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The Core, as the Project ALS Therapeutics Core is known, is a closely coordinated, all-out effort by world leading researchers and doctors to translate basic knowledge about ALS into better medicine for ALS.
In just six years, The Core has driven promising therapy candidates to ALS clinical trial. And there’s more in the pipeline. The strategy at The Core is to test new therapies for ALS for safety and efficacy before they reach clinical trials. By optimizing hopeful new drugs in early development, we increase the odds of those drugs making a difference in people living with ALS.
Most ALS clinical trials have failed. One big reason why is that ALS is hard to “model” outside of a person’s body. In cancer, doctors can study a biopsy taken from a patient, and learn critical information from that sample tissue, including the best drugs to try. That’s not possible with a brain disease like ALS.
The Core is changing that. Project ALS remains at the forefront of ALS disease modeling. In 2008, with partners from Columbia and Harvard, Memorial Sloan Kettering Cancer Center, and the Jenifer Estess Laboratory for Stem Cell Research, Project ALS was first in the world to generate iPS or stem cell-derived motor neurons from patients with ALS. One of the Core’s top three priorities remains the further development of ALS patient models of the disease. Improved patient models of ALS facilitate more responsible early drug development and treatment.
The only way we’ll slow or stop ALS is with powerful new analytic tools. The Core is building new tools to identify which genes play a role in ALS and how
to modulate their expression…how to deliver hopeful drugs across the blood-brain-barrier…how to mark the actual start of ALS and monitor its progression in a human being…how to show whether a drug hits its intended therapeutic target in a patient. Powerful new tools eliminate the guesswork from ALS research and discovery.
Most drugs that arrive in ALS clinical trial are repurposed FDA drugs approved for other illnesses. The Core is devoted to the design of drugs directed at ALS. Although Project ALS partners with drug companies and academic centers, the Core is neither a drug company nor a think tank. The Core is a hybrid, a proving ground for new strategies that may slow or even stop ALS progression.
The first new ALS drug candidate to have emerged from the Core is called prosetin, and it’s currently in ALS clinical trial. The Core was also instrumental in the development of jacifusen, which was engineered to treat a specific genetic mutation form of ALS. Today, drugs called paullones and proteases are being run through intensive Core studies for their potential efficacy in people living with ALS.
The Project ALS Therapeutics Core means better ALS models…better analytic tools…and, most of all, committed experts working together to optimize new ALS therapies.
Drs. Hynek Wichterle and Emily Rhodes Lowry (Columbia University) lead collaborative Core efforts to develop new tools for understanding ALS, and new drugs for slowing it. As stem cell pioneers, they are also co-inventors of prosetin, the first new ALS drug candidate to emerge from the Core, and are developing a promising drug called kleinerpaullone for clinical trial.
Using high-throughput protein engineering, Dr. Alejandro Chavez (UC San Diego) has designed a multiplex model system to identify at-a-glance similarities and differences among all forms of ALS. Dr. Chavez is contributing to Dr. Wichterle’s “motor neuron rejuvenation”—an exciting effort to restore ALS disease resistance to adult brains.
By the time a person is diagnosed, ALS is well underway. Dr. George Mentis (Columbia) is hunting for the earliest insults in ALS. That includes pinpointing, physiologically and anatomically, the pre-onset and onset ages of mice with ALS. Dr. Mentis has made similar breakthroughs in SMA, a related disease.
In a related study, Drs. Eiman Azim and Talmo Periera (Salk Institute) measure motor function to assess when in life the first motor deficits occur in ALS. Utilizing systems neuroscience, computer vision, and machine learning, they are monitoring the motor behaviors of mice with ALS over time.
Dr. Brent Stockwell (Columbia) is raising his medicinal chemistry superpowers to the next level. Many drugs look great on paper. But for ALS drugs to work, they must be soluble, brain penetrant, and more. Stockwell is working to optimize kleinerpaullone. He’s also generating therapies to prevent ferroptosis (cell death) in ALS. Congratulations to Brent, who was recently elected to the National Academy of Medicine.
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