From the Bench- The Lab of Dr. Mark Albers at Massachusetts General Hospital

At the Sean M. Healey & AMG Center for ALS, compassionate clinical care converges with cutting-edge research every day. The laboratories at the Charlestown Navy Yard are humming with investigators researching the latest breakthroughs in ALS and bringing us closer to a cure.

In this issue, we highlight research updates from the Albers Lab at Massachusetts General Hospital. The Albers lab combines chemical biology, genetics, and computational methods in human brain tissue and mouse models to understand how neurodegenerative diseases develop.

The lab is currently working on trials like the Neurodegenerative Alzheimer's Disease and Amyotrophic Lateral Sclerosis (NADALS) Basket Trial and the Therapeutic Repurposing in ALS clinical trial program. As of Fall 2024, the NADALS Trial is fully enrolled, with results expected in Q4 of 2025. Below is a description of TRIALS from Dr. Mark Albers. 

"Therapeutic Repurposing in ALS (TRIALS) is a clinical trial program that uses existing drugs to identify effective therapies for ALS. Repurposing of FDA approved drugs is a more rapid route to introduce therapies to ALS patients because many of the safety hurdles have been passed in the initial approval process. Secondly, elucidating the mechanism of action of approved drugs in motor and cortical neurons relevant to ALS can lead to the discovery of new drug targets for ALS, often due to the off-target effects of these approved drugs. For instance, a recent comprehensive study in my laboratory showed that the FDA-approved drug for rheumatoid arthritis, baricitinib, is likely acting on other drug targets in neurons. We are now developing more potent molecules that are brain penetrant against these drug targets.

In these efforts, we use machine learning to develop a predictor of disease progression in Alzheimer’s disease (DRIAD), which contributed to a clinical trial of an FDA-approved drug in patients with Alzheimer’s Disease. This work was published in 2021 and tweeted by the Director of the NIH as well as featured on the NIH website. We have updated this predictor to include cryptic exons as a proxy for TDP-43 pathology in our latest work. TDP-43 pathology is hallmark of 97% of ALS cases and this new tool will be applied to ALS with more gene expression profiles of ALS becoming available from the New York Genome Center, Target ALS. The newly formed Consortium of ALS Research Laboratories (CARL) has developed an informatics platform to harness this data. We are hiring a computational biologist to develop the TRIALS tool to predict ALS progression. This resource would be made open source, so any ALS researcher in the world could use this tool. For instance, new drug candidates can be discovered by adding FDA approved drugs to cell culture models of ALS (ALS in a dish) and studying what genes have different expression profiles induced by the drugs. Analyzing these gene lists in a comprehensive fashion using the TRIALS predictor would identify new drug targets and potentially new pathways. We have just completed a screen of chromatin modifier drugs to be fed into the TRIALS predictor after it is built. These data will be mined along with other drug classes."