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ALS Ice Bucket Challenge Returns for a Repeat Performance in 2015

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Last year's ice bucket challenge for amyotrophic lateral sclerosis netted $220 million in donations for ALS charities, and the 2015 challenge is off to a strong start with $100,000 from Major League Baseball. Alzforum looks at how all that money is being spent, on both clinical and basic research as well as patient care.

Divvying Up the Ice-Bucket Dollars: Challenge Speeds Trials, Research

On July 31, 2014, former college baseball player Pete Frates uploaded a 52-second video to Facebook. Frates, who has amyotrophic lateral sclerosis, bobbed his head to the tune of “Ice Ice Baby.” While he stayed dry to protect his health, Frates and his co-instigators encouraged others to dump frigid water over their heads to raise awareness, and funds, for ALS research. The result: An unprecedented amount of money started flowing into the coffers of amyotrophic lateral sclerosis charities. People from all walks of life took the plunge and sent money to various charities, supporting research on a disease many had not heard of before 2014 (see Sep 2014 news). The ice bucket challenge raised more than $220 million by summer's end, according to the ALS Association, a U.S.-based charity that alone took in $115 million. The ALS ice bucket challenge is back this summer. Frates and co-instigator Pat Quinn headlined the kickoff event today at Fenway Park in Boston, a day after Major League Baseball announced a $100,000 donation to The ALS Association. As donors get wet again, Alzforum asks, how is 2014’s ice bucket challenge money being spent?

Cold, Hard Cash.

The U.K. Motor Neurone Disease Association celebrated its windfall in ice. [Courtesy of MND Association.]

Different charities have taken different approaches, putting money toward care of people with ALS and their families as well as clinical trials and basic research. Some decided quickly how to spend the windfall, while others are still planning. ALS charities have been working together to share stewardship of the ice bucket challenge concept and ensure that funds are distributed wisely, said Terry Helman-Patterson of the Drexel University College of Medicine in Philadelphia. Helman-Patterson co-chairs the Northeast ALS Consortium and heads the ALS Hope Foundation, which netted $70,000.

The ALS Association has earmarked $77 million for research, $23 million for patient services, $10 million for public and professional education, and $5 million for fund-raising and donation processing fees. This is quite a change for an organization that normally operates on a $25 million annual budget, with about a quarter of that typically going to research. In October 2014, the association announced it would put $18.5 million toward seeding four new collaborations. ALS Accelerated Therapeutics, which aims to speed up trials, received $10 million to match $10 million from the ALS Finding a Cure Foundation. A sequencing project from the New York Genome Center received $2.5 million, matching a contribution from the Tow Foundation. The U.S. arm of an international sequencing effort, Project MinE, got off the ground with $1 million. Finally, the association offered $5 million to the Neuro Collaborative, a group of three California labs involved in several drug development projects. Those investments are seed money, and the association could offer more funding if the recipients meet milestone goals, said its chief scientist, Lucie Bruijn.

On July 14, the association announced the latest disbursements from its ice chest, with $11.6 million going to 58 new grants focused on genetics, disease mechanisms, biomarkers, drug development, and postdoctoral training. More research funding, totaling about $7.5 million, will be announced later this summer, Bruijn said. She said her board, in conjunction with peer review by experts, made funding decisions based on its goals of research, patient care, and advocacy.

The timing of the ice bucket challenge was perfect, said researchers who spoke with Alzforum. With the recent rapid-fire discoveries of new genes, and promising results from therapeutic approaches such as antisense DNA, the field was progressing and attracting interest from pharmaceutical companies, commented Clotilde Lagier-Tourenne of the University of California, San Diego (see Feb 2008 news; Sep 2011 news; Sep 2013 news story). However, scientists’ ideas were bigger than their bankrolls. Some stocked freezers full of DNA samples but had no money to sequence them; others cryopreserved patient cells that they would make into induced pluripotent stem cell (iPSC) lines if they only had the cash. Data from early stage studies of drugs languished with no backing to move ahead. With the new funding, trials are progressing, thousands of genomes are in line to be sequenced, and stem cells are morphing into motor neurons.

Once diagnosed, most people with ALS live for only a few years. Charities face enormous pressure to spend their ice bucket funds on studies that will quickly yield treatments for today’s patients. However, organizations also want to invest the one-time cash infusion wisely for the future. The ALS Association, for example, has yet to commit nearly $40 million of its planned research spending. Some researchers say that is fiscal responsibility. “You do not want to use funds on research today that could be better spent on research tomorrow,” pointed out Jonathan Katz of the Forbes Norris MDA/ALS Research & Treatment Center at the California Pacific Medical Center in San Francisco.

