Understanding ALS Disease Biology to Pursue Cell Repair and Regeneration
Investigating therapeutic options to increase STMN2 Levels: Clotilde Lagier-Tourenne, MD, PhD
The discovery that loss of the protein TDP-43 is common in a vast majority of individuals with ALS – both
sporadic and inherited – has quickly led to further insights about the gene most affected by that loss:
Stathmin-2 (STMN2). STMN2 provides instructions to make stathmin-2, a protein involved in the
development and repair of motor neurons and the formation of healthy neuromuscular junctions —
points of contact between neurons and muscle cells where they transmit signals to communicate with
each other. Failure of muscle function is a primary symptom of ALS, and so identifying molecules that can
restore STMN2 and allow surviving motor neurons to regenerate their axons and reconnect with the
muscles, will be an extraordinary breakthrough.
Researchers at the Sean M. Healey & AMG Center for ALS, along with their colleagues, demonstrated
that pharmacological compounds and gene therapy that increase the levels of STMN2 can restore the
ability of neurons to grow axons after injury. While partnering with industry on a gene therapy strategy,
Dr. Lagier-Tourenne’s team is also exploring chemical compounds that may increase the levels of STMN2.
To do this, they are developing screening tools to identify new modulators of STMN2 as potential
therapeutic targets. Her team’s initial screen identified statins (medication widely used to lower
cholesterol in individuals with heart disease) in six out of the first 10 hits. This was an unexpected result
since no prior research had identified a link between STMN2 and the pathway leading to the production
of cholesterol. The challenge for Dr. Lagier-Tourenne’s team now is to understand how neuronal axons
respond to statins. Researchers have observed that statins promote the growth of axons in cultured
neurons, but their impact needs to be tested in animal models before moving into clinical trials in
humans.
Statins are only one potential therapeutic option that needs to be investigated. The screening also
revealed other small molecules that can increase stathmin-2 levels by targeting other steps of the
pathway. Support for the Lagier-Tourenne lab will allow her team to perform the necessary pre-clinical
studies to reveal the mechanics behind molecules that increase STMN2 levels and allow neurons to
regenerate. In collaboration with ALS clinical researchers at Mass General, the team will also develop
biomarkers that will be crucial to accelerate the clinical development of drugs targeting STMN2.
Clotilde Lagier-Tourenne, MD, PhD is Associate Professor of Neurology at Mass
General and Harvard Medical School and inaugural incumbent of the Healey
Family Endowed Chair in ALS Research. She is an associate member at the Broad
Institute and has served on the NEALS Scientific Advisory Board since 2016. She
trained as a medical geneticist in France and at Columbia University and her lab
investigates the molecular mechanisms driving neurodegeneration in
amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and
Huntington’s disease, using innovative cellular and genomics techniques.
