December 15, 2006
Research Update — from ALSA’s National Office
Research Department Year-End Wrap Up: 2006 Builds on Progress Toward ALS Therapies
Roberta Friedman, Ph.D., ALSA Research Department Information Coordinator
New discoveries of genes and proteins tied to ALS provide a wide window into the disease. Such discoveries this year represent exciting steps toward effective therapies. A genome wide hunt for genes possibly involved in the disease is progressing rapidly as reported at the meeting of the MND/ALS Alliance in Yokohama. “Contributions from patients and the collaboration among funding organizations have enabled the genome search that is bringing clues to which genes might be involved in ALS,” said Lucie Bruijn, Ph.D., science director and vice president of The ALS Association.
Patients make this and other projects possible by deposits to banked DNA. The DNA repository housed at Coriell in New Jersey, established in collaboration with the National Institutes of Health, now contains more than 1,293 DNA samples from sporadic ALS patients and 126 familial DNA samples. “This is an example of the exciting partnerships that we can provide,” Bruijn said. “The repository is an important resource for progress in ALS.”
The hunt through the region on chromosome 9 that contains an ALS mutation has narrowed the region scientists now need to search. This region is linked to a form of ALS that can involve cognitive changes. Researchers this year discovered additional genes linked to frontotemporal dementia, which can overlap with ALS.
In a real step forward, a team at the University of Pennsylvania found that a protein appears in both ALS and in this type of dementia. The protein, called TDP-43, is apparently present in abnormal deposits within nerve cells in both disorders. In both it is tagged by ubiquitin, a protein which marks defective proteins for destruction. This solves a long standing mystery, the identity of ubiquinated proteins in cells damaged in each disorder. How the protein is involved in the disease process is currently under investigation with a clue provided at Yokohama by Michael Strong, M.D., of the Robarts Institute, London, Ontario, Canada.
Finding these common links builds on groundwork laid by the first workshop last year on FTD and ALS sponsored in part by The ALS Association. Also key to discovery of the TDP-43 link was contribution of samples after loved ones passed from families served by the Greater Philadelphia Chapter of The ALS Association. Ongoing studies by Catherine Lomen-Hoerth, M.D., Ph.D., at the University of California, San Francisco, seek a simple test to find those ALS patients at risk to develop cognitive changes.
As the year ended, The ALS Association announced funding through its TREAT ALS (Translational Research Advancing Therapy for ALS) initiative for a new biotech collaboration to establish a lab grown set of motor neurons derived from human stem cells. These cells will be engineered to express or shut off a large number of genes to see which might be able to modulate the cell response to challenges relevant to the disease process of ALS. Identification of new gene targets in this system may provide new clues for drug development. Biotech partners in the project are Galapagos and Stem Cell Innovations. The TREAT ALS initiative is The ALS Association’s new drug discovery program and clinical trials process.
With an eye toward new clinical trials, researchers led by Don Cleveland, Ph.D., published in the Journal of Clinical Investigation that silencing mutant protein prolongs life in rats with features of the disease. The approach called antisense is planned for clinical testing in ALS perhaps in the coming year. Investigators first must confirm safety of the direct delivery method to spinal fluid in research animals and meet other FDA requirements.
The antisense approach to ALS was funded from its inception by The ALS Association, and its progress into the clinic is supported by the TREAT ALS program. Two new trials are funded by the initiative this year to test new ways of gauging disease progress and possible clinical candidates.
Research publications this year have added hope for cell therapy in ALS. Jeff Macklis of Harvard, funded by The ALS Association, provided a way to follow and manipulate the brain cells lost in ALS. The new information should command the attention of those seeking to harness the promise of stem and other cell therapies. Other encouraging evidence favoring the stem cell approach to ALS appeared in publications by Johns Hopkins researchers.
Two workshops this past year brought together investigators new to the ALS field, and just recently, experts in the area of axon biology to discuss how the long fiber of nerve cells functions and what changes might come about in ALS. These workshops serve to build collaborations that will work toward finding effective therapies for the disease.
Anticipation of progress along many routes toward ALS therapy follows reports at the Neuroscience Meeting in the fall in Atlanta. The first participant in an ALS clinical trial of brain computer interfacing showed ability to learn within a day to control a computer cursor simply by thinking about it. The strategy could allow use of assistive devices to achieve better quality of life. Also at the meeting, Milton Safenowitz Post-Doctoral Fellow Christine Haenggeli, M.D., working at Johns Hopkins University with Jeffrey Rothstein, M.D., Ph.D., showed that delivery of a trophic factor directly to the spinal cord in mice produced a modest increase in survival. Ways to improve the action of this molecule are a renewed focus at the biotech company Ceregene. Peter Carmeliet, M.D., Ph.D., meanwhile said in a press conference at the meeting that a trial in ALS patients of new delivery methods for another trophic factor could start within the next year.
Patients with ALS can already enroll in a trial of combined, investigational therapies funded through TREAT ALS. Each of the combinations to be tested has prolonged survival in rodent models of the disease to a greater degree than any of the compounds used alone. A trial of ceftriaxone in ALS is also enrolling patients. “We recognize that the best hope for ALS may reside in combining promising treatment candidates to best address the entire disease process in what is obviously a complex disorder,” Bruijn said.
At the meeting of the American Academy of Neurology in San Diego, investigators at Metabolon, part of a consortium funded by The ALS Association, showed a set of biomarker molecules are altered in ALS. The consortium is working to further validate these markers in early stage ALS patients. Also at the April meeting, investigators at Trophos in Marseille, France showed a candidate compound rescued lab-grown motor neurons from deprivation of growth factors and increased survival in a mouse model of ALS. Pivotal clinical testing is being planned for ALS in Europe.
“We have several clinical trials in progress that are definitely exciting,” Bruijn said. “And the chromosome 9 progress and the other gene discoveries this year, together with our new drug target identification project, opens doors to additional therapeutic approaches.”
