Preclinical Testing of BACE1 Inhibitors in Fmr1KO Mice
Abstract
Fiscal Year 2015 Peer Reviewed Medical Research Program Topic Area: This proposal impacts the area of fragile X syndrome (FXS). Specifically, this study will assess the feasibility of employing Alzheimer s disease drugs for the treatment of FXS. Overview: FXS is the most common form of inherited intellectual disability and the leading genetic cause of autism. FXS is clinically characterized by highly variable mental retardation (overall IQ <70), autistic-like behavior and seizures. The disorder results from a mutation in a single gene on the X-chromosome, FMR1, which codes for a protein called fragile X mental retardation protein (FMRP). FMRP is absent or expressed at low levels in FXS, which disrupts normal nerve cell development. Specifically, FMRP controls the expression of numerous other proteins resulting in elevated levels of those proteins in FXS. One of those proteins is called amyloid-beta. Amyloid-beta is elevated in Alzheimer s disease and is the major target of drug discovery for that disorder. Central Critical Problem: There is a compelling need to identify effective treatments and ultimately a cure for FXS. This study will assess the feasibility of employing Alzheimer s disease drugs to reduce amyloid-beta in a mouse model of FXS. Innovation: This contribution is highly innovative in that it will utilize a known Alzheimer s disease pathway, and drugs targeted to that pathway, to treat FXS. The contribution is high risk, as this family of drugs has not been tested in FXS. However, the project is highly innovative in that it examines an existing problem from a new perspective in utilizing a known Alzheimer s disease APP processing pathway, and drugs targeted to that pathway, to treat FXS. There is potential for high reward if drugs in the pharmaceutical pipeline for Alzheimer s disease can be repurposed for a rare disorder, FXS. Ultimate Applicability of the Research: This application will determine if Alzheimer s disease drugs can rescue gold standard FXS symptoms in a mouse model of the disorder. Therapeutic efficacy of the Alzheimer s disease drugs in the FXS mice will be compared with a drug targeting the current lead FXS therapeutic target. These two families of drugs will be tested individually and in combination. Ultimately, these studies will determine if drugs developed by the Alzheimer s field can be repurposed for the treatment of FXS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610082
Entities
People
- Cara J Westmark
Organizations
- United States Army
- University of Wisconsin–Madison