Unlocking the Mystery: Report from the Tarrytown II ALS Conference

by Amy Madsen on Mon, 2013-10-07 02:37

Top ALS researchers pinpoint the most formidable challenges in research today and make recommendations to serve as a road map for the future

Article Highlights:
  • The Tarrytown II ALS Conference, held in September 2011, in Tarrytown, N.Y., was inspired by the collective desire of a group of the world’s top scientists to survey the landscape of ALS research; define challenges specific to the field; and determine the best, fastest, most efficient way to gain a clear understanding of ALS and develop effective treatments for the disease.
  • Findings and recommendations from the Tarrytown conference were published this year in the journal Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. These papers provide a road map for scientists conducting ALS research today.
  • This article summarizes each of the six Tarrytown sessions, with links to the journal papers, which are available online for free.

Not all amyotrophic lateral sclerosis (ALS) research happens in laboratories or clinical settings. Scientific conferences also play a central role in the search for ALS treatments and cures.

One important example of this is the Tarrytown II ALS Conference, which was held in Tarrytown, N.Y., in September 2011.

Attended by approximately 150 clinicians and researchers, as well as representatives from patient advocacy groups, funding agencies and pharmaceutical companies, the conference showcased the work of 60 experts in six sessions; each presentation focused on a unique topic that served as a springboard for extensive discussion and debate.  

In addition to discussing current impediments to clinical research, attendees addressed the ALS research infrastructure currently in place; resources available for patient-oriented research; and — perhaps most importantly — recommendations for how to best move forward.

A summary of the questions and possible answers posed by conference participants was published this year in a special supplement of Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration (Volume 14, Number S1, May 2013). The summary covers each of six separate conference sessions, providing an overview of the state of ALS research today, and a road map for future.   

"If one accepts that the mystery of ALS resides in the patient, then patient-oriented research … may hold the key to future progress in understanding ALS."

— Neurologist Hiroshi Mitsumoto, director of the MDA/ALS Center at Columbia University Medical Center in New York

A 'unique and provocative' conference

The number of ALS clinical trials is growing each year, testing experimental therapies that vary widely in terms of their intended biological targets and mechanisms of action. This diversity in design and purpose of potential treatments reflects the vast number of viable working hypotheses about what causes and drives ALS.

Despite the sizeable number of drugs that have been tested, however, only one medication — riluzole — has been approved by the U.S. Food and Drug Administration for the treatment of ALS. One possible explanation for the disappointing lack of success — and an idea that led to the Tarrytown II ALS Conference — may be the difficulties inherent in using animals (such as ALS research mice) to model human disease. Dozens of experimental ALS therapies that performed well in mice have failed to live up to their promise when tested in humans.

"This situation has led investigators to suspect that more sophisticated models for the human disease are needed," said Hiroshi Mitsumoto, director of the MDA/ALS Center at Columbia University Medical Center in New York.

"If one accepts that the mystery of ALS resides in the patient, then patient-oriented research to find its causes and discover its disease mechanisms may hold the key to future progress in understanding ALS and discovering more effective treatments."

Patient-centered research is challenging, Mitsumoto noted. Bringing together "the best minds in the many fields of ALS" to confront those challenges and explore ways of overcoming them became the focus of the Tarrytown conference, which was funded in part by MDA. MDA Executive Vice President and Chief Medical and Scientific Officer Valerie Cwik also served on the conference organizing committee.

The ALS scientific community “came together to produce a unique and provocative conference," Mitsumoto said, "exceeding our expectations and inspiring all who were present."

For more, read Promoting Clinical and Patient-Oriented Research to Identify the Pathogenesis of Amyotrophic Lateral Sclerosis.

Session 1: 'The main mystery' — defining the disease

Defining just what ALS is has turned out to be far more difficult than anyone could have predicted. However, over the last five years, increased understanding of the disease's clinical, molecular and genetic aspects has greatly improved the chance that therapies can be found.

The hallmark of ALS is the loss of motor neurons in the brain and spinal cord, which causes progressive weakness that spreads throughout different body regions, leading to paralysis of voluntary muscles, including those used for breathing.

Clear differences in site of onset, the pattern and rate of disease progression, and cognitive involvement provide clues and muddy the waters at the same time. 

The main mystery, participants noted, is whether ALS is "one disease with shared fundamental biologic mechanisms, or … many diseases with different fundamental mechanisms."

