Scientists Create First Transgenic Mouse Models of Common Inherited Form of Lou Gehrig's Disease

New Study in Neuron Offers Hope That a Common Hereditary Form of Amyotrophic Lateral Sclerosis, or ALS, May One Day Be Reversed by Gene Therapy

Contact: Sally Stewart | Email: sally.stewart@cshs.org

Los Angeles - Dec. 2, 2015 - Scientists have created the first transgenic mouse models of the most common type of inherited amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease — a fatal, incurable disorder that gradually kills nerve cells in the brain and spinal cord controlling muscle function. The scientists' work also offers hope that this form of ALS may one day be reversed by gene therapy.

Worldwide, ALS is one of the most prevalent neuromuscular diseases, and more than 12,000 people in the U.S. have been diagnosed with it, according to the National Amyotrophic Lateral Sclerosis Registry. In most cases, the cause is unknown, but up to 10 percent of patients inherit ALS. The most frequent mutation involves a gene called C9orf72, which also causes frontotemporal dementia. This type of dementia, which produces cognitive and behavioral deficits, can be found in addition to muscle weakness in some ALS patients.

In a study led by Cedars-Sinai, published today in the journal Neuron, investigators describe how they engineered mouse models of ALS by taking a piece of DNA from a patient who carried the mutant C9orf72 gene and inserting it into the mouse genome. Working independently, a team from the University of Massachusetts Medical Center in Worcester created similar transgenic ALS mice, and its findings were published today in a separate article in Neuron.

The mouse models provide unique insights into how cellular components may go wrong to cause ALS and how they might be repaired.

"The mice developed brain pathology similar to their human counterparts," said Robert H. Baloh, MD, PhD, senior author of the Cedars-Sinai study and director of Neuromuscular Medicine in the Department of Neurology and the multidisciplinary ALS Program. The abnormalities included aggregation of RNA transcripts from the mutated gene and production of so-called dipeptide repeat proteins. In a significant advance, researchers were able to suppress this pathology by using a form of gene therapy known as antisense oligonucleotides, Baloh said.

Interestingly, the transgenic mice did not develop the degeneration of nerve cells that characterize ALS and frontotemporal dementia. The researchers propose that these mice were instead recapitulating the pre-symptomatic phase of the disease seen in humans. "This makes them extremely useful for studying early stages of disease pathogenesis, and they will be invaluable tools for investigating therapeutic strategies," said Jacqueline O'Rourke, PhD, the study's lead author and a project scientist in Baloh's laboratory.

In future studies, the investigators will try to determine which factors in addition to the C9orf72 mutation, such as other genes, age or environmental exposures, are needed to produce ALS-related neurodegeneration, said Baloh, the Ben Winters Chair in Regenerative Medicine and associate professor of Neurology. He noted that although ALS is uncommon, estimates suggest that about 500,000 people in the U.S. carry the C9orf72 mutation.

Baloh is a prominent expert in genetic defects and molecular mechanisms that cause neuromuscular and neurodegenerative diseases. The Neuron study builds on his laboratory's earlier investigations of the C9orf72 gene and its role in ALS. In a study published in the journal Science Translational Medicine in 2013, Baloh and colleagues from the Cedars-Sinai Board of Governors Regenerative Medicine Institute and Induced Pluripotent Stem Cell Core Facility replicated ALS in a lab dish. In that context, they demonstrated that antisense oligonucleotides could block the damaging effects of C9orf72.

Other Cedars-Sinai scientists contributing to the study included Kevin Kim, PhD, project scientist in Baloh's laboratory; and Ritchie Ho, PhD, project scientist in the Board of Governors Regenerative Medicine Institute. Researchers also came from the Jackson Laboratory in Bar Harbor, Maine; the Mayo Clinic in Jacksonville, Florida; Washington University School of Medicine in St. Louis; and the University of Pennsylvania in Philadelphia.

The study was supported by National Institutes of Health under award numbers NS055980, NS069669, AG039510, AG000255, NS089979, NS084528, NS063964, NS077402, NS084974 and ES20395; the National Center for Advancing Translational Sciences under award number UL1TR000124; and the Department of Defense under award number ALSRP AL130125. Additional support was provided by the Mayo Clinic Foundation, Mayo Clinic Center for Individualized Medicine, ALS Association, Robert Packard Center for ALS Research at Johns Hopkins, Target ALS, the Robert and Louise Schwab Family and the Cedars-Sinai ALS Research Fund.