Strategic Initiatives
The outpouring of support from the ALS Ice Bucket Challenge has allowed the ALS Association to champion numerous new strategic initiatives in order to build understanding of the disease, target new therapies, expedite clinical trials and make RNA and DNA sequencing data available for the entire ALS research community. These collaborative initiatives have already lead us closer to ALS treatments and a cure. Central to all new collaborations is the people living with ALS.
Neuro Collaborative
The Neuro Collaborative is a partnership between three leading laboratories in California. The synergetic model brings together complementary expertise to advance understanding of ALS and drug development. From sharing information to attracting industry investment, The Neuro Collaborative is an essential initiative that is driving potential therapeutics for ALS quickly toward FDA approval.
The Neuro Collaborative is a partnership between three leading laboratories in California – including Clive Svendsen, Ph.D. at Cedars-Sinai in Los Angeles; Steven Finkbeiner, M.D., Ph.D. at Gladstone Institutes, affiliated with University of California San Francisco; and Don Cleveland, Ph.D. at University of California San Diego. The synergetic model brings together complementary expertise to advance understanding of ALS and drug development. From sharing information to attracting industry investment, The Neuro Collaborative is an essential initiative that is driving potential therapeutics for ALS quickly toward FDA approval.
The ALS Association Commitment
In 2014, The ALS Association Golden West Chapter, along with Advisory Trustees Jim Barber and Linda Della, partnered with the National ALS Association to build the Neuro Collaborative concept. That year, following the amazing outpouring of support from the ALS Ice Bucket Challenge, The ALS Association committed $5 million dollars to the project. With additional help from The ALS Association Orange County and Wisconsin Chapters, the Neuro Collaborative has become an engine for ALS therapeutics.
The goal of the Neuro Collaborative is to establish and invest in a leading team of experts to efficiently advance ALS drug development together with industry partners. This complements other programs including the Drug Development Contract Program in the TREAT ALS™ portfolio investing in academic and industry partnerships. This synergetic model leverages open dialogue and the scientific expertise of leading researchers to achieve therapeutic milestones as quickly as possible. The collaboration is designed to reduce risk in the drug discovery process and attract pharmaceutical companies to invest in drug development and clinical trials for ALS. With success, potential therapies for ALS will move more quickly than ever toward FDA approval and the open market.
- Identifies small molecules designed to eliminate SOD1 and C9orf72 – the two most common genetic causes of ALS (i.e. antisense therapy).
- Discovers novel, potential ALS drugs.
- Moves drug discoveries into clinical trials through partnerships with pharmaceutical companies in order to leverage various expertise in drug development (chemistry, toxicology, regulatory), which is lacking in academia.
- Reinforces the clinical trial process with pharmaceutical partnerships to move drugs toward FDA approval.
- Provides tools to the broader community and industry partners such as available induced pluripotent stem cell (iPSC) lines and screening capabilities through the Brain Bot.
- Each laboratory in the Neuro Collaborative focuses on different areas of ALS research to maximize shared knowledge and understanding of the complexities of the disease while increasing industry interest and investment in ALS drug development.
The Neuro Collaborative partners with prestigious scientific advisors including: Dr. John Dunlop, Ph.D., Former Vice President of Neuroscience Innovative Medicines at AstraZeneca; Fred Gage, Ph.D., Professor in Laboratory Genetics at the Salk Institute; and Harry Orr, Ph.D., Professor of Laboratory Medicine and Pathology at University of Minnesota.
Laboratories that represent the Neuro Collaborative
The Cleveland lab at the University of California San Diego focuses on gene therapy and antisense therapy development.
They developed antisense therapy drugs against the C9orf72 gene. Dr. Cleveland’s lab is also developing gene therapy approaches against SOD1 and other targets that they identify. His lab is collaborating with Martin Marsala, M.D. at University of California San Diego and Brian Kaspar, Ph.D. at the Research Institute at Nationwide Children’s Hospital in Ohio to develop novel gene therapies for ALS.
Antisense technology, which The ALS Association has helped fund since 2004, has high potential to become a therapeutic treatment for ALS targeting both SOD1 and C9orf72 – the two leading genetic causes of familial ALS – to slow or even halt ALS progression. A major breakthrough in ALS, antisense technology reduces the production of SOD1 and C9orf72 proteins in the body.
The Svendsen lab at Cedars-Sinai in Los Angeles focuses on iPSC models to be shared globally.
