In honor of the 20th year of our Milton Safenowitz Postdoctoral Fellowship Program, we are catching up with some of our funded fellows, like Clotilde Lagier-Tourenne, M.D., Ph.D., an associate professor of neurology at Massachusetts General Hospital and Harvard Medical School, to find out how the award impacted her research and career.

Having spent years training as an aspiring ballet dancer, Dr. Clotilde Lagier-Tourenne was no stranger to soaring jumps, but moving from her home country of France halfway around the world to San Diego, California to become a postdoctoral researcher required a different kind of leap—a leap of faith.

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“Probably the biggest risk I have taken was to decline a job offer in France when I was a postdoc, which was a lifelong job, not knowing what I would have in the U.S. It was a big, difficult decision, but it has opened a lot of doors,” said Dr. Lagier-Tourenne, who is now an associate professor of neurology at Massachusetts General Hospital and Harvard Medical School and a leading ALS researcher.

Dr. Lagier-Tourenne earned both her M.D. and a Ph.D. in molecular and cellular biology in Strasbourg, France before joining the lab of Dr. Don Cleveland at the University of California San Diego in 2008 as a postdoctoral researcher. This occurred at a “turning point” in ALS research, Dr. Lagier-Tourenne recalled. The protein TDP-43 had recently been linked with the disease, and within a year, mutations in the FUS gene were also implicated in ALS development.

For a trained medical geneticist, it was “a very exciting time” to enter the ALS field. “We really wanted to define what’s the normal function of these proteins. And that was very important because they had been identified in the disease, but at the time, we knew very little about what they were doing,” she said. “I had been thinking about transcriptomics and other genomic approaches before leaving France, and it was the right time to apply that to ALS.”

Transcriptomics is a way to catalogue and analyze all the RNA molecules found in a cell. RNA is the less well-known, single-stranded cousin of DNA. Its main role is to take the instructions found in genes (DNA) to the cell’s protein-making factories (ribosomes). By studying the full array of RNA being produced, researchers can learn more about how genes are working (or not working) and whether proteins are being produced as expected.

Using this approach, Dr. Lagier-Tourenne and her colleagues were trying to tease apart the normal function of TDP-43 and see what happens when this normal function is lost—something that occurs about 97% of the time in people with ALS and is thought to be a major driver of the disease. This information would not only help the field better understand the processes that could underly the development and progression of ALS but ultimately help find new targets that could be used to develop new treatments. 

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One such discovery, which has its origins in the work she began during her postdoc, involves a protein called stathmin-2. In collaboration with her past mentor Dr. Cleveland and a number of other colleagues and trainees, including Dr. Ze'ev Melamed, Dr. Lagier-Tourenne found that when TDP-43 function is lost in neurons, stathmin-2 function is also lost. Without stathmin-2, damaged neurons can’t regenerate, and the connections between neurons and muscles that control movement are disrupted.

In a paper published last year in the journal Science, the group described how TDP-43 in healthy neurons interacts with the RNA produced from the STMN2 gene to produce functional stathmin-2 proteins. Armed with this knowledge, the researchers collaborated with IONIS Pharmaceuticals to design antisense oligonucleotides (ASOs)—short, synthetic, single strands of genetic material that bind to specific segments of RNA—that could mimic this beneficial interaction. When they tested the ASO in ALS models, the treatment helped boost stathmin-2 protein levels and restore neuron repair processes even though the levels of normally functioning TDP-43 remained low.

“From what we know right now, stathmin-2 is a major target. I’m definitely excited by this. We have established close collaborations with many people in the field to move forward various approaches for rescuing stathmin-2,” Dr. Lagier-Tourenne said. 

The growing number of targets and approaches being pursued by researchers and industry gives Dr. Lagier-Tourenne hope that ALS will become a livable disease. Until then, she remains committed to making new discoveries, broadening our understanding of the disease, and training the next generation of ALS researchers. In fact, during her time at Massachusetts General Hospital, she has mentored four other Safenowitz Fellows: Fernande Freyermuth, Ph.D. (2015), Nibha Mishra, Ph.D. (2017), Xin Jiang, Ph.D. (2018), and Ananya Ray-Soni, Ph.D. (2018).

Her biggest advice to current and future Safenowitz Fellows? “Don’t be afraid. Take risks. And enjoy what you’re doing.” What she has accomplished in her career so far shows just how impactful that approach can be.

To learn more about genetically targeted therapies for ALS, click HERE.

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