Neuromuscular Platforms for Drug Discovery

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Mouse models, pioneered by The Jackson Laboratory (JAX), the renowned research institute headquartered in Bar Harbor, ME, provide a wealth of new opportunities to mimic and modulate human genetic abnormalities found within the population, as well as investigate therapeutic efficacy on a rapid timeline.

While model selection depends on the target and mode of action of the therapeutic, it is essential that the model has both face validity and construct validity seen in human disease. As examples of JAX’s neuromuscular platform work, consider two examples within neurodegenerative research: spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS).

SMA is caused by a deficiency of the survival motor neuron (SMN) protein, resulting in the selective loss of motor neurons in the spinal cord and lower brain, and progressive skeletal muscle atrophy and weakness. The genetic cause is a homozygous deletion or mutation of SMN1. Studies have also shown an inverse correlation between the copy number of the closely related SMN2 gene and SMA severity.

Over a 15-year period, SMA researchers built the foundation for the successful clinical trials of Biogen’s Spinraza™ (Nusinersen), which utilizes an antisense oligonucleotide (ASO) to control SMN protein expression. The FDA approved Spinraza in 2016.

To support cutting-edge research, JAX has been able to archive the most relevant in vivo mouse models and make them available to the research community. In addition to that, the scientists at JAX have used some of these models to define therapeutic windows and characterize the models further.

Arthur Burghes (Ohio State University) developed the first-generation SMA mouse models, which modeled the severity of the patients. Cat Lutz, director of JAX Rare and Orphan Disease Center, and collaborators at Columbia University, subsequently used an inducible mouse model to determine the optimal therapeutic window to restore SMN protein, and stop disease progression.

The Burgheron model was further characterized by Lutz and colleagues and was used to validate electrophysiological outcome measures to characterize the natural disease history, including the age of onset. The slower disease progression in this model allows a wider window for therapeutic intervention making it particularly useful for efficacy studies.

A more complex disease

ALS is a neurodegenerative disease predominantly affecting upper and lower motor neurons. It is characterized by the progressive degeneration of motor neurons in the brain and spinal cord that lead to relentlessly progressive weakness of voluntary muscles. Familial ALS (fALS) accounts for about 10% of cases.

The first genetic mutations found to cause ALS, reported in 1993, reside in the superoxide dismutase gene, SOD1. Since then, researchers have linked ALS to mutations in more than 50 genes; 16 of which have been unequivocally implicated in ALS pathogenesis.1 These findings reveal multiple ALS pathogenic pathways, opening the door for stratified therapeutics based on individual genes, pathways, or mechanisms.

While no single model can reflect the full spectrum of ALS, many current mouse models are excellent at emulating specific disease facets.2

For example, B6SJL-Tg(SOD1*G93A)1Gur/J (also known as SOD1-G93A) animals carry a transgene insertion of the human SOD1 gene with a single amino acid substitution (G93A). This model recapitulates many aspects of fALS and has been thoroughly characterized by JAX In Vivo Services using traditional readouts as well as electrophysiological

assessments to understand the disease’s complete natural history.

JAX expertise

Utilizing mouse models to develop treatments for specific human diseases requires the inclusion of robust phenotypes to examine potential candidates. JAX provides extensive expertise in these models as they have tested many of the strains both generated at JAX, as well as those donated from researchers around the world.

With their technical knowledge, JAX is able to operate as a high-quality “mini diagnostic hospital” to measure precise biological changes that accompany disease progression and recovery. JAX further has the ability to perform whole animal in vivo phenotyping including physiological, behavioral, sensory, cellular, and metabolic assays, in addition to in vivo imaging and high throughput phenotyping paradigms.

The ultimate goal of preclinical studies is to identify disease-relevant and translational endpoints that are robust, reliable, and reproducible, and that can be employed to evaluate the potential of novel therapeutic agents. Complex methods are employed for comprehensive neurophenotyping and pharmacological experiments using mouse models of neurodegeneration and are conducted by trained technicians with demonstrated proficiency.

With more than 90 years of experience and providing access to more than 11,000 unique strains, JAX is dedicated to providing the most appropriate, translationally-relevant animals models and assays to researchers worldwide.

References

1. Taylor et al., 2016. Decoding ALS: From Genes to Mechanism. Nature, 539(7628), 197—206.

2. Lutz C. 2018. Mouse Models of ALS: Past, Present and Future. Brain Research 2018.