However, others lament the gradual pace. “I think that people are making decisions very slowly, considering the life cycle of an ALS patient,” said Steven Perrin, chief executive officer of the ALS Therapy Development Institute (ALS TDI), which rapidly earmarked its $4 million bucketful of cash for two clinical trials and a precision medicine program.

Many ALS organizations have divvied their pot to fund both research and caregiving, and some scientists wonder if that was the right move. Katz suspects donors had science in mind. “I think the right thing to do is to cure the disease with [the ice bucket money],” he said. However, the ALS Association has always been up front about patient care being part of its mission, and used some of the new money to boost its grants to multidisciplinary clinics. In recent years, the association gave each of 33 clinics a grant of $12,500 annually. It has now raised that to $25,000, and added 13 more clinics to the list. The ALS Association expects to add four more clinics by the end of 2015, said Kimberly Maginnis, chief care services officer. Many centers use the grants to hire additional staff, Maginnis said. 

The U.K. Motor Neurone Disease Association, which took in a little more than £7 million ($10.8 million U.S.), and MND Australia, which received about $2.5 million Australian ($1.9 million U.S.), also have devoted funds to patient care. In fact, Australians who took the ice bucket challenge wanted exactly that. MND Australia gave contributors the choice to donate to research or to care and advocacy. “It was exactly a 50/50 split,” reported Janet Nash, the organization’s executive director for research.

Trials for Today
Even so, a substantial portion of ice bucket funding will go to speeding up the search for treatments. ALS-TDI is banking on immunotherapy with two antibodies. One is an antibody to SOD1, which misfolds and aggregates in the neurons of people with ALS. In preclinical studies, the antibody extended the lives of ALS model mice (see Apr 2013 conference news). In addition, TDI’s antibody to CD40L, a T-cell receptor ligand, delayed disease in ALS model mice and looked safe in primates, Perrin said (see Mar 2010 news). With $3 million in ice bucket funds, TDI will be able to produce enough of each antibody to get clinical studies off the ground, Perrin said.

ALS ACT also will be pushing trials forward. Merit Cudkowicz of Massachusetts General Hospital in Boston, one of the ALS ACT investigators, noted that some drugs with promising results have been stalled, waiting for funds to proceed to the next trial. The organization intends to disburse funding for up to two trials in each of the next three years.

On July 1, ALS ACT announced it would pay $3 million for trials of mexiletine and sodium chlorite. Scientists hope that mexiletine, a sodium channel blocker, will reduce hyperexcitability in motor neurons. People already take this drug to temper cardiac arrhythmia, and it proved safe for people with ALS in an earlier Phase 2 trial (Shibuya et al., 2015). 

Sodium chlorite, a salt used in water purification, has already been studied as a treatment for HIV, where it seems to downregulate macrophage activity (McGrath et al., 2002). Intravenous sodium chlorite showed promising results in a Phase 2 trial for ALS back in 2012, but funding to test it further was lacking, Cudkowicz said (see Jan 2013 conference news). In addition, ALS ACT will spend some ice bucket dollars on preclinical studies of therapeutic regulatory T cells and a treatment to silence the SOD1 gene.

Ice bucket donations are fueling trials beyond U.S. borders as well. ALS Canada, which received $17 million Canadian ($13.4 million U.S.), will spend $500,000 Canadian on a nationwide study of pimozide. This inexpensive, generic antipsychotic came to Canadian scientists’ attention in a screen using a zebrafish model of ALS, said Lawrence Korngut of the University of Calgary Cumming School of Medicine, lead investigator on the trial. Pimozide, a calcium channel blocker, strengthens neuromuscular junctions. A 25-person Phase 2 trial was already in motion, and with the new money, Korngut will conduct a separate Phase 2 trial of 100 people. In the United Kingdom, the Motor Neurone Disease Association plans to contribute £500,000 (about $778,000 U.S.) to a European trial of low-dose interleukin-2, which researchers predict will promote the neuroprotective activity of T cells.

