Trailblazer Pilot Award: Dbr1 inhibitors: a novel drug treatment for the neurodegenerative disease ALS

By Kelly Hale, Communications Coordinator

Apr 22, 2024

Name: Thomas Menees, Ph.D., University of Missouri – Kansas City

Study Title: Dbr1 inhibitors: a novel drug treatment for the neurodegenerative disease ALS

Area of Eligibility: Drug and Medical Device Development

Thomas Menees’ project advances a promising drug therapy for amyotrophic lateral sclerosis, more commonly known as ALS or Lou Gehrig’s disease. Currently, there are no treatments that significantly alter the course of this disease, and death typically occurs within 2 – 5 years of diagnosis.

Most ALS cases are associated with aggregation, or clumping, of the RNA-binding protein TDP-43 inside motor neurons of the brain and spinal cord. TDP-43 aggregation is strongly correlated with motor neuron death, which results in loss of voluntary muscle movement and death of the ALS patient. Because cells require TDP-43 for survival, shutting off production of this protein is not a therapeutic option.

Menees’ collaborator, Aaron Gitler of Stanford University, discovered that inhibition of the RNA lariat debranching enzyme, Dbr1, suppresses TDP-43 aggregation. Menees studies the Dbr1 enzyme, which cuts looped RNA molecules called RNA lariats. Dbr1 inhibition causes RNA lariats to accumulate in cells and is well-tolerated at low levels.

Menees’ prior work led to the discovery that Dbr1 is required for replication of the AIDS virus, HIV. Since they were both working in the field around Dbr1, Menees and Gitler teamed up to identify Dbr1 inhibitors for treating ALS and HIV infection.

Since ALS is a rare disease with no truly effective treatments, Menees decided to focus his efforts on ALS and TDP-43 aggregation. Surprisingly, RNA lariats that accumulate during Dbr1 inhibition bind TDP-43 and prevent it from aggregating. Dbr1 inhibition also “dissolves” preexisting TDP-43 aggregates. Thus, Dbr1 inhibitors are a promising approach for developing a therapy to untangle TDP-43 aggregates in motor neurons.

Menees and Gitler identified three Dbr1 inhibitors out of a collection of 128,000 drug-like chemicals. Menees plans to carry the work forward by using the best inhibitor to develop a drug for ALS.

“We’re in the ‘Valley of Death’ stage right now in the drug development process,” Menees said. “This is where basic research discoveries that could help patients have advanced to a point where targeted, applied research funding is important, but hard to get. Our project will take our best Dbr1 inhibitor and design novel, more effective inhibitors that could slow or stop the progression of ALS.”

This project is a collaboration between the University of Missouri-Kansas City, Stanford University, and the University of Kansas.

Kelly Hale

Communications Coordinator

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