ALS researchers at Harvard uncover new biomarker and drug target

Blue purple pink 3d rendering of brain
Repairing defects in the STMN2 gene might halt the degeneration of motor neurons in ALS, Harvard researchers believe. (monsitj/iStock/Getty Images Plus)

A mutated form of the gene that makes a protein called TDP-43 has been implicated in the brain disorder amyotrophic lateral sclerosis (ALS). New research out of Harvard has revealed a connection between TDP-43 and another gene called Stathmin2 (STMN2)—a link that could yield new approaches to treating the disease.

The Harvard scientists initially set out to identify all the genes that change when TDP-43 is manipulated, specifically in human neurons. Working with stem cell models of ALS, they observed that STMN2 changes in lockstep with TDP-43. That’s important, because STMN2 is involved in neuron growth and repair—processes that break down in ALS. They published their findings in the journal Nature Neuroscience.

When the TDP-43 gene malfunctions, aggregates of the protein can build up in the cytoplasm of nerve cells, leading to the degeneration that is characteristic of ALS. Mutations in the gene that encodes TDP-43 can be passed on in families.

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For their experiment, the Harvard researchers zeroed in on STMN2 after discovering its link to TDP-43. Specifically, they wanted to learn if fixing STMN2 might be able to halt the degeneration of motor neurons. So working with their stem cell models of ALS, they lowered levels of TDP-43 in the cell nucleus. That destroyed the instructions STMN2 needs in order to repair or grow motor neuron axons, said Joseph Klim, Ph.D., a postdoctoral fellow in the Harvard Department of Stem Cell and Regenerative Biology, in a statement.

RELATED: Neurimmune’s anti-SOD1 antibody shows promise in ALS mouse studies

The researchers believe the information they obtained from the stem cells is more valuable than what they may have learned from mouse models of ALS. “Because we had pluripotent stem cells of human origin, we could make cells in a dish that are relevant to ALS and investigate this very specific problem in the right context: with a human genome and all of the genetic factors that regulate motor neurons,” said team member Luis Williams, Ph.D., who is now director of cell biology at the startup Q-State Biosciences, in the statement.

Attacking ALS by targeting genetic mutations is an increasingly popular idea among researchers specializing in the disease. Swiss biotech Neurimmune, for example, is focused on mutations in the SOD1 gene, which are believed to contribute to 20% of familial ALS cases. The company has developed an antibody that binds to the misfolded enzyme the mutated gene produces, and in December it said positive results from a preclinical trial would lead to the first human testing of the compound this year.

The next step for the Harvard team is to figure out whether repairing the STMN2 gene can slow or halt ALS.

“The discovery we have made suggests a clear approach for developing a potential therapy for ALS—one that would intervene in all but a very small number of individuals, regardless of the genetic cause of their disease,” said Kevin Eggan, Ph.D., a professor of stem cell and regenerative biology and principal faculty at the Harvard Stem Cell Institute.

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