“For C9ORF72 ALS, dipeptide repeat protein (DPR) aggregation seems to be uncorrelated with degeneration in autopsy tissue,” Timothy Miller says. “Further, studies measuring levels of DPRs in various brain regions via immunoassay found few or no correlations between DPR concentration and clinical characteristics. Thus, while DPRs are an attractive target for therapeutics, there remains a missing link between promising cell/animal work and human disease.”

Timothy Miller, professor of neurology at Washington University in St. Louis, was awarded an MDA research grant totaling $282,417 over three years to shed light on ALS (amyotrophic lateral sclerosis) disease mechanisms.

The most common genetic cause of ALS is a hexanucleotide repeat expansion in the C9ORF72 gene, causing at least 30 percent of familial ALS and 5-10 percent of sporadic ALS cases. This repeat expansion causes the accumulation of abnormal dipeptide repeat proteins (DPRs), which aggregate in human tissues and have been found to be toxic in cellular and animal models. However, pathological characteristics of the DPRs do not seem to correlate with clinical characteristics or degenerative severity in patients, making it challenging to determine whether these DPRs directly contribute to degeneration in human ALS.

Using innovative methodologies, Miller and colleagues will investigate aspects of DPRs to determine their significance to human disease. The team will develop a novel way to understand DPR size in human tissues and cerebral spinal fluid (CSF), as well as a method to determine the turnover rate of DPRs in CSF of C9ORF72 expansion carriers. The turnover rate of DPRs may correlate with disease measures and could help define when and how to apply therapeutics.

The results from Miller’s work could have important implications in the understanding and treatment of C9ORF72 ALS. In addition, DPRs could serve as biomarkers that could directly inform the design of future clinical trials.  

"Udai Pandey says his team’s small molecule screening project could help identify drugs that might be useful for testing in vertebrate ALS models and, ultimately, in human clinical trials."

Udai Pandey, associate professor at the Children’s Hospital of Pittsburgh in Pennsylvania, was awarded an MDA research grant totaling $300,000 over three years to identify new drugs for ALS (amyotrophic lateral sclerosis) caused by a mutation in the FUS gene.

Pandey and colleagues are interested in understanding the basic mechanisms of FUS-mediated ALS and are working to identify drugs that can suppress mechanisms associated with the disease. 

The team recently performed a large drug screen, using a library of 400,000 drugs in a yeast model of FUS-mediated neurodegeneration, and identified about 80 drugs that strongly suppress toxicities associated with FUS. Now they are working to follow up on testing these drugs in a fly model of FUS, as well as in nerve cells created from ALS patient stem cells.

If successful, Pandey’s pre-clinical studies may help identify potential drugs for ALS caused by the FUS gene or related forms of ALS that could be tested in clinical trials.