RESEARCH FEBRUARY/MARCH 2015 BY GINA SHAW Azer the Wildly Successful Ice Bucket Challenge ~e Ice Bucket Challenge raised big bucks on social media. Now, the ALS Association tells us where that cold, hard cash is going. As snowstorms and icy winds batter much of the country, it's hard to imagine willingly pouring a bucket of ice water over your head for any reason. But last August—when temperatures were much more forgiving—that's exactly what about 3 million people did. In an astonishing example of the power of social media, a July 31 dare from former Boston College baseball player Pete Frates, who was diagnosed with amyotrophic lateral sclerosis (ALS) in 2012, quickly went viral. The dare? Dump ice water on your head within 24 hours of being challenged or donate $100 (or whatever amount you could afford) to the ALS Association or another organization supporting ALS research. Pretty soon, the Ice Bucket Challenge meant dumping ice on your head and donating money, and everyone from your neighbor's preschooler to Bill Gates (with a custom-built ice douser), Oprah Winfrey, Jon Bon Jovi, and entire casts of Broadway shows were doing it—and posting their videos online. Even 86-year-old Ethel Kennedy took the challenge. (President Obama donated but declined the ice; actor Patrick Stewart posted a video of himself writing a check.) In La Jolla, CA, prominent ALS researcher Don Cleveland, PhD, who pioneered a novel therapy that turns off the defective genes that contribute to neurodegenerative diseases, watched the online commotion with skepticism. But as the buzz grew into a cacophony of donations and awareness, he, too, saw the value of the challenge. By the end of August, when Dr. Cleveland and his lab taped their own Ice Bucket Challenge video, Frates's dare had raised more than $100 million. As of last fall, donations totaled approximately $115 million. "Every time I think about it, I am overwhelmed," says Nicole Ferrari, a mother of two grade-school children who was diagnosed with ALS three years ago at age 39. "I would not have been able to tell you what ALS was before I was diagnosed. But something as simple as dumping ice over your head has meant that now millions of people across the world are aware of this disease and the impact it has on people like me." For scientists like Dr. Cleveland, who have been cobbling together research grants from the National Institutes of Health (NIH) and much smaller donations to fund their ALS research, the challenge means their work can move forward faster. And the Money Goes to... In early October, the ALS Association announced an initial commitment of $21.7 million to four major programs; with matching gifts, the funds actually total $34.2 million. The programs were chosen because they "had synergies that strengthened each other," says Lucie Bruijn, PhD, the ALS Association's chief scientist. Neuro Collaborative: $5 Million The Neuro Collaborative will harness the efforts of four major ALS research groups around the country, including Dr. Cleveland's lab, that are working on several promising avenues of research. These include studies focusing on novel gene therapies to fix or replace defective genes associated with ALS, the therapeutic potential of human stem cells, and new targets for drug development. Dr. Cleveland says that by the fourth quarter of 2015, the group hopes to begin human trials of an "antisense" drug that will attempt to block mutated genes from producing proteins that contribute to ALS in some patients. Research on gene therapy, which involves delivering an "improved" version of a defective gene directly to a targeted cell, where it will be expressed as a "good" gene, is further back in the pipeline. Still, Dr. Cleveland is optimistic that within three years a gene therapy will be nearly ready to go to trial. "Without the ice bucket funding, this would be going at a much slower pace," he says. ALS ACT: $10 Million ALS ACT (Accelerated Therapeutics), an academic-industry partnership that aims to accelerate testing treatments in clinical trials, has received a matching gift of $10 million from the ALS Finding a Cure Foundation, in addition to the $10 million they received from the ALS Association. The organization plans to use that money to develop brain imaging tools to look for biological signs, or biomarkers, of ALS progression. "Good, objective biomarkers not only help us see how the disease is progressing, but also help us determine whether new treatments may be slowing progression," says Dr. Bruijn. The biomarker initiative will help reveal the underlying biology of ALS, says Merit E. Cudkowicz, MD, MSc, co-chair of the Northeast ALS Consortium, chief of neurology and director of the ALS Program at Massachusetts General Hospital, and a