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 at Massachusetts General Hospital
Director, Drug Discovery Lab at Columbia University
Location: New York, New York