They created clinical-grade iPSC lines from people living with ALS using a standardized, rapid and effective method through the Cedars-Sinai Stem Cell and Motor Neuron Core Facility headed by Dhruv Sareen, Ph.D. iPSCs are then converted to motor neurons, one type of cell that dies in ALS. iPSCs are like a person’s avatar in a dish, containing the same exact genetic information.
iPSCs are used to test drug efficacy and are paired with the clinical data of a person living with ALS. This helps scientists understand the connection between ALS symptoms and cell pathology. Advancements in iPSC development and technology are shared globally and can also help advance understanding of other neurodegenerative diseases.
The Finkbeiner lab at the Gladstone Institutes, which is affiliated with UCSF focuses on high performance drug screening and drug target validation.
They use robotic microscope technology, the Brain Bot, which tracks the health of cells (like motor neurons and glia) over many months from healthy to sick to death. It measures millions of individual cells, each tagged with their own signature, derived from people living with ALS and compares them to cells from healthy people.
The Brain Bot allows rapid drug screening and validation of potential ALS drugs by measuring whether a potential ALS drug improves or worsens the health of the cells.
Cleveland Lab:
Dr. Cleveland and Ionis Pharmaceuticals developed the first ever-antisense drug to treat a neurological disorder, ALS. The ALS Association initiated funding for the development of this revolutionary technology and has supported its development through continued funding for over a decade. A phase I/II study of the SOD1 antisense drug is currently underway since January 2016 with improved safety and chemical design that will test safety in persons living with ALS. A similar trial focused on antisense technology targeting C9orf72 is anticipated in early 2017 through partnerships with Ionis Pharmaceuticals and Biogen. The Cleveland team has also developed a C9orf72 mouse model that is shown to mirror some of the characteristics to people having the C9orf72 mutation and will be used for continued antisense drug development.
Svendsen Lab:
Dr. Svendsen’s lab has successfully made 24 iPSC lines derived from 11 healthy controls, 4 C9orf72 mutation carriers, 6 SOD1 mutation carriers and 3 sporadic ALS cases that are available to researchers worldwide. A recent review from Dr. Svendsen’s laboratory highlights the importance of iPSCs as a tool in ALS research that have the potential to identify new disease mechanisms and individual disease susceptibilities that cannot be revealed in other models. In efforts to improve iPSC models, Svendsen and colleagues also recently found that it might be beneficial to induce some aspects of aging in iPSC-derived motor neurons, thereby reflecting critical vulnerabilities similar to those of aged neurons that die from ALS.
Finkbeiner Lab:
Dr. Finkbeiner’s Brain Bot drug screening system attracts many industry partnerships. Using the Brain Bot, his team identified potential ALS compounds targeting autophagy, one mechanism the cell uses to get rid of unwanted by-products. His team found that adding potential autophagy compounds to motor neurons derived from people living with ALS was protective. Partnerships with several companies are in negotiations to optimize these compounds for a clinical trial. In addition, in January 2016 Gladstone Institutes, through the leadership of Dr. Finkbeiner, partnered with Biogen to discover novel drug targets for the treatment of ALS.
Project MinE
Project MinE is an international, large-scale research initiative devoted to discovering genetic causes of ALS and to ultimately find a cure. Project MinE is based on the fact that genes are thought to contribute, directly or indirectly, to many cases of ALS. Many ALS genes have been identified, but researchers suspect that many more, much rarer variants that affect the risk of ALS are awaiting discovery.
Once Project MinE is concluded, new ALS genes, including rare genetic variants will be identified. Researchers can then zoom into these genes to better understand the disease pathways causing ALS and then ultimately understand whether those pathways can be targeted for new ALS therapies.
The ALS Association Commitment
The Association committed an initial $1 million in partnership with the Greater New York and Georgia Chapters, establishing the U.S. arm of Project MinE. Funding was announced in October 2014.
The goal is to identify genes associated with ALS by performing whole genome sequencing (reading DNA) of at least 15,000 ALS people with ALS + 7,500 healthy people worldwide resulting in an open-source ALS genome database, in conjunction with the collection of skin samples to make ALS patient induced pluripotent stem cell lines (iPSCs).
- Collects samples from healthy people (7,500) and people living with ALS (15,000).
- Sequences whole genomes to read the full sequence of DNA in each person.
- Collects skin samples for researchers to make iPSCs.
- Further analyzes the genome, such as how the genes are modified.
