May 11, 2007
Research Update — from ALSA’s National Office
Report on The ALS Association’s Drug Company Working Group Meeting on April 30, 2007 in Boston
Roberta Friedman, Ph.D., Research Department Information Coordinator
Every year at the meeting of the American Academy of Neurology (AAN), The ALS Association convenes the Drug Company Working Group to discuss progress toward ALS therapeutics in a gathering of experts from industry, government agencies and academia. Since its inaugural meeting in Philadelphia in 1995, this group has provided a forum for vital dialogue, a unique opportunity not only to discuss the status of collaborative efforts in studying amyotrophic lateral sclerosis (ALS) but also to identify the challenges, obstacles and opportunities that are available to bring promising new research from the lab rapidly into clinical trials.
The Drug Company Working Group is also an opportunity to make sure ALS patients and their families are active participants in the drug development process and that their concerns and their hopes are addressed as we engage the entire ALS community to seek new, effective treatments.
The collaboration of advocacy, research and patient services departments at The Association was represented by the participation at the forum of the vice presidents, respectively, of these departments: Steve Gibson, Lucie Bruijn, Ph.D., and Sharon Matland, as well as Gary Leo, president and CEO of The ALS Association. Partnerships that The Association fosters were evident by presence and participation of scientists from the biotech and pharmaceutical industries, university researchers, ALS clinicians, and representatives of government agencies such as the National Institutes of Health.
Lee Rubin, Ph.D., of the Harvard Stem Cell Institute, spoke about his efforts, with funding from The ALS Association’s TREAT ALS initiative, to use stem cells as the basis of a drug screening effort. He and his colleagues can now generate motor neurons from the stem cells of mouse embryos. This allows the vast numbers of motor neurons needed for automated screening, which can be done automatically by robotics once the parameters are set for the cells, which grow in tiny wells in plates that the robot scans.
The Harvard researchers have identified a simple recipe for generating the motor neurons: just two small molecules will prompt the mouse stem cells to commit to becoming motor neurons. They will start with embryonic stem cells from mice with the mutation linked to some inherited cases of ALS.
With the same approach that is showing success for another motor neuron disease, spinal muscular atrophy, the investigators will look for compounds that can rescue the motor neurons from the challenge of growing in a dish without the usual supportive molecules called trophic factors. Rubin concluded by saying, “we feel confident we can carry this out in short order.” The team will be developing screening tests from the mutant mice and also will be using motor neurons that do not carry the mutant SOD1 gene. They will also test for protection against another stressful situation, excess stimulation by the nerve cell messenger, glutamate, also implicated in ALS.
James Kelly, Ph.D., of Stem Cell Innovations, Inc, presented a similar approach underway at his company and collaborator BioFocus DPI. Also as a way to screen for candidate drug molecules, these companies with TREAT ALS funding will be using the stem cells that are set to become the reproductive organ tissues, as these cells have advantages that make them relatively simple to grow in the lab. They can be directed, with appropriate signal molecules, to become motor neurons instead of the reproductive cells.
With the technology of BioFocus, the cells can then be given so-called “druggable” genes carried in by a virus tool. The genes can then be made to increase or decrease their activity. The cells are tested to see if they can now withstand challenges related to the ALS disease process. Any gene change that rescues cells could then serve as a target for drug development. Automated equipment can then screen large numbers of challenged cells rapidly. The testing so far is in the exploratory phase of characterizing the developing cells for markers of motor neurons.
New progress in the ongoing effort by Cambria Biosciences to find candidate drugs for ALS was presented by Donald Kirsch, Ph.D. This company is testing for compounds that will work by targeting the abnormal clumping of protein suspected in ALS. The motor neurons in the disease show aggregated protein, a feature common for other neurodegenerative disorders such as Alzheimer’s and Huntington’s diseases. The company has a type of lab cell called PC12 that has many properties of neurons. These cells have been engineered to make the ALS-implicated, mutant SOD1 protein. Cambria has identified several potential candidates that rescue these cells from death. Not all protect by directly removing the aggregates; some appear to help the cells by a new, different action not yet clearly understood. The next step for Cambria is testing the most promising leads in the mouse model.
Jasbir Seehra, Ph.D., noted that his company Acceleron Pharma, Inc., has ALS as a focus and is working on a way to increase quality of life through the protein, myostatin, that can build muscle although it does not affect the disease process. The compound available combines the human myostatin with an immune protein. The end result should be to allow muscles to maintain their strength a bit longer. The aim is to protect diaphragm function as much as possible in the face of ALS.
All of these developments provide encouraging progress in the search for more effective treatments of ALS. The Association and its collaborators will keep working to continue along this pathway of hope.
