If you’ve been following Project ALS, you have probably heard us mention PHB, our working name for The Core’s first drug candidate-in-development. Now, we are proud to announce the final version of PHB—the real thing—a fully optimized, comprehensively tested drug for ALS called prosetin.
Project ALS is thrilled to welcome Dr. Ai Yamamoto to the Research Advisory Board and recognizes her leadership as she is joining our decision-making body. Dr. Yamamoto is the Associate Professor of Neurology and Pathology and Cell Biology at Columbia University and is a foremost expert on protein clearing, or autophagy, in neurodegeneration, particularly in Huntington’s and Parkinson’s diseases.
Project ALS has partnered with Dr. Yamamoto for about three years, as we strive to identify the role of autophagy in Huntington’s, ALS, and related diseases. We look forward to seeing where her leadership will take us.
Columbia University and Project ALS today announced the Project ALS Therapeutics Core at Columbia, a 3-year, $6.3M initiative toward the first meaningful therapies for ALS. The Core is the world’s first and only partnership between a world-class academic institution and a leading nonprofit organization dedicated to a full-spectrum approach to ALS drug development, preclinical evaluation, and human clinical trials.
The goal is better clinical trials—and the first effective treatments for people with ALS, a uniformly fatal neurodegenerative disease closely related to Alzheimer’s, Parkinson’s, and Huntington’s diseases. Already, the Core has yielded a novel drug, and evaluated dozens of commercial compounds in partnership with pharmaceutical companies.
The Core begins and ends with ALS patients—it will utilize patient blood samples toward drug screening, biomarker discovery, and genetics studies, and deliver better therapeutic options back to the clinic, to patients who have participated at the start of the process.
“For the first time, ALS patients can directly participate in research that will move us toward therapies that actually work,” said Neil Shneider, MD, PhD, Director of the Eleanor and Lou Gehrig ALS Center at Columbia. “The Core provides an immensely exciting opportunity to capitalize on decades of ALS advances and translate them into meaningful treatments now.”
Q&A with Project ALS Researcher Dr. Sebastian Thams, Karolinska Institute, on His Recent Discovery, Published in Molecular Therapy
Can you describe your discovery that was recently published in Molecular Therapy?
In our recent paper, we present a new screening platform, in which we elicit neurodegeneration by exposing ALS motor neurons to a biological stressor. We used this assay to screen for neuroprotective compounds reversing ALS-associated cell stress. We identified two groups of promising compounds, which increased motor neuron survival in mouse and human cultures, and delayed loss of muscle nerve endings in ALS mice. These compounds included protein kinase inhibitors and a bile acid. Altogether, our results have now enabled us to start the development of completely new drugs for ALS.
How does this discovery add to the field of ALS drug testing?
Our study demonstrates that stem cell-based screening models are valuable tools for swift and robust evaluation of potential drug candidates. As a proof-of-concept, we showed neuroprotective drug effects in mouse and human cell cultures, as well as in muscles from ALS mice, thereby strengthening the notion that important results from cells in cultures can be applied to ALS patients in the future.
How does this bring us closer to treatments for patients?
We have now identified promising compounds that reverse disease-related processes in motor neurons. While most of these compounds are not suitable for direct testing in patients in their present form, they possess important neuroprotective properties, which we are now taking advantage of. The compounds are in the process of refinement and modification to be more suitable for treatment in patients. We are optimistic that the compounds can soon be ready for testing in ALS patients.
How has Project ALS affected your career?
Project ALS has created a stimulating academic environment for cutting edge translational stem cell research, which I had the great opportunity to be a part of during my time at Columbia University. My experience at the Project ALS laboratory provided me with essential tools that I now use in my own laboratory. The nurturing setting fostered an invaluable international network, which I benefit from in current collaborations.
What did you focus on in your early work with Project ALS?
I was particularly interested in setting up new platforms for drug screening using stem cell-derived neurons. I focused specifically on the intrinsic properties of motor neurons that render them susceptible to neurodegeneration. My outstanding goal was to gain new insights into motor neuron vulnerability, and subsequently, use this knowledge to design new therapies for ALS.
What else have you been working on recently?
