Amyotrophic Lateral Sclerosis

Generation of precision animal models for newly identified variants for Amyotrophic Lateral Sclerosis in inbred and diversity outbred (DO) mice.

Project Leader: Cathleen Lutz, Ph.D.

Co-Investigator: Robert Baloh, M.D. (Cedars-Sinai Medical Center)

The objective of this project is to leverage ongoing human patient exome and whole genome sequencing efforts to generate precision models of Amyotrophic Lateral Sclerosis (ALS). These new mouse models will not only capture individual disease-causing mutations but also recapitulate the genetic “background” variations found in human populations known to modify disease presentation. They will be evaluated for clinically relevant phenotypes of motor neuron disease and used to identify sensitization or resistance genetic variants as well as to test new therapeutics to prompt clinical trials.

Background and Rationale

ALS is a degenerative condition that destroys motor neurons and denies patients of voluntary muscle movements. The disease most often strikes after age 50, but can occur earlier.  Early symptoms of ALS include a loss of muscle strength and coordination that eventually progresses to paralysis and death within a few years of diagnosis.

ALS is not a single disease but a syndrome. Clinical heterogeneity in patients is significant with variations in the rate of progression, age of onset, and the muscles that are affected. While the final common end result is motor neuron loss, many pathways are implicated, including RNA processing, excitotoxicity, protein misfolding and aggregation, oxidative stress, axonal transport and mitochondrial function. The cause of the majority of ALS cases is classified as unknown or sporadic nature (sALS), because inheritance cannot be established.  Familial ALS (fALS) represents only 5-10% of cases and is associated with disease-causing genes such as TARDP, FUS, SOD1, and the most recently discoveredC9ORF72, which is implicated in an estimated 34% of all fALS cases.  The complexity of ALS is increased by the fact that disease characteristics can be modified by other genes as well as by environmental factors and to unravel this complexity will require more sophisticated animals models and experimental approaches.   

Current clinical trials typically involve an experimental drug, often tested on no more than one mouse model during pre-clinical work, and then given to a clinically diverse group of ALS patients whose results are compared to patients given a placebo.  Despite decades of trials with more than a dozen drugs, Riluzole is the only developed therapy that has achieved even a modest increase in patient survival time.  It now seems unlikely that a single drug will emerge as a definitive treatment, but with advances in genome sequencing, a new path forward has emerged. This path involves defining clear genetic and/or biological subgroups, within ALS that ultimately allow for tailored treatment for each defined subgroup.

The critical first step down this new path is underway with the genome sequencing of a large number of ALS patients.  These data will extend insight into the genetic contributions of ALS while establishing a catalog of rare disease-associated variants and the associated clinical features of the patients.  These variants can then be explored in mice and other model organisms to associate the pathogenesis of motor neuron degeneration with the underlying genetic variation.

In this project we will create mice carrying the human pathogenic mutations identified by our collaborators.  The mutations will be introduced onto both a standard, stable genetic background (C57BL/6J strain) and, to better emulate the human situation, onto a highly diverse genetic background (Diversity Outcross (DO) mice).  The resulting new mouse models will be utilized to recapitulate and study key features of ALS pathophysiology.  Successful models will be used to test drugs already approved by the FDA as well as to develop new drugs tailored to specific mechanisms of action and the impaired biological pathways of the mutated genes.