Although familial, or inherited, ALS (FALS) and the sporadic (uninherited) form of the disease demonstrate similar progression patterns after symptoms appear, the causes for sporadic ALS remain elusive, while a number of genetic mutations that cause FALS have been — and continue to be — uncovered.
Such progress in FALS research was the focus of an hourlong webinar broadcast March 25, 2010, by the ALS Therapy Development Institute in Cambridge, Mass. In addition to advances in technology that are making it easier for scientists to probe the mechanisms that drive FALS, a growing body of knowledge is revealing targets at which researchers can aim therapeutics, reported ALS TDI CEO and Chief Scientific Officer Steve Perrin.
FALS by the numbers
The familial form of ALS makes up 10 percent to 20 percent of all cases. Approximately 15 genes are now known to cause FALS. The three most common are superoxide dismutase 1 (SOD1), fused in sarcoma (FUS) and TAR DNA binding protein (TARDBP, or TDP43), with each of these accounting for approximately 10 percent of all FALS cases.
Perrin reported, however, that the number of genetic mutations associated with FALS is growing as researchers find more sophisticated methods of uncovering them. New technological tools, he said, soon will help to identify cases now classified as sporadic as, in fact, familial.
ALS TDI’s preclinical (laboratory-based) therapeutic development efforts begin with describing the basic mechanisms for disease onset and progression. This is followed by the development of drugs that are systematically and rigorously tested in a preclinical animal model.
ALS TDI uses a mouse model classified as SOD1 G93A and has done a lot of work toward creating an optimized study design that eliminates so-called “noise,” or “unrecognized variables,” that may cloud study results.
The SOD1 mouse model, Perrin said, is a good one for learning about the mechanisms of ALS and for testing drugs in a systematic fashion before moving into human clinical trials. It’s “very well-characterized” and “has a predictable disease course, just like in man,” he said.
ALS TDI also has begun establishing a colony of the recently developed TDP43 mouse model, in which an ALS-like disease is caused by a TDP43 gene mutation, with plans to characterize that model and use it in testing as well.
FALS research at ALS TDI
Perrin noted that disease progression, not cause, is “what you can build drugs against,” so ALS TDI focuses on developing therapeutics directed not at what triggers the disease (such as a genetic mutation or an unknown cause), but at slowing or stopping it once it’s started.
One payoff of ALS TDI’s research efforts is a promising drug called ALSTDI-00846, an antibody that targets what is called the “costimulatory pathway” (see “Immune System Modulator,” Research Roundup May-June 2010).
“It’s the first drug ALS TDI has ever tested that slows down muscle loss, slows down disease progression, slows down the decrease in neurological scoring, and extends survival,” Perrin noted. “It has quite a significant effect, which makes it quite exciting.”
ALS TDI’s first quarter 2010 Research Update webcast is scheduled for 6 p.m. EDT, May 18.
To view a complete schedule of ALS-related news and topics, as well as archived webcasts, webinars and conference calls, visit the ALS TDI website at www.als.net and click on “Research.”