I presently divide my time between working as a physician and a scientist at the Department of Neurology, Karolinska University Hospital in Stockholm, Sweden. I am involved in both clinical trials for new ALS treatments and basic research projects related to cell stress mechanisms in ALS. Time management is a struggle when you split your attention, but I have the great opportunity to work on projects ranging from cells to patients. My goal is to improve the clinical management for ALS patients, and hopefully contribute to the development of more potent treatments for the disease.
Read the published study here.
Joesph Klim, PhD, a Kirchhoff Family Fellow at the Lab of Kevin Eggan, PhD at Harvard University has discovered that restoring expression of the gene Stathmin2, or STMN2, rescues motor neuron degeneration, a hallmark of ALS. Findings were published on January 14th, 2019 in Nature Neuroscience.
Dr. Klim has spent the last three years studying TDP-43, a protein previously known the be involved in ALS. His recent discovery shows that TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair. So when TDP-43 is perturbed, STMN2 is diminished and motor neurons suffer as a consequence, causing the body to lose the ability to move. Klim used patient stem cell models of ALS, as well as spinal cord samples donated by dozens of ALS patients, to show that boosting STMN2 could slow motor neuron degeneration in patients, regardless of their cause of ALS.
Said Klim, “Our work highlights STMN2 as a credible drug target for ALS and a potential new biomarker.”
Named in honor of former Project ALS board member and inspiration Tom Kirchhoff who passed away from ALS in 2015, the Tom Kirchhoff Family Post-Doctoral Fellowship at Project ALS is given to promising young scientists already making a difference in ALS research. “After meeting the Kirchhoff family”, said Klim, “I was inspired by their strength and courage to pursue ALS treatments as Tom battled this devastating disease and by their resilience and determination to continue this fight after his passing. As the Tom Kirchhoff Family Postdoctoral Fellow, I had the freedom to pursue this complicated and long-term project, and I was bolstered in my efforts by the strong Kirchhoff family spirit.”
Klim’s breakthrough demonstrates the power and interconnectedness of those who are affected by the disease, and those researching it – an important tenet of the Project ALS mission. Said Dr. Kevin Eggan, “These experiments…point towards a clear path for testing whether repairing STMN2 in our friends and family can slow or stop their disease.”
Read more about the study on the Harvard Department of Stem Cell and Regenerative Biology’s website.
(Photo: Dr. Kevin Eggan discusses Klim’s findings at the Project ALS gala onstage with the Kirchhoff family)
Project ALS and Columbia University’s Eleanor and Lou Gehrig ALS Center have opened the ALS Families Project to study relatives of ALS patients who carry genetic mutations associated with the disease.
“Studying the relatives of these patients provides the opportunity to understand the earliest steps in the onset of ALS, which may occur months or even years before obvious symptoms appear,” says Neil Shneider, MD, PhD, who directs the Families Project. “By closely following relatives who carry the same mutation,” Shneider says, “we hope to develop markers of ALS that can guide our efforts to intervene early in the course of the disease.”
“Project ALS recognized an unmet need to follow and examine asymptomatic family members of ALS patients throughout their lives as they, more than any lab model or subject, have great potential to unlock mysteries of the disease, for familial, but also sporadic cases as well,” said Valerie Estess, Project ALS director of research. “We are very excited to partner with Columbia on this program and plan to expand it significantly.”
The program has already enrolled more than 12 pre-symptomatic gene carriers from New York City and elsewhere. Participants will come to Columbia once or twice a year for examination and testing.
Read more about the Families Project and how it will bring us closer to treatments on Columbia Medical Center’s website. Contact [email protected] or 212-420-7382 if you or someone you know would like to participate.
(Photo: Dr. Neil Shneider meets with participants of the Families Project)
Last year, we announced the formation of a six-lab collaboration at the direction of Project ALS to focus on the cell process known as autophagy, or a cell’s ability to clear itself of unwanted proteins. Autophagy Team director, Tom Maniatis, and his laboratory, have led efforts to identify what goes wrong with autophagy in ALS, and how we might fix it. The original team includes leading labs from Columbia, Cornell, University of California San Francisco, and the New York Genome Center. One major focus of this year’s work has been the gene TBK-1, a player in the cell clearing process. Project ALS and Dr. Maniatis recently added collaborators from the New York Structural Biology Center to generate helpful 3-D models of TBK-1 and other autophagy-related genes and targets for use by the team. More recently, Project ALS recruited the eminent Dr. Erika Holzbauer, from the University of Pennsylvania, who is focused on the dynamics of the active transport of cargoes—unwanted protein aggregates—in ALS neurons.