- More research will place newly identified genes into ALS disease pathways that could potentially be targeted for ALS therapeutics.
Entrepreneurs and people living with ALS, Bernard Muller and Robbert Jan Stuit, along with Leonard van den Berg, M.D., Ph.D., Director of Netherlands ALS Center, developed the Project MinE concept. In 2011, Bernard and met Robbert Jan Stuit and decided that together they could change the ALS field. After a tour of the Research ALS Center in the Netherlands, they found that 5,000 DNA samples collected from people living with ALS were stored in a freezer and were not being used because it was too expensive to conduct research experiments. That was the beginning of Project MinE.
Now 16 countries are participating in Project MinE – a global collaborative effort.
The ALS Association funding supports the U.S. arm of this initiative led by Jonathan Glass, M.D. at Emory University in Atlanta and John Landers, Ph.D., University of Massachusetts Medical School in Worcester, Mass.
It costs approximately $2,000 to sequence the whole genome of one person. As of August 1, 2016, Project MinE has achieved 35 percent of its total goal equaling 7,835 DNA profiles collected out of the total 22,500.
The U.S. arm of Project MinE has raised $1,500,395, which is 58 percent of its overall goal of $2,600,000. So far, 577 DNA profiles have been collected out of 1,000 goal.
Already from the data collected by Project MinE, researchers have discovered two new genes – NEK1 and C21orf2 – that were published in back-to-back articles in Nature Genetics. Two other genes, MOBP and SCFD1, were also identified as new associated risk genes that still require further validation. These gene discoveries will lead to the identification of novel ALS disease pathways that will be further explored as possible therapeutic targets.
Researchers funded by The Association are currently exploring how these newly identified genes contribute to ALS disease, by making mouse models that will be shared with the entire ALS community.
Genomic Translation for ALS Care (GTAC)
Genomic Translation for ALS Care (GTAC) is a collaboration with Biogen and Columbia University Medical Center (CUMC) to better understand how different genes contribute to various clinical forms of ALS. This will in turn help researchers design better, more focused clinical trials for the development of more effective treatments. This kind of precision medicine, in which treatment is tailored to each person’s unique genetic makeup, will be effectively applied to ALS.
The ALS Association committed $3.5 million that was announced in August 2015. This commitment comes directly from money raised through the Ice Bucket Challenge. This study is also being funded through Biogen’s strategic alliance with CUMC.
This initiative aims to set the stage for a nationwide effort to ensure the genomic characterization of all people with ALS. The study will follow 1,500 people living with ALS in the clinic over a three year period with three month visit intervals to collect clinical data, sequence their DNA and store blood samples to generate induced pluripotent stem cells (iPSCs). This information will allow the correlation of ALS clinical manifestations to the genetic causes and help stratify patients for future clinical trials. Ultimately, it will provide a basis for the development of precision medicine, or more individually tailored therapies for ALS.
- Collects clinical progression data at the clinic
- Historical ALS data (onset and disease progression) for deep clinical phenotyping (comprehensive study of clinical history and disease progression)
- Family history
- Exposures and epidemiologic data
- Neurological examinations
- Collects blood samples from people living with ALS
- To sequence whole genomes to read the full sequence of DNA of each participant
- Analyzes transcriptomics (study of messenger RNA (mRNA)
- Collects pBMCs (peripheral blood mononuclear cells) archived to make iPSCs in the future
- Shares information in a database that will allow for a large investigation of the clinical correlates of the genetic causes of ALS
- Matthew Harms, M.D., Director GTAC and Assistant Professor of Neurology at CUMC
- David Goldstein, Ph.D., Director of the Institute for Genomic Medicine at CUMC and Professor of Genetics and Development at CUMC
- Dhruv Sareen, Ph.D., Director of Induced Pluripotent Stem Cell Core Facility, Cedars-Sinai, Los Angeles.
Participant blood cells will be stored at the Induced Pluripotent Stem Cell (iPSC) Core, a facility supported by The ALS Association, at the Cedars-Sinai Board of Governors Regenerative Medicine Institute in Los Angeles led by Dhruv Sareen, Ph.D. Clinical data will be collected and curated through The ALS Association supported NeuroBANK™ at Massachusetts General Hospital in Boston. Each sample will have a unique identifier called a global unique identifier {GUID). Whole genome sequencing and transcriptomics are performed in collaboration with the New York Genome Center.
