December 22, 2006
Research Update — from ALSA’s National Office
Yokohama Symposium Reports on Genetics, Clinical Trials Progress in ALS Highlights
Roberta Friedman, Ph.D., ALSA Research Department Information Coordinator
The international symposium on ALS/MND held in Yokohama, Japan, in December and sponsored by the Motor Neurone Disease Association provided the first reports from ongoing efforts to screen for variant genes that might be related to ALS. Reports from the project underway suggest there might be clues that will emerge from these efforts that could point to new genetic influences on the disease. The project itself and its rapid progress were unthinkable even two years ago but now are possible due to rapid advances in technology—and to the willingness of ALS patients to donate DNA samples.
Bryan Traynor, M.D., of the National Institutes of Health who is funded by The ALS Association and the Packard Center at Johns Hopkins reported at the meeting that the partnership had so far screened 276 ALS cases and 275 control samples. Other scientists in a parallel effort using other gene finder chips gave preliminary indication that gene variants are present in ALS patients that they sampled. Any gene variants from these screening efforts will have to be confirmed by direct gene sequencing. These variations are unique to the ALS patients.
The idea behind these projects is that genes vary among people without necessarily a change in function. But such a change is possible and might predispose people to ALS if environmental exposures and life style converge with any gene-based difference to lower the threshold for the motor neurons to be damaged. ALS could arise from genes, the environment or an interaction of both. The opening session of the meeting discussed the proposed environmental factors at work in Pacific Island areas where a form of ALS was prevalent, and it seems genetics of the people might be a part in the phenomenon.
While the newest technology can rapidly pan for variations in the genes, only directly examining each gene highlighted in the screening technology can confirm if a gene is changed in ALS and if that change might alter its function. The coming year should bring more progress in this direction.
Newly Found Protein’s Possible Role in ALS
Other noteworthy reports at the conference included a possible way that a newly discovered protein might play a part in ALS. Canadian ALS researcher Michael Strong, M.D., of the Robarts Research Institute in London, Ontario, presented early evidence that the protein TDP-43, newly implicated in both ALS and a type of cognitive change, interacts with the supporting framework within the long fiber of motor neurons, called the neurofilaments. Strong suggested that the interaction might prompt formation of abnormal deposits of protein within the nerve cell. If confirmed, this would suggest that TDP-43 might affect the processes by which the nerve cell maintains its flow of supplies and its health.
Mouse Genetics: an Influence on Therapeutic Progress
Mice that model the disease process in ALS aid the search for candidate therapies, and studies of mouse genetics might help uncover genes to target. Martina Weidau-Pazos, M.D., Ph.D., at the University of California, Los Angeles, is comparing two mouse models with mutations relevant to ALS. One is the mouse model with mutant SOD1 protein responsible for some inherited ALS cases, and another is a mouse model with a mutation in tau, a protein whose change can produce the cognitive loss in frontotemporal dementia. FTD can occur in ALS and vice versa. There are genes in common in the two mouse models of these diseases that change expression before symptoms even appear. The changes occur in motor neurons micro-dissected from these mice. These gene changes will be worth exploring further.
Denise Figlewicz, Ph.D., formerly at the University of Michigan, Ann Arbor, and now director of research with The ALS Society of Canada has collaborated with Terry Heiman-Patterson, M.D., at Drexel University, Philadelphia, to show that the background genetics of the mouse bred to create the SOD1 mutant can influence the time of disease onset as well as the duration of the disease. This is another line of evidence that ALS may represent an interaction of genetic factors, and that modifying genes may be able to affect the appearance and course of the disease. Once identified, these modifying genes could serve as therapeutic targets. Figlewicz indicated similar studies by Gregory Cox, Ph.D., and Kevin Seburn, Ph.D., at the Jackson Laboratories, Bar Harbor, Maine, that also show how mouse genetics influence the expression of the disease due to mutant SOD1.
Limits to Mouse Model of ALS
Data presented by researchers with the ALS Therapy Development Foundation (ALS-TDF) indicates limitations to the existing mouse model of the disease. Many compounds are effective in modestly prolonging the lifespan of the SOD1 mutant mouse. Yet this has not borne out in clinical trials and in fact could be a chance variation, the researchers said. There is obviously a need to improve the design of experiments that use this mouse model to clearly demonstrate efficacy of drug candidates. Other issues are at play in the lack of translation of mouse findings to man. The most effective but safe dose and the ability of therapeutic candidates to reach target tissues must be determined adequately in the animals before proceeding to clinical testing.
Efforts are underway to standardize the mouse and its testing to improve its predictive value for patient trials. For instance, as with people, animal testing needs to be blinded to rule out unintended bias on the part of investigators. Perhaps the background genetics of the mutant mouse can be standardized as well. Albert Ludolph, M.D., University of Ulm, Germany, reviewed the proposed standards that are being suggested as part of ongoing discussions on mouse models to more accurately reflect the disease and predict therapeutic efficacy. ALS-TDF researchers among others are meanwhile working to identify biomarker genes whose expression consistently changes in the SOD1 mouse that will help its validity as a model of the disease and will also point toward therapeutic targets.
Progress toward New Therapeutics
The SOD1 molecule remains a crucial window into the disease process. Since the inherited and spontaneously appearing diseases are nearly indistinguishable, the mutation involved in some inherited forms serves as a therapeutic target that could be relevant in all ALS. Somehow, the mutation turns the protein toxic. Studies in the lab of Raymond Roos, M.D., at the University of Chicago are finding proteins that specifically interact with the mutant SOD1 protein in a strategy called phage display. Some proteins identified in this manner are players in transport and proper folding of cell materials, processes implicated already in ALS. The team is testing these clue compounds in cell models of the disease.
Researchers working with Harvard investigator Peter Lansbury, Ph.D., at Massachusetts General Hospital reported in Yokohama a set of compounds that can interfere with the ability of mutant SOD1 protein to clump together in abnormal fashion. This aggregation is implicated in the disease process. The active molecules have low toxicity in cell tests and in preliminary mouse testing and might serve as prototypes for drug development.
A session at the meeting provided information about the role of different cells of the nervous system in ALS. Dr. Luis Barbeito’s group at the Pasteur Institute in Montevideo, Uruguay, presented findings on the way that the surrounding astrocytes might factor into the disease. One player is a protein abbreviated as Nrf2, which appears to call into action an array of responses to oxidative damage within cells. Converging lines of evidence implicate Nrf2 and the protective genes that it controls in the disease process of ALS, a process that could be inadequate on its own. Association-funded investigators are actively pursuing this important new lead toward correcting the damage in ALS.
Presentations by the teams led by Don Cleveland, Ph.D., at the University of California, San Diego, and Stanley Appel, M.D., Methodist Hospital, Houston, Texas, highlighted the role of the microglial cells in ALS. Microglial cells that do not make mutant SOD1 are able to prolong survival robustly in mutant SOD1 mice, according to Cleveland’s group. Appel’s team confirmed that microglia expressing mutant SOD1 are toxic and accelerate the disease.
Clinical trials are testing compound candidates, and the meeting gave updates of some progress. Arimoclomol is appearing safe so far, and this candidate will move into a Phase IIb trial. A candidate molecule discovered by the company Trophos is also showing safety and may enter a pivotal clinical trial in Europe in the coming year.
For full program details click here.
