This is part 2 of a 2-part series.
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.
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.”