New ALS Gene and Signaling Pathways Identified

Findings point to potential therapeutic targets 

HUNTSVILLE, Ala., CAMBRIDGE, Mass., and NEW YORK — February 19, 2015 — Using advanced DNA sequencing methods, an international consortium that includes scientists and clinicians from HudsonAlpha Institute for Biotechnology, Columbia University Medical Center (CUMC) and Biogen Idec (NASDAQ: BIIB) has identified a new gene that is associated with sporadic amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease.

The newly associated gene, called TBK1 (TANK-Binding Kinase 1), plays a key role at the intersection of two essential cellular pathways: inflammation (a reaction to injury or infection) and autophagy (a cellular process involved in the removal of damaged cellular components). The study was published today in the online edition of Science.

Image caption: Motor neurons from an ALS patient (left) compared with normal cells (right). The cells are being used to study the role of the genes TBK1 and OPTN in ALS. (Credit: Laboratory of Tom Maniatis)

ALS is a devastating neurodegenerative disorder that results in the loss of all voluntary movement and is fatal in the majority of cases. The next-generation genetic sequencing of the exomes (protein-coding portions) of 2,874 ALS patients — including patients from Alabama — and 6,405 controls represents the largest number of ALS patients to have been sequenced in a single study to date. Though much is known about the genetic underpinnings of familial ALS, only a handful of genes have been definitively linked to sporadic ALS, which accounts for about 90 percent of all ALS cases.

“Industry and academia often do things together, but this is a perfect example of a large, complex project that required many parts, with equal contributions from Biogen Idec, Dr. Tim Harris, our collaborator there, and his team, as well as David Goldstein and his team, now at Columbia University, as well as our teams here at HudsonAlpha,” said Dr. Myers. “I love this research model because it doesn’t happen very frequently, and it really shows how industry, nonprofits, and academic laboratories can all work together for the betterment of humankind.  The combination of those groups with a large number of the clinical collaborators who have been seeing patients with this disease for many years and providing clinical information, recruiting patients, as well as collecting DNA samples for us to do this study, were all critical to get this done.”

“The Alabama Chapter of the ALS Association and our patients here living with ALS were pleased to be a part of this major research initiative,” stated Stuart Obermann, Chairman Emeritus and co-founder of the Alabama Chapter. “By partnering with HudsonAlpha and Conversant Bio, our Chapter has enabled the ALS patient community in Alabama to participate in this DNA sequencing project. Patients who visit our multi-disciplinary ALS Care Clinic at Crestwood Medical Center, which is an ALS Association Certified Treatment Center of Excellence, were given the opportunity to voluntarily submit tissue samples to be banked at Conversant Bio for use in this important study, and future ALS research projects.”

Searching through the enormous database generated in the ALS study, Myers and his colleagues found several genes that appear to contribute to ALS, most notably TBK1 (TANK-Binding Kinase 1), which had not been detected in previous, smaller-scale studies. TBK1 mutations appeared in about 1 percent of the ALS patients—a large proportion in the context of a complex disease with multiple genetic components, according to Dr. Goldstein. The study also found that a gene called OPTN, previously thought to play a minor role in ALS, may actually be a major player in the disease.

“The identification of TBK1 is exciting for understanding ALS pathogenesis, especially since the inflammatory and autophagy pathways have been previously implicated in the disease,” said Lucie Bruijn, Ph.D., Chief Scientist for The ALS Association. “The fact that TBK1 accounts for one percent of ALS adds significantly to our growing understanding of the genetic underpinnings of the disease. This study, which combines the efforts of over two dozen laboratories in six countries, also highlights the global and collaborative nature of ALS research today.”

Co-leaders of the study are David B. Goldstein, Ph.D., professor of genetics and development and director of the new Institute for Genomic Medicine at CUMC and Tim Harris, Ph.D., D.Sc., Senior Vice President, Technology and Translational Sciences, Biogen Idec.