member of the American Academy of Neurology (AAN). "Is this one disease or 100? I hope this helps us target patient populations for treatment trials—maybe some of the past trials have failed because we're lumping together people with different disease biologies." That's very important to Madeline Kennedy, a 61-year-old nurse from Troy, NY, who was diagnosed with ALS in 2012. She now uses a power wheelchair most of the time and has recently noticed that the strength and dexterity in her hands is deteriorating. "It's still hard to believe that this is consuming me, relentlessly," she says. "When I talk to researchers, I ask, 'What if some of these rejected therapies might work in some of us, just not all of us?' People with ALS are a diverse group. It's more of a syndrome than a single disease. We can't let therapies that might work for some people sit on a shelf because we don't have a way to understand the differences among us." Funding for ALS ACT will also support the development of therapies targeting two biological processes that contribute to ALS: the production of misfolded proteins— proteins that have developed structural "errors"—within motor neurons, and inflammation in brain cells. And it will buttress big data-sharing projects, including NeuroBANK, which gathers data from many clinical studies, and the Northeast ALS Consortium Biorepository, which is building a large bank of biological samples for ALS investigators. The samples are matched with extensive clinical, environmental, and demographic information. ALS ACT has also requested proposals for larger clinical trials to test the efficacy of different therapies, which it is hoping to fund, with $1.5 million from the Ice Bucket Challenge, by March 2015. New York Genome Center: $2.5 Million Thanks to Ice Bucket Challenge donations and a matching gift from the Tow Foundation, the recently established New York Genome Center, under the leadership of Robert Darnell, MD, PhD, and Hemali Phatnani, PhD, has carved out a niche just for ALS, says Dr. Bruijn. "The center hopes to identify the unique targets and pathways linked to the diseases," she says. Project MinE: $1 Million Efforts at the New York Genome Center will be complemented by Project MinE, an international program started by Bernard Muller, a Dutch ALS patient. The program aims to identify mutations in genes linked to inherited or familial forms of the disease, as well as to sporadic ALS, which is not linked to a specific cause, in at least 15,000 people. "A global effort is essential in identifying new genes, as various populations have more prominent representation of one or another gene or may have gene How much has been committed so far? mutations unique to a particular geographic population," says Dr. Bruijn. The project will be led by John Landers, PhD, at the University of Massachusetts in Worcester, MA, and AAN member Jonathan Glass, MD, at Emory University in Atlanta. Certified Treatment Centers of Excellence: $3 Million The ALS Association awards grants annually to its 43 Certified Treatment Centers of Excellence, which are centers established around the country to define and support a national standard of care, and the Ice Bucket Challenge money allows them to increase these grant amounts from $12,500 to $25,000 per center for the next three years. Some of the funding will also be used to develop regulatory guidance for ALS drug development. And the Rest Goes to... The ALS Association plans to work with a wide range of partners and will continue to solicit ideas from the broader ALS community on how to distribute the remaining $90 million in Ice Bucket Challenge funds, says Dr. Brujin. "We're talking with other ALS organizations about partnerships, including more recently Target ALS, the group at Columbia University led by Chris Henderson, PhD." Dr. Henderson is director of Columbia's Project ALS/Jenifer Estess Laboratory for Stem Cell Research, as well as the ALS foundations Prize4Life and Team Gleason. Other initiatives in the pipeline include a program to build mouse models of ALS more quickly and a grant program designed to move promising drugs through the preclinical phase of testing so they can get into clinical trials faster. "There's great work being done in academic medical centers, but you need an industry partner to develop treatments," says Dr. Bruijn. "We will cast our net wide initially with smaller funds, and then focus on the most promising initiatives." The call for these proposals will likely be issued this spring, she says. Missed ~e Ice Bucket Challenge? You don't need to dump ice on your head to donate to ALS research, as Sir Patrick Stewart so eminently proved in his own brilliant video (which featured the actor sitting at a desk and writing a check).