"Defining just what ALS is has turned out to be far more difficult than anyone could have predicted, but increased understanding in the last five years of the disease's clinical, neuropathological, molecular and genetic aspects has greatly improved the chance that therapies can be found."

John Ravits, neurologist and neurophysiologist at the University of California, San Diego, who serves on MDA’s Scientific Advisory Committee, and colleagues

The problems in defining ALS include a vast degree of variation in the way the disease is described and understood, noted the team of experts that authored the session report. (The team included John Ravits, a neurologist and neurophysiologist at the University of California, San Diego, who serves on MDA’s Scientific Advisory Committee; Stanley Appel, chairman of MDA's Medical Advisory Committee, and longtime research grantee who co-directs the MDA/ALS Center at Methodist Neurological Institute in Houston; and former MDA grantee Robert Baloh — who currently serves on MDA's Medical Advisory Committee — at Cedars-Sinai Medical Center in Los Angeles, and colleagues.)

For example, clinical descriptions of ALS may be based on a variety of different elements, including:

  • the level of involvement of different types of motor neurons (upper motor neurons, which are in the brain; and lower motor neurons, which are in the spinal cord and brainstem);
  • the body region that is first affected at the onset of disease — bulbar-onset or limb-onset, each of which may be further broken down into subtypes, or variants;
  • the involvement of nonmotor regions of the brain (such as frontotemporal dementia, or FTD), or the involvement of other biological systems such as metabolism;
  • the presence or absence of molecular protein clumps called aggregates that contain ALS-associated proteins such as SOD1, FUS or TDP43; or
  • gene mutations.

Whether or not correlations exist between particular onset and progression patterns and underlying molecular mechanisms remain largely unclear. But "genetics is giving us clues," the team noted.

“Mechanisms both converge and diverge” in ALS, reported the team. For example, different gene mutations can cause identical clinical characteristics, indicating there must be multiple mechanisms that cause ALS, and that ALS is a syndrome rather than a single disease. Conversely, a single genetic mutation can cause many different physical or biochemical characteristics, indicating that single mechanisms can lead to clinical differences.

For more, read Deciphering Amyotrophic Lateral Sclerosis: What Phenotype, Neuropathology and Genetics are Telling Us About Pathogenesis.

Session 2: A need for biomarkers

An "intense need" exists to identify biomarkers of ALS — biological signposts that can help with diagnosis, prediction of likely disease course and disease activity in the presence of experimental therapeutics, reported Martin Turner of the University of Oxford, United Kingdom, and colleagues, who authored the session 2 report.

Biomarkers have a number of valuable applications. Biomarkers that could lead to earlier diagnosis would facilitate earlier treatment; biomarkers that predict disease course could help in the creation of care plans and in categorizing trial participants; and biomarkers that enable detection of drug and disease activity could greatly improve clinical trial design and outcomes.

The session identified common molecular pathways that are the subject of intense focus in ALS research and that may yield clues in the search to identify biomarkers:

  • excitotoxicity (a process in which nerve cells are damaged and killed by excessive stimulation of neurotransmitters);
  • oxidative stress (a type of damage that results from high levels of toxic byproducts of energy production inside cells);
  • dysfunction of mitochondria (problems with the energy-producing subunits of cells);
  • neuroinflammation (inflammation of a nerve or parts of the nervous system); and
  • altered energy metabolism.

The group also identified possible sources for biomarkers, including biofluids such as cerebrospinal fluid, blood, urine and saliva; muscle; skin; and tissues taken from muscles, brain and the spinal cord after death.

"Biomarker candidates are emerging with the potential to refine the diagnosis, stratify patients prognostically, and facilitate therapeutic development."

Martin Turner of the University of Oxford, United Kingdom, and colleagues

Methods under investigation for their potential to detect and/or measure established biomarkers are:

  • electromyography (EMG) and motor unit number estimation (MUNE), which are able to measure certain aspects of motor neuron health;
  • transcranial magnetic stimulation (TMS), which can detect motor neuron abnormalities even in the absence of clinical signs;
  • electrical impedance myography (EIM), which can assess the integrity and structure of muscle; and
  • imaging techniques such as single photon emission computed tomography (SPECT), positron emission tomography (PET) and ligand PET, and magnetic resonance imaging (MRI) — all of which are used, with varying degrees of precision, to detect brain changes.

