The ALS Association’s TREAT ALS Portfolio (Translational Research Advancing Therapies for ALS) is a research endeavor enabling important research to progress from the laboratory to the bedside. The focus of the program is to support novel ideas, build tools, partner with academia and industry to identify new potential therapies and support the infrastructure for clinical trials, with the goal to find meaningful treatments for ALS and a cure. The ALS Association is pleased to announce several new grants that will contribute significantly to our understanding of ALS and help us develop therapies for the disease.
Virginia Lee, Ph.D. Center for Neurodegenerative Disease Research, Philadelphia, PA
Funded by the Greater Philadelphia Chapter of The ALS Association through the generosity of Jim and Marianne Koller
Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease, but increasingly it is recognized that ALS patients can manifest behavioral and cognitive impairments, including dementia, that are consistent with another neurodegenerative disorder known as frontotemporal lobar degeneration (FTLD).
Most ALS is sporadic (SALS), but approximately 10% is familial. The recent identification of TDP-43 as the building block proteins that accumulate as abnormal clumps in brain and spinal cord of patients with ALS and FTLD by Dr. Lee’s laboratory, has provided the first molecular link to explain the significant overlap in the clinical spectrum of FTLD (also known as FTLD-TDP) and ALS. Indeed, this scientific breakthrough supports the transformative concept that these two syndromes represent a clinical and pathological continuum of the same neurodegenerative disorder. This disease spectrum is referred to as TDP-43 proteinopathy, and it has profound implications for biomarker and drug discovery research for ALS. TDP-43 pathology is also found in nearly 50% of patients with FTLD now known as FTLD-TDP.
TDP-43 pathology links motor neuron degeneration in ALS and behavioral and motor impairments in FTLD showing that they represent different clinical manifestations of the same disorder. Further support for the view that abnormal TDP-43 causes of SALS and FALS came from a series of subsequent studies reporting >35 mutations in the TDP-43 gene on chromosome 1 that are pathogenic for SALS and FALS as well as some cases of FTLD plus ALS thereby providing genetic evidence implicating abnormal TDP-43 in the onset/progression of ALS with and without FTLD-TDP. However, despite increased knowledge of the genetics and neuropathology of ALS, it is unclear how and why some but not all ALS patients develop behavioral and cognitive impairments, including dementia consistent with FTLD-TDP.
Thus, to elucidate why some ALS patients develop FTLD-TDP, Dr. Lee proposes to recruit clinical ALS patients with and without cognitive impairments, obtain blood for DNA and plasma, collect spinal fluids, identify patients with a family history, follow their disease progression over time and conduct autopsy postmortem. All relevant information will be entered into a secure database and these biosamples will be the focus of their research on disease mechanisms and biomarkers for ALS, and they will be made available to other ALS investigators for research. This comprehensive approach will provide for a more in depth and complete understanding of individual patient’s genetic risks, clinical manifestation, disease progression and disease pathology that are essential for the diagnosis and treatment of ALS with or without associated FTLD-TDP.
Michael Benatar, M.D., University of Miami, Florida; Paul Taylor, Ph.D. St. Judes Children’s Research Hospital
Funded by the Wisconsin Chapter of The ALS Association
Rational efforts to develop treatments for patients with ALS would be greatly facilitated by an improved understanding of the basic biology of the disease. Insights from the genetics of familial ALS (FALS) offer great potential to shed light on the biological mechanisms that underlie ALS. FALS caused by mutations in the TDP-43 gene, for example, provides a mechanistic link between sporadic and non-SOD1 FALS, as well as between ALS and fronto-temporal dementia. Mutations in the valosin-containing protein (VCP) gene have recently been identified as the cause of disease in a small number of patients with FALS (/news/archive/genome-study-identifies-link.html). Mutations in VCP have previously been described in patients with another degenerative disease known as IBMPFD (Inclusion Body Myopathy with Paget’s disease and Fronto-temporal Dementia). Interestingly, closer inspection of families with IBMPFD suggests that affected family members may have ALS. This proposal aims to determine the frequency with which ALS occurs in families with IBMPFD as well as the frequency with which mutations in VCP gene are responsible for ALS in families without mutations in the SOD1, TDP-43 and FUS genes. Valosin-containing protein (VCP) plays an essential role in multiple ubiquitin dependent pathways important for clearing accumulated proteins in the cell. Mutations in the VCP gene have been identified in five families with familial ALS.
