Targeting alpha synuclein to improve constipation
Original article: Targeting neurons in the gastrointestinal tract to treat Parkinson’s disease. Clinical Parkinsonism & Related Disorders, 1, 2-7..
A phase II open label trial of a novel drug targeting alpha synuclein, which however does not enter the brain, was shown to be safe and well tolerated, and lead to a reduction in constipation.
Why is it important?
This finding suggests that the nervous system of the gut is not irreversibly damaged and that a drug that targets alpha synuclein in neurons may actually restore their function.
Parkinson’s causes a range of symptoms, and affects not only the brain but also other organs including the gut, or gastrointestinal tract. The gut itself is a long muscular tube which is controlled by a dedicated system of nerves, called the enteric nervous system. Alpha synuclein is the protein which when misfolded, forms clumps which are the main culprit in Parkinson’s, and causes damage to neurons in the parts of the brain that control movement, as well as the neurons that supply the organs around the body. Alpha synuclein can also be found in the neurons that supply the gut, and is thought to be underlying cause of many troublesome symptoms such as constipation in people with Parkinson’s.
A new drug called ENT-01 which targets alpha synuclein inside cells, though does not enter the brain, has been shown in a range of studies in cultured neurons and a worm model of Parkinson’s, to dislodge alpha synuclein from where it sticks inside neurons, and to even prevent the formation of the toxic clumps.
A phase II study was run in order to assess the safety and efficacy of ENT-01 on bowel function, specifically as a means of reducing constipation. This was an open label study, meaning that the participants and the research team had knowledge of the drug they were taking and its dose. In Stage I, the response of 9 people with Parkinson’s was assessed after they received increasing doses of ENT-01 to determine that it was safe and well tolerated at the different doses used. In Stage II, 34 people were assessed in terms of their response to ENT-01, using also different doses in order to find the dose that was optimal for each individual.
The researchers observed that ENT-01 was well tolerated, and that the most notable side effects of nausea and diarrhea could be reduced by changing position when taking the drug and reducing the dose, respectively. They also observed that the drug improved constipation. Since the blood levels of ENT-01 were very low (less that 0.3%), it is much more likely that the drug had its effects through local action directly in the gut and the neuronal population that supplies it which apparently responded positively. The authors also noted that by the end of the study, there were some improvements in terms of several Parkinson’s symptoms in their participants, including movement (with UPDRS scores improving), cognition and sleep. Interestingly, ENT-01 also appeared to improve circadian rhythms, or the body’s natural clock and daily periodicity, as measured by skin temperature sensors.
As this was an open label study, a placebo effect cannot be ruled out. The researchers however have indicated that a double blind placebo controlled trial is already underway. Watch this space.
Original article: Hauser, RA, Sutherland, D, Madrid, JA, …..Barbut, J. 2019. Targeting neurons in the gastrointestinal tract to treat Parkinson’s disease. Clinical Parkinsonism & Related Disorders, 1, 2-7.