(photo: Drs. Steven Altschuler and Lani Wu of UCSF, researchers on the Project ALS Autophagy Team)
In the medical research world, a “post-doctoral fellow” is the official title for a gifted, young scientist who works 25 hours a day in a laboratory toward research breakthroughs. Thanks to the generosity of its donors, Project ALS has proudly supported several of the world’s finest post-doctoral fellows in ALS and related fields.
This fall, the Tom Kirchhoff Family Fellowship for ALS Research at Project ALS celebrated the three-year success of Joseph Klim, in the lab of Kevin Eggan, at Harvard University. Thanks to the support of the Kirchhoffs, Dr. Klim discovered recently that TDP-43, a protein involved in ALS, was way more involved in the health of motor neurons than previously thought. He also devised a potential therapy, which modulates the effects of TDP-43 in ALS. Says Kevin Eggan, “The discovery that Joe and our team made—supported all the way by Project ALS—suggests a strategy for intervening in all but a very small number of individuals with ALS, regardless of the genetic cause of their disease.”
Dr. Klim now passes Tom Kirchhoff Family Fellowship honors to Emily Lowry, PhD, in the Wichterle Lab at Columbia. Dr. Lowry has devised a method of approximating ALS in a petri dish. Her in vitro model system sheds light on the ALS disease process, and provides a model for testing drugs.
“My dad would be so proud of Project ALS and how far we’ve come in the last eight years,” said Bryn Kirchhoff, who spoke at a recent event, on behalf of her brothers Tommy Jr., Sam, Ty, and the entire Kirchhoff Family. Project ALS is proud of the many post-doctoral fellowships it has supported through recent years, including the Eric McLaren Family Fellowship and the ongoing Carol and Robert Kleiner Family Fellowship.
Let’s be honest, for the most part, experts have failed to deliver potent drugs to clinical trial in ALS. Part of the reason is we haven’t known enough about the genes contributing to ALS…the cellular pathways involved in ALS…or when or how to intervene effectively in the disease process, to truly make a difference. That has all changed.
The newly minted Project ALS Pre-Clinical Core at Columbia University draws on decades and up-to-the-minute ALS breakthroughs throughout genetics, medicinal chemistry, drug screening platforms, disease modeling, drug delivery to the brain, and basic neuroscience research, to identify promising ALS therapies before they ever reach clinical trial.
The Core, as it is known, has been functioning as a virtual drug-screening effort for nearly eight years. Now it’s official—the Project ALS Pre-Clinical Core at Columbia’s Motor Neuron Center, is currently the best available opportunity for drug companies and academic laboratories to test potential ALS drug candidates thoroughly and comprehensively, under one roof. The mission of the Core is to deliver its top performers toclinical trial at the Columbia ALS Clinic, and beyond.
Directed by Neil Shneider, MD, PhD, Serge Przedborski, MD, PhD, and Hynek Wichterle, PhD, the Core comprises five interrelated units: in vitro testing, in vivo testing, custom antibody and viral vectors, neurolipidomics, and a clinical research nurse. Core operations are co-directed by Erin Fleming and Emily Rhodes Lowry, PhD.
The Core is unique among ALS drug screening efforts for its ability to assess drugs in all stages of pre-clinical development. For example, the molecule kenpaullone, a molecule whose therapeutic promise has been known to academic researchers for years, is finally getting its work-over for ALS. Originally deemed a slow track project for the Core, kenpaullone has emerged as a strong finisher…and a clue of intense interest. The Core has also assessed four FDA approved drugs for other indications that may also be useful in ALS. Project ALS and the Core will continue to work with drug companies and academic laboratories to identify additional FDA drug candidates for systematic Core assessment. Finally, the Core is developing novel therapeutics for ALS. Initial efforts to develop all-new approaches look encouraging.
Project ALS is grateful to neurodegenerative disease research, patients, and the growing family of supporters that will beat ALS, for allowing us to build a systematic approach to ALS drug screening based on decades of love, loss, teamwork, and breakthroughs.