Besides these trials, ALS organizations are investing in projects they can leverage for future research. See Part 2.—Amber Dance

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References

News Citations

  1. After a Summer of Icy Showers, What Will Happen with Buckets of Cash for ALS?
  2. Gene Mutations Place TDP-43 on Front Burner of ALS Research
  3. Corrupt Code: DNA Repeats Are Common Cause for ALS and FTD
  4. Lou Gehrig’s RNA Interference Success in Mice, Monkeys
  5. Human-Derived SOD1 Antibodies Show Promise in ALS Mice
  6. ALS-TDI Scours Transcriptome, Targets CD40L
  7. Chicago—ALS Clinical Trials: New Hope After Phase 3 Setbacks
  8. Divvying Up the Ice-Bucket Dollars: Looking Long-Term

Paper Citations

  1. Shibuya K, Misawa S, Kimura H, Noto Y, Sato Y, Sekiguchi Y, Iwai Y, Mitsuma S, Beppu M, Watanabe K, Fujimaki Y, Tsuji Y, Shimizu T, Mizuno T, Nakagawa M, Sawaguchi K, Hanaoka H, Kuwabara S. A single blind randomized controlled clinical trial of mexiletine in amyotrophic lateral sclerosis: Efficacy and safety of sodium channel blocker phase II trial. Amyotroph Lateral Scler Frontotemporal Degener. 2015;16(5-6):353-8. Epub 2015 May 11 PubMed.
  2. McGrath MS, Kahn JO, Herndier BG. Development of WF10, a novel macrophage-regulating agent. Curr Opin Investig Drugs. 2002 Mar;3(3):365-73. PubMed.

External Citations

  1. ALS Association
  2. Project MinE
  3. ALS Therapy Development Institute
  4. U.K. Motor Neurone Disease Association
  5. MND Australia
  6. SOD1
  7. ALS Canada

Further Reading

Papers

  1. Take the plunge (for charity). Nat Med. 2014 Oct;20(10):1079. PubMed.
  2. Wicks P. The ALS ice bucket challenge - can a splash of water reinvigorate a field?. Amyotroph Lateral Scler Frontotemporal Degener. 2014 Dec;15(7-8):479-80. PubMed.

Divvying Up the Ice-Bucket Dollars: Looking Long-Term

Thanks to the ice bucket challenge for ALS, several clinical trials are picking up steam (see Part 1). However, as there are no guarantees these trials will succeed, ALS charities are also planning long-term. “We want to establish a platform that will allow us to do bigger and better work in the future,” said Brian Dickie, director of research development at the Motor Neurone Disease Association in the United Kingdom. Part of that will involve establishing collaborations and providing clinics with the training and infrastructure needed to test new treatment ideas as they arise. In addition, ALS organizations are investing ice bucket dollars in early drug development and in basic research on genetics and biomarkers.

Getting Wet for ALS: Researchers at the Queensland Brain Institute in Australia take the ice bucket challenge. [Courtesy of Janet Nash, MND Australia.]

Seed funding from the challenge jump-started two major sequencing initiatives, the international Project MinE and a program at the New York Genome Center. Combined, they plan to sequence an unprecedented number of whole human genomes. The former aims to sequence the DNA of 15,000 people with mainly sporadic ALS and 7,500 controls. “Project MinE is one of the biggest gene-hunting initiatives in the world for any condition,” said Dickie. “The collaboration was just getting off the ground. [The ice bucket challenge] has given it a considerable shot in the arm.”

For comparison, the 1000 Genomes project, a huge endeavor when it started in 2007, published 1,092 sequences in 2012 and plans to keep going until it reaches 2,500 (see Nov 2012 news). In the Alzheimer’s field, the National Institutes of Health has committed $25 million to the Alzheimer’s Disease Sequencing Project. The project plans to sequence the exomes of about 5,000 sporadic cases, 685 familial cases, and 5,000 controls, plus whole genomes of 584 people from kindreds with AD (Dec 2013 news). In addition, between the Alzheimer’s Disease Neuroimaging Initiative, other NIH efforts, and European cohorts, AD researchers can expect to see a further 2,300 or so exomes and 2,300 whole genomes, estimated Alison Goate of the Icahn School of Medicine at Mount Sinai (see Oct 2013 news).

Project MinE, founded in 2013 by scientists and people with ALS in the Netherlands, invites other nations to join. The catch? Scientists in those countries must raise their own cash for sequencing. For many organizations that received ice bucket donations, the fledgling Project MinE was an obvious way to put the money to good use quickly, Dickie said. Since last summer, the U.K. MND Association has committed more than £2 million (about $3.1 million U.S.) to the project. It will send in previously banked DNA for sequencing (Smith et al., 2015) and, if it has the extra funds, also sequence DNA from other U.K. collections, Dickie said. MND Australia has earmarked $100,000 Australian (about $74,000 U.S.) for Project MinE, to sequence 100 cases and 50 controls.

In the United States, too, scientists and the ALS Association were interested in Project MinE, but could not join until the ice bucket challenge came along, said John Landers of the University of Massachusetts Medical School in Worcester. The Association has committed $1 million to the project so far, allowing it to kick off in the States. Landers estimates a single genome costs about $2,000 these days, so that money enabled his group to sequence 384 samples and pay for sample collection and increased data storage.