The potential importance of VCP to ALS is underscored by the connections to both FTD and TAR DNA-binding protein 43 (TDP-43) as described in Dr. Lee’s study. There is increasing recognition that ALS is a multi-system disease and that ALS & FTD may represent two ends of the spectrum of the same neurodegenerative disease. Since mutations in VCP may cause both ALS and FTD, it represents a potentially important mechanistic link between the two disorders. Furthermore, TDP-43 is now recognized to be the main protein component of ubiquitinated inclusions found in most cases of fronto-temporal lobar degeneration with ubiquitinated inclusions (FTLD-U), as well as in patients with both sporadic and non-SOD1 familial ALS. VCP-related disease is similarly characterized by TDP-43 pathology in affected tissues.
The Investigators’ long-term goal is to improve their understanding of the pathophysiology of ALS in order to guide the development of an effective treatment. As a first step towards accomplishing this goal the investigators aim to correlate phenotype and genotype in mutant VCP families, with a particular focus on clinical and electrophysiological manifestations of both upper and lower motor neuron dysfunction.
Bryan Traynor, M.D., National Institute of Aging, Bethesda, M.D.; Adriano Chio M.D.., Department of Neuroscience, Torino, Italy
Funded by the Wisconsin Chapter of The ALS Association
The overall goal of this project is to discover the genes that cause familial ALS using a newly developed, state-of-the-art technique called exome sequencing. Exome sequencing exploits the massive parallel sequencing capabilities of next generation sequencers to rapidly analyze the portion of the human genome that code for proteins. The power of exome sequencing stems from the fact that the vast majority of mutations, more than 85%, underlying inherited forms of disease are found in the roughly 1% of the genome that encode for proteins. This technique has been commercially available for less than a year, but its ability to find genes has already been proven: indeed, we have recently successfully applied this new technology to find a new gene (VCP) for familial ALS. The discovery of each gene causing familial disease is an important milestone in ALS research, as it not only provides a fundamental insight into the cellular pathways involved in neurodegeneration, but it also guides future molecular biology experiments to understand this process. Ultimately, the finding of each gene may yield a new array of drugable targets, facilitating the development of new therapeutic agents effective in slowing the progression of this fatal disease. In addition, the raw sequence data generated from this project will be made publicly available so that other researchers may data mine the dataset and combine it with their own exome sequence data, thus increasing the power of future studies to find causative genes. The ALS Association will be partnering with NINDS and The Robert Packard Center for ALS Research to fund this program.
It is envisaged that this study will advance the field of ALS genetics by identifying the genetic variants that cause ALS. Indeed, the identification of genes underlying rare familial forms of ALS has had significant impact on our understanding of the molecular mechanisms underlying typical ALS. Much of the ongoing molecular biology work in the ALS field is based on the discovery of mutations in genes encoding SOD1, TDP-43 and FUS. Each new gene implicated in the etiology of ALS provides fundamental insights into the pathogenesis of motor neuron degeneration, as well as facilitating disease modeling and the design and testing of targeted therapeutics; hence, there is much interest in the identification of novel genetic mutations.
Nicholas Maragakis, M.D., Johns Hopkins University Department of Neurology, Baltimore, Maryland; Merit Cudkowicz, M.D., Massachusetts General Hospital, Boston.
The first questions asked by patients with a new diagnosis of ALS often include: ―Does exercise help slow the progression of the disease? ―Is there any harm in exercising? or ―What type of exercise (endurance or resistance) is most appropriate? At this time, however, there is a paucity of answers for people who suffer from an illness that affects their strength above all else. Yet the beneficial effects of exercise in both healthy people as well as people with other diseases have been extensively studied and resulted in recommendations about the types of exercise that are beneficial. In this study the investigators will ask participants with ALS to exercise in one of three ways: Weightlifting (resistance exercise), stationary bicycling (endurance exercise), and range of motion exercise (the current ―standard of care for ALS patients). They will use several different types of tests to determine whether one type of exercise is tolerated and safer than another. They will also collect information about how the body responds to exercise in ALS. This study will help in the development of a larger national study to understand how exercise can be combined with other treatments to potentially improve strength and alter the course of the disease. This pilot trial is designed to be the first step in rigorously addressing the role of exercise in ALS. It is necessary to point out that a ―cure is not expected of this intervention but rather the potential for slowing the course of disease and/or improving function through a combination of central and peripheral nervous system effects. The investigators anticipate that the data gathered in this study will aid in the design of a larger efficacy study and eventually the inclusion of recommendations for exercise in an ALS practice parameter. Despite decades of discussion over the potential benefit or harm of exercise in ALS, no study has compared these two forms of exercise, resistance and endurance, with the current standards of ALS care—stretching and range of motion exercise. This pilot trial will address these questions in a randomized, controlled study with the long term goal of establishing a larger efficacy study and eventually a consensus statement on the potential benefits (or detriments) of exercise in this neurodegenerative disease.
The study sites and details for enrolment will be provided in the coming weeks.