Objective/Rationale:
Posiphen is a small molecule drug that inhibits expression of alpha-synuclein, a protein involved in Parkinson's disease (PD) pathogenesis. We propose studies in a pre-clinical model of PD to test the potential of Posiphen as a treatment of PD. Since Posiphen has been shown to be safe in three phase 1 safety trials in humans, efficacy in the proposed studies could allow for rapid transition of Posiphen to clinical testing for efficacy and safety in PD patients.
Project Description:
We have pre-clinical models that express mutant forms of alpha-synuclein that have previously been shown to cause PD in people. These pre-clinical models have the gastrointestinal manifestations commonly seen in early PD, including constipation and slow transit of food from the stomach through the intestine to the rectum.
We will treat these pre-clinical models with Posiphen and measure the levels of alpha-synuclein in brain and gut, as well as determine whether lowering levels of alpha-synuclein will prevent or reverse the gastrointestinal manifestations in these pre-clinical models.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
This would constitute proof of principle that lowering the amount of abnormal alpha-synuclein made in nerve cells can prevent or reverse the early manifestations of the disease. Ultimately, we believe we can develop a preventive treatment of PD early before major neurological damage occurs.
Anticipated Outcome:
We expect to learn if we can lower levels of alpha-synuclein in the nerve cells of the gut, as well as in the brain, using a well tolerated drug that has already passed early human trials. If so, will we reverse the gastrointestinal manifestations of PD shown by lines of genetically engineered pre-clinical models that demonstrate many of the disease symptoms seen early in PD.
Final Outcome
Posiphen is a small molecule drug that inhibits expression of alpha-synuclein (aSYN), a protein in Parkinson’s disease (PD) pathogenesis. We conducted studies in two pre-clinical models of PD to test the potential of Posiphen to prevent/reverse gastrointestinal and movement disorders. In the first batch of pre-clinical models, Posiphen is well absorbed, readily enters the brain and lowers aSYN and APP levels in the brain.
In a new batch, Posiphen was administered starting at 6 weeks of age up to 8 months of age. The drug does prevent/reverse the non-motor symptom - gut motility - in both transgenic PD pre-clinical models. When the αSYN levels are measured in gut, untreated pre-clinical models show high levels of αSYN, while treated pre-clinical models show statistically significant reduced αSYN levels, proving that it is the αSYN in the gut that causes the reduced gut motility and that by reducing αSYN levels gut motility can be fully restored.
Posiphen does not act as a laxative, since when given to two different control breeds that do not develop constipation; it does not affect their gut motility.
We conclude that increased levels of SYN in gut cause slowed gut motility and that lowering aSYN levels in gut normalizes gut motility.
Contrary to our expectation at 8 months of age these pre-clinical models had not developed any movement symptoms as measured by rotarod and open field behavior. Upon further investigation it was interesting to note that these PD pre-clinical models, while showing increased aSYN levels in gut as expected, did not show increased αSYN levels in brain. Consistent with this finding, they show constipation but no motor symptoms.
The pre-clinical models seem to normalize their own aSYN levels in brain by translational regulation that is now under investigation and will be discussed as far as understood.