"Biomarker candidates are emerging with the potential to refine the diagnosis, stratify patients prognostically [according to the predicted likely future course of the disease], and facilitate therapeutic development," the group noted. "A key aim for further biomarker development, beyond validation across multiple centers, is the routine incorporation of biomarker measurement into future clinical trials."

For more, read Mechanisms, Models and Biomarkers in Amyotrophic Lateral Sclerosis.

Session 3: ALS risk factors

A number of strategies have been employed to determine the cause of ALS: basic laboratory studies, studies in animal models or cell-based models, autopsy studies and molecular genetics studies.

Another kind of study — called an epidemiologic study — aims to identify social, demographic, clinical and geographic characteristics of people with ALS as a means of detecting environmental or lifestyle factors that can increase the risk of developing the disease.

Findings from recent epidemiological studies in ALS, as well as limitations and potential new directions in epidemiological research, were reviewed in session 3. The team in charge of writing the report included Pam Factor-Litvak at Columbia University (N.Y.), and Adriano Chiò at the University of Torino (Italy).

Although a lot of effort has been made in the last two decades to identify risk factors associated with ALS, the disease has proven difficult to study and to understand. Much of the difficulty, the group said, stems from inconsistent use of a standard definition of ALS across studies.

Future areas of research suggested by the group are:

  • collaborative multicenter studies and analyses that turn their focus from the identification of individual risk factors, to finding the underlying ALS-causing mechanisms associated with a particular exposure;
  • examination of potential ALS risk associated with exposures such as maternal smoking or medication use in early (before birth) development; and
  • the study of ALS as a spectrum disorder, with spectrum being defined by different aspects of disease such as survival time, site of onset, type and pattern of progression and presence of cognitive impairment.

For the greatest success in identifying nongenetic factors associated with ALS risk, the group recommends the use of clearly described groups of people with a new ALS diagnosis and well-matched unaffected "controls." In addition, it suggests the use of national ALS registries as a study resource; and collaboration among a wide array of experts from different fields (such as statisticians, microbiologists, clinicians, psychologists and other behavioral scientists) to address the issues associated with the complexities of ALS.

For details, see Current Pathways for Epidemiological Research in Amyotrophic Lateral Sclerosis.

"Each genetic discovery provides another view of the pathway to neurodegeneration that we hope will at some point come into sharp focus, allowing the design of targeted treatments."

Ammar Al-Chalabi, professor of neurology and complex disease genetics at King's College London (United Kingdom), and colleagues

Session 4: The value of identifying genetic factors

"Research into the causes of ALS is essential for the rational design of therapies," explained the team of researchers that wrote the session 4 report; the team included Ammar Al-Chalabi at King's College London (United Kingdom).

A number of genes are associated with familial ALS: SOD1, TDP43, FUS, ANG, OPTN, UBQLN2 and C9ORF72. In the sporadic form of the disease, mutations in at least two genes — ATXN2 and C9ORF72 — have been identified.

There also are genetic modifiers that can have an effect on survival, age of onset, the site of first symptoms and rate of disease progression. Because changing the course of ALS is the goal in ALS therapy development, the identification of gene variants that naturally modify ALS could greatly impact ALS the search for treatments.

Controversies and problems are not uncommon in the field of ALS genetics research and several were discussed at Tarrytown, including:

  • It's unclear which may be more valuable: searching for single-gene mutations or variants associated with ALS; or looking for sets of multiple contributors.
  • Funding agencies may resist financially supporting innovative ideas viewed as being "high-risk."
  • An understanding of mechanisms is critical to therapy development, but often remains unclear even in cases where a genetic factor is identified. For example, although TDP43 protein is associated with ALS, it's not understood whether its harmful effects are the result of toxicity caused by its aggregation into clumps, or whether the problem is a loss of the normal function that the protein would have were it not bound up into aggregates. 
  • It's unknown whether genetic studies or environmental studies may be of more value in future ALS research efforts.

Despite the difficulties, "each genetic discovery provides another view of the pathway to neurodegeneration that we hope will at some point come into sharp focus, allowing the design of targeted treatments," the scientists wrote.

For more, read Genetic and Epigenetic Studies of Amyotrophic Lateral Sclerosis.

Session 5: Infrastructure and resources

This session aimed to identify resources available for ALS research, such as clinical trial networks, shared clinical databases and repositories for housing biological samples from people with ALS.

James Berry at Massachusetts General Hospital, Boston, and colleagues, noted in the session 5 report that more than 100 specialized ALS clinics are part of the infrastructure dedicated to advancing clinical and patient-oriented ALS research and conduct clinical trials.

