Development of Therapeutics for Amyotrophic Lateral Sclerosis (ALS)

NU 2008-163 and NU2009-098

Inventors

Richard B. Silverman*

Richard Morimoto

P. Hande Ozdinler

Short Description

Three series of New Chemical Entities (NCEs) that exhibit efficacy in an ALS animal model 

Background

ALS causes muscle weakness and atrophy due to the degeneration of the upper and lower motor neurons. This disease is both genetic and sporadic in nature. The most common ALS-causing mutation is a mutant superoxide dismutase (SOD1) gene and aggregate accumulation of SOD1 is suspected to play a role in disrupting cellular functions.

Abstract

Professor Richard Silverman and his colleagues have synthesized and evaluated three series of compounds. These analogs were designed to inhibit SOD1 protein aggregation with cytotoxicity protection and aimed to combat ALS as well as other motor neuron diseases. These novel compounds exhibited drug-like properties and have favorable pharmaco-kinetic characteristics. These compounds are easy to synthesize and involve less than 10 synthetic steps. One of the compounds tested showed a lifespan extension of > 13% in G93A SOD1 ALS mice animal model (Figure 1). While no ALS drug has successfully emerged from clinical trials over the last 30 years, Profs. Silverman and Ozdinler set to reverse that trend with a novel approach to ALS drug discovery by focusing on the health of the brain's motor neurons as a preclinical marker instead of extending mouse survival. Prof. Ozdinler's lab developed the reporter line for corticospinal motor neuron (CSMN) in UCHL1-eGFP mice, allowing the visualization of upper motor neurons in vivo, while intact in the brain. By crossbreeding these mice with well-defined mouse models of ALS, they also generated CSMN reporter lines of ALS disease, such as mSOD1, absence of Alsin and TDP43 (Figure 2). Moreover, in vivo studies with these animals will help to evaluate Prof. Silverman's compounds for the improvement of overall CSMN health. These compounds are being evaluated for their improvement in CSMN survival relative to the control. STAGE OF DEVELOPMENT AND COMMERCIALIZATION Preclinical Stage. Established proof-of-concept in an animal model. Additional proof-of-concept in other animal models is in progress.

Applications

• ALS
• Diseases related to motor neurons

Advantages

• Proof-of-concept in ALS mouse models. Initial proof-of concept in other cell lines and additional animal models
• Northwestern University's unique strength in battling ALS lies in having dedicated researchers, including Teepu Siddique (Feinberg), who spearheaded the creation of a 'research standard' model system for ALS.

IP Status

US Patent Nos. 8,722,939 and 9,162,968 and additional patents that have been issued or are in prosecution