Posiphen as a Well-tolerated Alpha-synuclein Inhibitor and a Potential 5'UTR Directed Drug Treatment of Parkinson's Disease
Rapid Response Innovation Awards, 2008
An inter-relationship exists between the Parkinson’s disease-related protein alpha-synuclein and the Alzheimer’s Aß-amyloid plaque protein. Phenserine reached clinical assessment for AD as an anticholinesterase and blocker of amyloid precursor protein translation (anti-amyloid). This well-tolerated compound also reduced neural alpha-synuclein expression over a similar dose range. We will pursue posiphen (stereoisomer of phenserine) for its clear capacity to lower alpha-synuclein expression, first in cell culture, then progressing to animal models.
Posiphen will soon undergo phase II clinical trials for AD, but we found that posiphen also inhibited alpha-synuclein expression in cultured neural cells. Since alpha-synuclein mediates neurotoxicity in Parkinson disease, we will test how posiphen exerts therapeutic action by acting as an inhibitor of alpha-synuclein expression. Posiphen may repress alpha-synuclein mRNA translation by its 5’ leader sequences similar to the pathway established for its inhibition of APP mRNA translation for anti-amyloid efficacy in AD. We will test the hypothesis that posiphen interferes with the selective binding of an essential Ironregulatory Protein, IRP-1, to the functional RNA enhancer in front of the alpha-synuclein messenger. This pathway could provide therapeutic efficacy in future Parkinson’s disease models.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Fibrilized alpha-synuclein is associated with striatal neuronal death. This project will characterize whether posiphen represses alpha-synuclein expression by a translational control mechanism and pursue its medicinal development as a protective agent against PD lesioning in vivo by MTTP treatment and in alpha-synuclein PD transgenic models.
We will discover whether posiphen represents a class of new Parkinson’s disease specific drugs that blocks super-repress translation the alpha-synuclein messenger by IRP-1. This route will permit selective neuronal alpha-synuclein repression for therapeutic consequences.
Dr. Rogers demonstrated that a drug called posiphen can selectively regulate the levels of alpha-synuclein in a cell model. Dr. Rogers also identified a novel mechanism by which one may change the levels of alpha-synuclein in a cell. Dr. Rogers is continuing his work through an award from MJFF's Novel Approaches to Drug Discovery 2009 program.
Associate Professor of Psychiatry-Neuroscience at Harvard Medical School
Massachusetts General Hospital
Location: Charlestown, Massachusetts
Director, Drug Discovery Lab at Columbia University
Location: New York, New York