Infrastructure resources for ALS clinical research in North America include multidisciplinary clinics, various clinical trial networks, multisite clinical study databases, repositories (sometimes called "biobanks") for collections of human biological samples, governmental funding, and regulatory agencies including the National Institutes of Health (NIH), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), and voluntary disease organizations that support ALS research activities, such as MDA.

Infrastructure deficiencies identified by the team include a lack of "broadly accessible and coordinated" efforts for banking autopsy tissues; a need for Web-based solutions that can make it possible for clinics to share de-identified clinical data; and deficient data mining practices.

Based on these deficiencies, the Tarrytown team recommends:

  • establishment of shared electronic databases among ALS clinics to enhance the coordination of resources and data analyses;
  • expansion of biospecimen banks to collect and store ALS-affected biological samples; and
  • adoption of uniform data standards, such as the recently developed Common Data Elements (CDEs) for ALS clinical research.

"Understanding the current resource 'landscape,' including the obstacles and impediments that need to be overcome, is imperative if we are to improve ALS clinical research infrastructure and move ALS research forward," the team wrote.

For more details, read Infrastructure Resources for Clinical Research in Amyotrophic Lateral Sclerosis.

Session 6: Funding agencies and disease organizations

In this session, 10 groups presented their perspectives on facilitating clinical research in ALS.

Federal agencies included the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute of Environmental Health Sciences (NIEHS), the Office of Rare Diseases Research (ORDR) and the Department of Defense (DOD).

Representatives from NINDS stressed the importance of setting priorities and using stringent scientific standards so as to get the most out of every study. In addition, they proposed bridging preclinical and clinical research programs through implementation of multidisciplinary teams, and helping "bring the research community together" through the use of shared data standards and standard operating procedures.  

Speakers from NIEHS noted their belief that "a complex interplay between genetic susceptibility and environmental exposure is likely to be important" in ALS, and described the organization's mission to study exposure to chemicals as possible risk factors for ALS.

ORDR representatives encouraged ALS researchers to apply for Rare Diseases Consortium Research grants, and those from the DOD noted that DOD ALS research is focused on therapy development, but that if availability of funding increases, it might be interested in fostering opportunities for basic scientists and clinicians to work together on development of new ALS models. 

Representatives from four disease organizations — the Muscular Dystrophy Association (MDA), ALS Association (ALSA), ALS Society of Canada, and the Motor Neurone Disease Association UK (MNDA) — talked about training programs designed to encourage development of ALS clinician scientists, epidemiology studies in ALS, development of additional ALS registries and biobanks, and building "bridges of collaboration" between research groups.

Sanjay Bidichandani, then-MDA vice president of research, touched on MDA's basic and translational research programs, and called attention to the organization's fellowship training programs that are designed to increase the number of young researchers and clinician-scientists entering the ALS research space.

To read more, see Funding Agencies and Disease Organizations: Resources and Recommendations to Facilitate ALS Clinical Research.

There is unanimous agreement that we must continue to investigate ALS in our patients, using all of our intelligence, imagination and passion with state-of-the-art studies."

David Chad and colleagues

Wrap-up and recommendations

"As we consider the strong infrastructure and reliable resources that support ALS research today, we realize that we have come a long way over the past 30 years," wrote David Chad, based at Massachusetts General Hospital, Boston, and colleagues. "However, an enormous task lies ahead, and a greater depth and breadth of infrastructure and resources will be necessary to understand and modify … ALS."

A broad range of conclusions was generated by those who attended Tarrytown II, such as the need to address the systemic nature of ALS.

Participants suggested that epidemiology will play a crucial role in identifying the causes of ALS, but that its success will depend on large studies conducted across multiple centers.

In addition, the team noted that the field of genetics has made great strides in understanding basic mechanisms of disease, but that knowledge has not yet translated into the ultimate goal of effective therapies.

It's also important, as ALS research advances, to ask questions, the Tarrytown team concluded, such as: "Are we attracting and supporting a sufficient number of ALS research neurologists?" and "Can we foster harmonious relations among clinicians, research scientists and advocacy agencies?"

Most importantly, the team reported, "There is unanimous agreement that we must continue to investigate ALS in our patients, using all of our intelligence, imagination and passion with state-of-the-art studies."

To read the entire conference wrap-up, see Peer Recommendations on How to Improve Clinical Research, and Conference Wrap-Up.

Amy Madsen
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