Human-focused research to find answers about ALS

Updated October 17, 2018

The first ALS gene was discovered over two decades ago. By the end of 2017, scientists had found more than 25 genes. By studying these genes that are involved in familial ALS, which accounts for 5 to 10 per cent of ALS cases, researchers hope to learn more about the 90 per cent of sporadic ALS cases that are not linked to a family history.

One of the most common ways researchers study the role of genes in ALS is in animal models in the lab. However, within each study, they are investigating one gene mutation at a time. As a result, the animals display similar disease onset and progression, unlike human ALS that affects people in many different ways. “Finding new ALS-related genes is definitely important. However, we also need human-focused research so that we can learn why people with ALS experience such a wide range of onset, symptoms, progression and duration,” says Dr. David Taylor, VP Research at ALS Canada.

Understanding how ALS affects people so differently will guide the development of personalized treatments. It will also help researchers determine which participants should be included in clinical trial groups to ensure the best chance of finding out whether new treatments may work.

Large-scale research involving humans with ALS would not have been possible a decade ago, but it is today, thanks to advances in biobanking, DNA sequencing, stem cell technologies and computer analytics. The ALS Canada 2018 Virtual Research Forum on Wednesday, October 17, 2018, included speakers from three international organizations that are collecting clinical information and biological samples from people with ALS and studying massive amounts of data to uncover new insights.

Answer ALS Research Program

Magnifying GlassThe Answer ALS Research Program is the most comprehensive study of ALS ever conducted. The overall goal of the program is to discover biological signatures of the disease that may help speed up diagnosis and match people with ALS to targeted therapies to counteract disease progression, based on the underlying biology of their ALS.

In 2016, researchers started collecting whole blood, plasma, serum and optionally, cerebrospinal fluid from people living with ALS. Their goal is to collect biological samples from 1,000 volunteers with ALS at eight ALS clinics in the United States.

The Answer ALS Research Program is a collaboration of experts from multiple scientific fields: clinical research, regenerative medicine, cell biology, multi-omics, big data and machine learning. Scientists at the New York Genome Center are extracting DNA from blood samples and performing whole genome sequencing. At Cedars-Sinai Medical Center (CSMC) in Los Angeles, researchers are isolating stem cells from blood samples and reprogramming them to become motor neurons; the cell type affected in ALS. Scientists at other collaborating centers are examining the motor neurons using multi-omics and generating massive amounts of information about how they function. Throughout the collection and analysis of samples, the ALS clinics are tracking disease progression in study participants.

“Incredible advances in biological techniques, including stem cell biology, have made it possible for us to generate motor neurons from each individual patient to begin to understand the true variability of the disease,” says Dr. Emily Baxi, Program Director for Answer ALS. “Multi-omics analyses are generating a huge amount of data. Together with the clinical data, we estimate a total of six billion data points will be generated per study participant. We’re analyzing that data using different methods of machine learning and artificial intelligence to pull out the subtle signatures that may distinguish one form of ALS from another.”

“We are on a mission to generate more knowledge than we’ve ever accumulated about ALS before,” says Dr. Baxi. “Nobody can solve ALS in isolation. We will share our data with the global ALS research community.”

At the ALS Canada Virtual Research Forum, Dr. Jeffrey Rothstein, founder and executive director of the Answer ALS Research Program provided an update about Answer ALS, including how close they are to reaching their goal and what’s next for analyzing the data for results. Dr. Rothstein is also the John W. Griffin Director for the Brain Science Institute (BSI), a professor of neurology and neuroscience and founding director of the Robert Packard Center for ALS Research at Johns Hopkins University’s School of Medicine.

Project MinE

Magnifying GlassProject MinE is a multinational initiative of collaborating organizations from 19 participating countries. It was founded by two entrepreneurs, Robbert Jan Stuit and Bernard Muller, who are both living with ALS and want to find faster answers about the cause of ALS.

To find out why some people develop ALS and others do not, researchers are analyzing full DNA profiles of 22,500 people to compare results for 15,000 people with ALS to 7,500 people without ALS. By investigating the differences in DNA between these two groups they hope to uncover gene variations associated with ALS. The information will help identify biological clues that may help accelerate the development of new treatments for slowing or halting disease progression and help to find a cure.

As of mid-September, Project MinE has sequenced over 10,480 DNA profiles. ALS Canada is leading Canada’s participation in Project MinE through fundraising to support the mapping and analysis of up to 1,000 DNA profiles. By the end of 2018, Canada will be more than a third of the way there. Our contribution brings together four leading geneticists from across the country. Further, we recently awarded Jay Ross, a PhD student at McGill University, who is working in the lab of Dr. Guy Rouleau at the Montreal Neurological Institute, a $75,000 Trainee Award to process a subset of DNA profiles collected for Project MinE.

At the ALS Canada Virtual Research Forum, Dr. Jan Veldink, one of the Project MinE initiators, provided an overview of the project and an update on discovery achievements to date. Dr. Veldink is a professor of neurology and neurosurgery and head of the Human Neurogenetics Unit at the University Medical Center, Utrecht, Netherlands.


Magnifying GlassA Multicenter Biomarker Resource Strategy In ALS (AMBRoSIA) is a research project led by the Motor Neurone Disease Association in London, United Kingdom. The project goal is to speed up diagnosis and understand the causes of ALS by identifying the unique biological fingerprints, or “biomarkers,” that could be used to diagnose ALS and predict its progression.

Researchers are collecting blood, urine and skin samples from 900 people with ALS and 400 people without ALS. Since 2016, scientists have been collecting and analyzing blood and urine samples to search for chemicals that might act as biomarkers of ALS. They are also engineering participants’ skin cells into stem cells and then reprogramming the stem cells to become motor neurons. In the lab, they are studying how the motor neurons respond to drugs and whether different drugs affect subtypes of ALS differently.

Biomarkers are also important for measuring responses to experimental therapies in clinical trials. Typical ALS studies to date have measured ALS responses using the ALS Functional Rating Score Revised (ALSFRS-R) and slow vital capacity, a measure of the volume of air exhaled without forced effort after a full breath. A better understanding of ALS may lead to targeted treatments for subtypes of the disease in the future.

At the ALS Canada Virtual Research Forum, Dr. Martin Turner, principal investigator of Project AMBRoSIA, discussed the project status two years into the five-year mandate and the biomarkers that have been discovered to date. Dr. Turner is a professor of clinical neurology and neuroscience at the John Radcliffe Hospital, University of Oxford, UK.

Posted in: Research