There are 10 centers across the U.S. and in Scotland collecting samples. Participating clinical centers include: Cedars-Sinai Board of Governors Regenerative Medicine Institute, Columbia University Medical Center, University of Michigan, Houston Methodist, Scotland ALS Clinic Network, University of Minnesota and Hennepin County Medical Center, University of Utah, University of Washington, Penn State Hershey Medical Center and Washington University in St. Louis.
Study started enrolling in June 2016 with a projected timeline of three years with follow-ups in three month intervals. Data will be shared immediately to the CGND consortium and publically at later stages. This collaborative effort is already responsible for identifying ALS gene TBK1 in 2015 that was published in the journal Science.
New York Genome Center - Center for Genomics of Neurodegenerative Diseases (NYGC CGND)
Recent discoveries have indicated that genes may contribute to a much larger percentage of ALS cases than previously thought. Finding these genes and understanding how they work will allow development of new therapeutic approaches.
The Center for Genomics of Neurodegenerative Disease (CGND) at the New York Genome Center (NYGC) is dedicated to the study of neurodegenerative diseases such as ALS and Alzheimer’s disease. CGND’s vision is to establish a framework for applying state-of-the-art genetics, genomics and bioinformatics to the study of neurodegenerative disease mechanisms by building partnerships with clinicians, basic scientists, geneticists and computational biologists.
The CGND has formed an international ALS Consortium to apply integrated genomics to advance the clinical diagnosis and care of ALS. Through a multidisciplinary collaborative effort that spans multiple ALS centers and bridges ALS clinicians and scientists, researchers are using whole genome sequencing to discover and study mutations and mechanisms underlying ALS.
The ALS Association Commitment
The CGND’s research program in ALS was established with the help of generous support from The Tow Foundation and The ALS Association that was announced in October 2014. The Association, in partnership with the Greater New York Chapter of The Association, committed $2.5 million to fund this research, directly from money raised through the ALS Ice Bucket Challenge. This matched a gift of $2.5 million from The Tow Foundation.
The CGND’s goals are to use whole genome sequencing to identify mutations that cause neurodegenerative disease. To gain insights into the relationship between mutations, gene expression and disease mechanisms, whole genome sequencing data will ultimately be integrated with other genomic-scale data such as RNA-Seq (i.e. RNA sequencing), RNA-protein interactions and DNA methylation patterns (i.e. a type of post-translational modification).
The CGND is helping to create a uniform system of collecting clinical annotation to better enable the integration of genomic data with clinical profiles. This information will be freely available to the research community in a data warehouse for whole genome sequencing and RNA-Seq analyses.
- Target Groups: Familial ALS, Sporadic ALS, C9orf72 carriers
- Data being collected now:
- Blood samples to make DNA
- Autopsy tissue to make RNA
- Some induced pluripotent stem cells (iPSCs)
- Clinical data (longitudinal clinical data targeted for ~1300 of a total of 1800 participants)
- Pre-competitive Data Sharing with all Consortium Members, samples consented for broad sharing for all medical research
- Current Studies:
- ALS gene discovery efforts: (1) understanding unexplained familial ALS and (2) increasing power through increased numbers of sporadic patients for co-analysis with existing datasets
- Genotype (i.e. genetic code)-phenotype (i.e. observable clinical characteristics) correlations
- Integrating whole genome sequencing (i.e. reading the full sequence of DNA for each participant) with tissue-specific transcriptomics (i.e. study of messenger RNA (mRNA)) for understanding the impact of regulatory variation and cell type-specific contributions
- C9orf72 promoter methylation
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- Hemali Phatnani, Ph.D., Director of the Center for Genomics of Neurodegenerative Disease, NYGC
- Tom Maniatis, Ph.D., Columbia University, Advisor
- Cheryl Moore, NYGC, Advisor
- David Goldstein, Ph.D, Columbia University, Advisor
- Robert Darnell, M.D., Ph.D., Founding Director, NYGC
The consortium is composed of research teams from Columbia University Medical Center, University of Pennsylvania, Massachusetts General Hospital, Hershey Medical Center at Pennsylvania State University, University of Maryland, Johns Hopkins University, Henry Ford Health System, University of California at San Francisco, Massachusetts Institute of Technology, Academic Medical Center, University of Amsterdam.
The NYGC CGND maintains partnerships with the Answer ALS Consortium, Genomic Translation for ALS Clinical Care (GTAC) Consortium and Target ALS (for the Post Mortem Core, iPS Core, biospecimen collection).