“This study shows us that large-scale genetic studies not only can work very well in ALS, but that they can help pinpoint key biological pathways relevant to ALS that then become the focus of targeted drug development efforts,” said Goldstein. “ALS is an incredibly diverse disease, caused by dozens of different genetic mutations, which we’re only beginning to discover. The more of these mutations we identify, the better we can decipher—and influence—the pathways that lead to disease.”

Harris said these findings demonstrate the power of exome sequencing in the search for rare variants that predispose individuals to disease and in identifying potential points of intervention. “We are following up by looking at the function of this pathway so that one day this research may benefit the patients living with ALS,” said Dr. Harris. “The speed with which we were able to identify this pathway and begin our next phase of research shows the potential of novel, focused collaborations with the best academic scientists to advance our understanding of the molecular pathology of disease. This synergy is vital for both industry and the academic community, especially in the context of precision medicine and whole-genome sequencing.”

The researchers are currently using patient-derived induced pluripotent embryonic stem cells (iPS cells) and mouse models with mutations in TBK1 or OPTN to study ALS disease mechanisms and to screen for drug candidates. Several compounds that affect TBK1 signaling have already been developed for use in cancer, where the gene is thought to play a role in tumor-cell survival.

“This is a great example of the potential of precision medicine,” said Tom Maniatis, Ph.D., the Isidore S. Edelman Professor, chair of biochemistry and molecular biophysics, and coauthor on the paper.  Dr. Maniatis is also a member of the Zuckerman Mind Brain Behavior Institute and director of Columbia’s university-wide precision medicine initiative. “It now seems clear that future ALS treatments will not be equally effective for all patients because of the disease’s genetic diversity. Ultimately, as candidate therapies become available, we hope to be able to use the genetic data from each ALS patient to direct that person to the most appropriate clinical trials and, ultimately, use the data to prescribe treatment.”

The study was funded by Biogen Idec, Wellcome Trust and Medical Research Council Grants, MND Association, the ALS Association, National Institutes of Health (R37 NS083524, 5RO1NS050557, 5R01 NS067206, 5R01NS065847, 1R01NS073873, 5R01NS079836, R01NS065847, and R01NS073873), the Angel Fund, Project ALS/P2ALS, the ALS Therapy Alliance, the Pierre L. de Bourghknecht ALS Research Foundation, a Francesco Caleffi donation, the Medical Research Council, the Heaton-Ellis Trust and AriSLA cofinanced with support of ‘‘5 x 1000’’—Healthcare research of the Italian Ministry of Health, the National Institute for Health Research Dementia Biomedical Research Unit at South London, Maudsley NHS Foundation Trust, King’s College London, the Motor Neurone Disease Research Institute of Australia, United Kingdom Medical Research Council under the aegis of JPND, the National Health and Medical Research Council of Australia, Canadian Institutes of Health Research, Muscle Dystrophy Association, Instituto de Salud Carlos III – ISCIII, FUNDELA (Spanish foundation for the development of ALS research), the Mireia Barneda project, the Netherlands ALS Foundation, and the European Community’s Health Seventh Framework Programme.

About HudsonAlpha

HudsonAlpha Institute for Biotechnology is a genomic science and applications nonprofit organization.  It is both a high-volume genomic data producer serving hundreds of academic, clinical, and commercial clients’ needs and a global scientific collaborator valued for its genomic data analysis and interpretation to solve some of the most pressing questions in cancer, undiagnosed disease, neuro-psychiatric disorders, immune-mediated disease, agriculture, and public health.  Its unique 152-acre campus melds the boundaries between nonprofit scientists, educators, and commercial business people so that collaboration sparks innovation and growth.

About Columbia University Medical Center

Columbia University Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast. For more information, visit or

About Biogen Idec

Through cutting-edge science and medicine, Biogen Idec discovers, develops and delivers to patients worldwide innovative therapies for the treatment of neurodegenerative diseases, hematologic conditions and autoimmune disorders. Founded in 1978, Biogen Idec is the world’s oldest independent biotechnology company and patients worldwide benefit from its leading multiple sclerosis and innovative hemophilia therapies. For product labeling, press releases and additional information about the Company, please visit