“The globalization of Project MinE outside the Netherlands was clearly fueled by the ice bucket challenge,” said Terry Helman-Patterson of the Drexel University College of Medicine in Philadelphia. The investment and volume of sequencing should make a real difference to research, she said. “The more people who get into Project MinE, the sooner we will be able to identify new genes linked to ALS.”

Also in the United States, Hemali Phatnani and colleagues at the New York Genome Center initiated a sequencing project with ice bucket funds. They plan to sequence at least 1,727 whole genomes from people with both familial and sporadic ALS over a three-year period. They will also analyze RNA sequences of some samples to correlate genotypes with expression profiles and clinical data. Phatnani and colleagues intended to start this project before the summer of the ice bucket challenge, she said, and the Tow Foundation had promised them a $2.5 million contribution if someone else would match it. Thanks to the challenge, the ALS Association stepped up. “The ice bucket challenge made this possible,” Phatnani said.

MND Australia also invested its research donations in a project focused on non-familial ALS. The Sporadic ALS Australian Systems Genomics Consortium will include single-nucleotide polymorphism (SNP) and methylation analysis of 200 people with ALS and 200 controls. Knowing thousands of genome sequences will be particularly important in teasing out genetic factors involved in sporadic ALS, Landers said. Phatnani noted that having multiple projects means that if a new gene pops up in one, other scientists could quickly try to confirm it. Historically, scientists have often been unable to replicate genetic discoveries.

Beyond genetics, ice bucket grantees are hunting for new treatments. The Neuro Collaborative, sponsored by $5 million in seed money from the ALS Association’s ice bucket windfall, links Steven Finkbeiner’s lab at the Gladstone Institutes in San Francisco with Don Cleveland’s at the University of California, San Diego, and Clive Svendsen’s at the Cedars-Sinai Medical Center in Los Angeles. The researchers aim to bridge the divide between academic scientists and drug companies. Often, researchers have good ideas but not enough preclinical data for industry to take an interest. The Neuro Collaborative aims to develop some of those ideas to the point where the academic labs could collaborate with a company. Each researcher brings different expertise to the table. Svendsen will differentiate patient-derived stem cells into motor neurons and other cell types relevant to the study of ALS, while Finkbeiner’s lab focuses on drug discovery in such cell lines. Cleveland will test gene therapies in mouse models as a prelude to people, and help identify good targets for small molecules. 

Other groups are putting ice bucket money toward stem cell research. In the United Kingdom, the MND Association was sitting on cryopreserved blood cells that match the samples in its DNA bank. It can now convert those into induced pluripotent stem cell (iPSC) lines, and from there into neuron or glia types relevant to ALS, Dickie said.

In the United States, the generation of iPSC lines is just one part of the ALS Therapy Development Institute’s multipronged precision medicine program. For this project, ALS-TDI has invited people with ALS—150 so far—to undergo a detailed genetic, cellular, and clinical analysis. That will include genome sequencing and generation of a personal iPSC line. ALS-TDI will also collect longitudinal clinical data, such as voice recordings and movement ability, the latter from wrist and ankle accelerometers. When ALS-TDI launched the project early last summer, it aimed for 25 patients; now it aims for 300, thanks to ice bucket donations, said chief executive officer Steven Perrin.

In addition, ice bucket funds will help scientists seeking a crucial ingredient for future clinical trials—biomarkers. Currently, clinicians determine how well an ALS drug candidate performs by assessing symptoms and survival. The right biomarkers can better indicate if a drug works as predicted. As part of ALS Accelerate Therapeutics (ALS ACT), another initiative funded by the ALS Association, General Electric Healthcare—makers of MRI and PET scanners—and members of the ALS ACT collaboration will develop imaging tools and PET ligands as potential biomarkers.

On June 3, the ALS Association announced that it would spend nearly $2 million on three more biomarker-related projects. One will test a promising ALS signature, the ratio of neurofilament heavy chain to complement C3, in the cerebrospinal fluid (Ganesalingam et al., 2011). The other two are biosample repositories. The funding will help expand a collection of blood and cerebrospinal fluid managed by the Northeast ALS Consortium. It also will support a repository started by the Clinical Research in ALS and Related Disorders for Therapeutic Development Consortium (CReATe), a newly funded collaboration aiming to help stratify patients in future trials. In both cases, researchers will collect samples of fluids, such as blood, as well as clinical data, longitudinally. The U.K. MND Association also committed the largest chunk of its ice bucket research investment, about £2.3 million ($6 million U.S.), to a longitudinal biomarker study still at the planning stages. They will collect blood and cerebrospinal fluid plus associated clinical data.

