain, including medications used to treat neurodegenerative diseases like Parkinson’s and Alzheimer’s. Prothena and Roche Holding are collaborating to develop new drugs targeting agents that boost (CNS) penetration.
PRX002 will advance to Phase II trials this year to further evaluate safety and effectiveness of the treatment.
Parkinson’s Disease Psychosis Medication Approved
The FDA approved the first medication specified for the treatment of PD psychosis in May 2016. The drug, Nuplazid, may help relieve symptoms such as hallucinations and delusions experienced by the approximately 50 percent of Parkinson’s patients with PD psychosis.
Nuplazid™ (pimavanserin) is the first and only FDA-approved therapy proven to control hallucinations and delusions in PD psychosis with no known adverse impacts on motor function. The drug was granted priority review and breakthrough therapy designation prior to its approval last spring. Breakthrough therapy designation is designed to expedite the development and review of drugs intended to treat a serious condition and where preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy.
The hallucinations and delusions experienced with Parkinson’s disease can lead to thinking and emotions that are so impaired that the people experiencing them may not relate to loved ones well or take appropriate care of themselves, the FDA stated in its announcement of the drug’s approval. The psychiatric disturbances of PD psychosis often are the result of standard Parkinson’s drugs.
Scientists Believe Cancer Drug Candidate Could Treat Parkinson’s
Researchers have identified a way to block the action of a toxic protein believed to play a role in Parkinson’s disease through an antibody that already is the subject of clinical trials targeting cancer and autoimmune disorders.
LAG3 is a protein which in humans is encoded by the LAG3 gene that plays an important role in the immune system. Johns Hopkins University researchers discovered a previously unrecognized role for LAG3 which may have critical implications for understanding how α-synuclein is connected to development of PD.
The university’s Parkinson’s study hinges on how abnormal clumps, or aggregates, of α-synuclein enter brain cells by passing through transmembrane receptors, which act as a gate admitting only the correct proteins to enter brain cells. Researchers found that LAG3 has a heavy preference for latching onto α-synuclein and plays a role in transporting them between cells.
They followed up by studying how mice bred without the toxic protein and mice injected with the LAG3 antibodies reacted to α-synuclein protein. They found that mice injected with LAG3 antibodies were almost completely protected from the Parkinson’s-like symptoms that would typically result from α-synuclein than control mice.
If the trials targeting LAG3 antibodies prove them safe and effective then drugs already in the pipeline for cancer treatment could potentially benefit PD patients as well, researchers said.
Low-dose Lithium Reduced Involuntary Motor Movements
Low-dose lithium reduced involuntary motor movements in a mouse model of Parkinson’s disease, a condition that is diagnosed in about 60,000 Americans each year.
Lithium, in the form of Lithium Carbonate, is most commonly used at higher doses to treat patients with Bi-Polar disorder. It is a naturally occurring element that can be found in negligible amounts in food and water. Foods high in lithium include milk, eggs, tomatoes, beef, mushrooms, and cucumbers.
Low-dose lithium was shown to reduce involuntary motor movements–the troubling side effect of Cabidopa/Levidopa, the medication most commonly used to treat PD–in lab mice with a condition that mimics Parkinson’s disease. There has been some evidence that Lithium, even at low doses, offers a form of neuroprotection, and one study showed possible new neuronal growth at higher dosing.
A study by the Buck Institute for Research on Aging showed lithium significantly prevents the build-up of toxic proteins and cell loss associated with PD. Researchers administered a dosage that is one-quarter what is typically given and observed a clear reduction in motor difficulties typical in PD.
The study also reported that the area of the brain normally damaged by Parkinson’s also was protected. The mechanism of action is not completely understood; however, a study found a reduction of inflammation in astrocytes and microglia, cells that play a housekeeper role in the brain. Low-dose Lithium has also been shown to increase serotonin turnover and enhance neurotransmission.
While there are promising studies, Lithium is not patentable, and therefore larger studies are not likely to be undertaken given the lack of financial incentives to invest in vigorous research.
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