CReATe Consortium
The Clinical Research in ALS and related disorders for Therapeutic Develoment (CReATe) Consortium is a collaborative effort to foster the discovery and validation of biomarkers relevant to therapy development for people living with ALS and related disorders including frontotemporal dementia (FTD), primary lateral sclerosis (PLS), hereditary spastic paraplegia (HSP), and progressive muscular atrophy (PMA).
CReATe is a Rare Diseases Clinical Research Consortium (RDCRC) that forms part of the National Institutes of Health (NIH) Rare Diseases Clinical Research Network.
In partnership with The ALS Association, CReATe is able to advance its goals through the release of an annual request for applications to fund biomarker pilot projects. CReATe also fosters biomarker development by making its substantial repository of biological samples available to the broader scientific community.
The ALS Association Commitment
The Association supports three areas through CReATe:
- Pilot Biomarker Study: Dr. Benjamin Murdock at the University of Michigan in Ann Arbor, Mich. The project aims to identify immune cell populations to serve as biomarkers and therapeutic targets in ALS patients. The Association committed $50,000 over 1 year.
- Sample Collection: Dr. Michael Benatar at the University of Miami in Miami. Supports a CReATe Consortium Biorepository to store biological samples collected from all study participants. Biomarker studies require that samples are collected, stored and processed in a harmonized manner, along with collection of clinical data. These samples are used to support biomarker studies within CReATe Consortium and within the broad scientific community. The Association committed $400,000 over 3 years. The CReATe Biorepository was announced in September 2015.
- Sequencing Study: Drs. Paul Taylor and Jinghui Zhang at St. Jude Children’s Hospital in Memphis, Tenn. and Michael Benatar at University of Miami in Miami. The project aims to characterize clinical variability and progression amongst a large cohort of people living with ALS. The investigators plan on performing whole genome sequence analysis of at least 750 CReATe participants. All data will be made public to the ALS community. The Association committed $835,937 over 60 months.
The CGND’s goals are to use whole genome sequencing to identify mutations that cause neurodegenerative disease. To gain insights into the relationship between mutations, gene expression and disease mechanisms, whole genome sequencing data will ultimately be integrated with other genomic-scale data such as RNA-Seq (i.e. RNA sequencing), RNA-protein interactions and DNA methylation patterns (i.e. a type of post-translational modification).
The CGND is helping to create a uniform system of collecting clinical annotation to better enable the integration of genomic data with clinical profiles. This information will be freely available to the research community in a data warehouse for whole genome sequencing and RNA-Seq analyses.
- Target Groups: Familial ALS, Sporadic ALS, C9orf72 carriers
- Data being collected now:
- Blood samples to make DNA
- Autopsy tissue to make RNA
- Some induced pluripotent stem cells (iPSCs)
- Clinical data (longitudinal clinical data targeted for ~1300 of a total of 1800 participants)
- Pre-competitive Data Sharing with all Consortium Members, samples consented for broad sharing for all medical research
- Current Studies:
- ALS gene discovery efforts: (1) understanding unexplained familial ALS and (2) increasing power through increased numbers of sporadic patients for co-analysis with existing datasets
- Genotype (i.e. genetic code)-phenotype (i.e. observable clinical characteristics) correlations
- Integrating whole genome sequencing (i.e. reading the full sequence of DNA for each participant) with tissue-specific transcriptomics (i.e. study of messenger RNA (mRNA)) for understanding the impact of regulatory variation and cell type-specific contributions
- C9orf72 promoter methylation
- Hemali Phatnani, Ph.D., Director of the Center for Genomics of Neurodegenerative Disease, NYGC
- Tom Maniatis, Ph.D., Columbia University, Advisor
- Cheryl Moore, NYGC, Advisor
- David Goldstein, Ph.D, Columbia University, Advisor
- Robert Darnell, M.D., Ph.D., Founding Director, NYGC
The consortium is composed of research teams from Columbia University Medical Center, University of Pennsylvania, Massachusetts General Hospital, Hershey Medical Center at Pennsylvania State University, University of Maryland, Johns Hopkins University, Henry Ford Health System, University of California at San Francisco, Massachusetts Institute of Technology, Academic Medical Center, University of Amsterdam.
The NYGC CGND maintains partnerships with the Answer ALS Consortium, Genomic Translation for ALS Clinical Care (GTAC) Consortium and Target ALS (for the Post Mortem Core, iPS Core, biospecimen collection).