If these projects go well, scientists hope pharmaceutical companies will capitalize on the findings when running trials. To help assist drugmakers new to this orphan disease, the ALS Association will devote some funding to developing guidelines for conducting ALS trials. How many subjects do trials require? How can drugmakers balance risk and benefit for these fatally ill patients? What biomarkers should trial designers use? The Food and Drug Administration publishes such guidance for other diseases, and is finalizing one for early stage Alzheimer's. The draft guidelines have already made a difference to clinical trials in the AD field, said Maria Carrillo of the Alzheimer’s Association. “The FDA has acknowledged that biomarkers in the field are maturing … it has really encouraged clinical trials to be confident to use biomarkers,” she said. Because the FDA offers no such guidance for ALS trials, the ALS Association will submit its own as a suggested starting point. It hopes this will make trials faster and cheaper, and help attract pharmaceutical companies to the field. “That [document] is going to be extremely important,” said Jonathan Katz of the Forbes Norris MDA/ALS Research & Treatment Center at the California Pacific Medical Center in San Francisco.

Sustaining Momentum
Overall, ALS charities worldwide received more than $220 million from the 2014 ice bucket challenge. A year later, some groups still have cash to burn. The ALS Association expects to announce a further $7.5 million in grants this summer, but that still leaves nearly $40 million of its $77 million research budget unspent. That money is not nearly enough to carry even one treatment from the bench to FDA approval, a process estimated to cost $1 billion to $2 billion (see press release).

Nonetheless, researchers celebrate how the ice bucket challenge brought a rare disease to the fore of the world’s consciousness. “ALS is now a household name,” said Perrin. “The awareness raised by the challenge almost dwarfs the money.” For example, the ALS Association’s charity walks have attracted more participants over the past year than ever before; one in Pittsburgh enrolled 3,277 walkers in 2014, compared to 1,977 in 2013. The awareness also means people and their doctors might recognize ALS symptoms earlier, said Lawrence Korngut of the University of Calgary Cumming School of Medicine. He has noticed that people with ALS symptoms now seem to reach his clinic at earlier stages of the disease.

Many researchers are entering the field for the first time, bringing fresh perspectives, noted Finkbeiner. Merit Cudkowicz of Massachusetts General Hospital (MGH) in Boston added that ALS has transformed from a niche field with few job opportunities into a hot topic. At MGH’s Institute for Neurodegenerative Disease, she estimates that approximately 10 percent of her colleagues worked on ALS last year; now about half are pursuing ALS projects.   

To keep up the momentum, the original instigators of the ice bucket challenge hope for more icy showers this summer. Pete Frates and Pat Quinn state online, “Until we find a cure, every August is ice bucket challenge month.”—Amber Dance

References

News Citations

  1. Genetics Project Update: Over 1,000 Genomes and Counting
  2. Alzheimer’s Whole-Genome Data Now Available From the NIH
  3. ADNI Full Genetic Sequences Now Available for Download

Paper Citations

  1. Smith L, Cupid BC, Dickie BG, Al-Chalabi A, Morrison KE, Shaw CE, Shaw PJ. Establishing the UK DNA Bank for motor neuron disease (MND). BMC Genet. 2015 Jul 14;16:84. PubMed.
  2. Ganesalingam J, An J, Shaw CE, Shaw G, Lacomis D, Bowser R. Combination of neurofilament heavy chain and complement C3 as CSF biomarkers for ALS. J Neurochem. 2011 May;117(3):528-37. PubMed.

Other Citations

  1. Part 1

External Citations

  1. Motor Neurone Disease Association
  2. Project MinE
  3. New York Genome Center
  4. 1000 Genomes
  5. Alzheimer’s Disease Sequencing Project
  6. Alzheimer’s Disease Neuroimaging Initiative
  7. MND Australia
  8. ALS Association
  9. ALS Therapy Development Institute
  10. Northeast ALS Consortium
  11. Clinical Research in ALS and Related Disorders for Therapeutic Development Consortium
  12. one for early stage Alzheimer's
  13. press release
  14. online

Further Reading

Papers

  1. Take the plunge (for charity). Nat Med. 2014 Oct;20(10):1079. PubMed.
  2. Wicks P. The ALS ice bucket challenge - can a splash of water reinvigorate a field?. Amyotroph Lateral Scler Frontotemporal Degener. 2014 Dec;15(7-8):479-80. PubMed.