Amyotrophic lateral sclerosis (ALS) is a complex progressive set of neurological diseases that kills motor neurons and results in a devastating loss of motor function and death. Approximately 90% of ALS cases do not have a family history of the disease. These patients are referred to as having sporadic ALS (sALS). The lack of knowledge of the underlying causes of sALS presents a huge barrier to finding effective therapies. Sometimes genetic mutations are found in patients with sALS, even though there is no known family history of disease. By far the most common genetic cause of sALS, accounting for ~10% of sALS cases, is a repeat expansion mutation in a gene located on chromosome 9 called the chromosome 9 open reading frame 72 (C9orf72) gene. The repeat expansion mutation is a GGGGCC repeat with too many copies. This type of mutation is called a microsatellite repeat expansion and more than 50 human diseases are caused by similar types of mutations with different repetitive stretches. The most common genetic form of ALS is caused by a repeat expansion mutation in a gene located on chromosome 9 called the chromosome 9 open reading frame 72 (C9orf72) gene.

In 2011, the Ranum lab made the surprising discovery that microsatellite repeat expansions produce unexpected repetitive proteins without the normal signals that were previously thought to be required for cells in the body to produce proteins. These repetitive proteins are called repeat-associated non-AUG (RAN) proteins because they are made without the normal "AUG" protein start signal. RAN proteins have been shown to be toxic to cells and to play an important role in C9orf72 ALS and more than 10 other repeat expansion diseases. Dr. Ranum's laboratory has recently shown that the type 2 diabetes drug metformin, already approved by the Food and Drug Administration (FDA), reduces the production of these toxic proteins and Dr. Ranum's lab has shown C9orf72 mice treated with metformin show improved behavior, increased motor neuron survival, and decreased neuroinflammation.

This proposal is built on the innovative hypothesis that novel RAN proteins contribute to sALS and uses a pioneering approach to identify these previously unknown disease-causing repeat expansion mutations. This approach, which can identify de-novo mutations, will be applied in a unique and novel bench-to-bedside manner to generate patient-derived cell culture and organoid models that can be used to test immediately available treatment approaches and FDA-approved drug libraries. This innovative personalized medicine approach could fundamentally change diagnostic and treatment opportunities for sALS patients.

Identifying RAN positive RAN(+) sALS cases, novel repeat expansion mutations in sALS and testing the response of disease models to RAN modulating therapies will provide critical insight into the mechanisms facilitate the development of novel biomarkers and drugs to fight this terrible disorder.