Rapid Flow Cytometry Screen for Identifying Novel ALS Drug Leads
Abstract
Amyotrophic lateral sclerosis (ALS) is a disease that causes the death of nerve cells controlling voluntary movement and results in difficulties speaking, swallowing, and breathing and ultimately results in death. In the vast majority of cases the cause is unknown. There are currently no known effective treatments for the devastating consequences of ALS. It is imperative that new drugs be identified to provide treatments. This project will harness a new high-throughput screening platform to search for drug leads to treat ALS. We have developed a new cell-based assay that provides a unique way to rapidly and quantitatively examine the effects of large numbers of small drug molecules on a process that is strongly implicated in disease causation, i.e., the mislocalization and aggregation of a protein, TDP-43, to form insoluble inclusions inside of motor neuron cells, and the survival of these cells. The primary drug screening assay will be performed by flow cytometry and hits further tested in cell models expressing other aggregation-prone proteins implicated in ALS. We will test drugs from Compounds Australia, Australias premier drug management and logistics facility, which manages small-molecule compound libraries (comprised of >670,000 compounds) for access by national and international life science research teams. Samples submitted to Compounds Australia differ from those available in commercial collections and contain compounds not available anywhere else in the world. This therefore provides us with a unique screening set to test in our cell and animal models for activity against TDP-43 aggregation and pathology. Those molecules identified as protecting motor neuron cells from the formation of protein inclusions and the associated loss of viability will then be examined for their ability to provide protection in both zebrafish and mouse models of ALS, in which TDP-43 and (in zebrafish) other ALS-associated proteins are expressed in motor neurons. Clearly, if small molecules are identified that provide significant protection or amelioration of ALS pathology across both the cell and whole animal models, these will present as highly promising drug leads. The transition of such molecules to therapeutic application to treat ALS patients would require additional work outside the scope of the current project and would require input from drug development synthetic chemists and future human clinical trials. These requirements will apply to any new drug lead discovered, by any route, for the treatment of ALS. We are willing to collaborate with any drug company that has a stake in the development or production of the drug, including informing them of our findings, to more rapidly progress the development of a therapeutic. Additionally, moving forward, we are willing to share our detailed protocols with pharma, or perform screens on commercially sensitive drug libraries on a cost recovery basis. The search for these drug leads is imperative if we are ever to have the capacity to save individuals from the debilitating and cruel afflictions imposed by this horrid disease. Impact: This is an early-stage drug discovery project. In the absence of any existing effective drugs to treat ALS, projects such as this are crucial to identify new compounds that can lead to the development of treatments for ALS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910195
Entities
People
- Mark R. Wilson
Organizations
- United States Army
- University of Wollongong