- The annual International Symposium on ALS/MND (Motor Neuron Disease) brings together researchers and clinicians who specialize in ALS from around the world.
- Experts in all aspects of ALS and newcomers to the ALS field exchanged ideas about ALS biology, clinical care, diagnosing and measuring ALS, clinical trial design and trial results, and strategies for therapeutic development.
New insights and perspectives on the biology of ALS, best practices in the care of individuals with the disease and future directions for development of ALS therapies were the central themes of the 21st International Symposium on ALS/MND (Motor Neuron Disease) that took place in Orlando, Fla., Dec. 11-13, 2010.
About 800 people attended this year’s meeting, including dozens of MDA-affiliated physicians and MDA-supported research grantees (several of whom presented their work), and representatives of MDA’s research, health care services and public health education programs.
Below is an overview of the topics addressed at the symposium.
Clinical aspects of ALS
At least two somewhat surprising aspects of the clinical picture in ALS emerged.
One was that pain, caused by abnormal joint mobility or cramps, is a frequent part of the disease.
A second was that mild, subtle cognitive and behavioral impairments are often present in ALS and may have a negative impact on social interactions and communication.
Among the themes explored in ALS biology were the multiple pathways influenced by the TDP43 protein. TDP43 biology is proving to be a fruitful area for uncovering possible disease mechanisms and targets at which to aim experimental therapies.
The protein is known to be abnormally located and aggregated (stuck together) in many cases of ALS, and to be abnormal because of a genetic TDP43 mutation in other cases.
Another theme was the major contribution made by glial cells to the ALS disease process. Glial cells in the central nervous system (the site of ALS-related damage) include astrocytes, microglia and oligodendrocytes. Although they are not neurons (nerve cells), glial cells provide vital functions to support neurons, including motor neurons (the main cells that are lost in ALS).
There’s increasing evidence that motor neurons are not the only cells affected in ALS. Glial cells are also part of the problem and, if treated or replaced, could become part of the solution.
It’s been known for decades that two sets of motor neurons — those that control the movements of the eyes and those that control the external sphincter muscles of the anus and urethra — are spared in ALS. Another theme explored at the symposium was that learning why these particular motor neurons are resistant to ALS could shed light on disease mechanisms and provide new therapeutic directions.
Tracking, measuring and diagnosing ALS
Several lectures focused on new ways to diagnose and track the progress of ALS, particularly in the context of clinical trials, where it’s crucial to quickly and accurately determine the effect of an experimental treatment.
New developments include:
- a portable device called ATLIS (accurate test of limb isometric strength), which is an adjustable tilting chair in a frame that can accurately measure strength changes in a cost-effective manner;
- new applications of ultrasound imaging and magnetic resonance imaging (MRI);
- a new type of electrophysiological measurement called a “combined motor action potential scan progression score,” which appears to show disease progression more accurately than current related techniques; and
- the possibility of diagnosing ALS and predicting its progression by measuring the levels of proteins called neurofilament heavy chain, cystatin C and complement C3 in the spinal fluid and blood.
Clinical trial design
A major area of interest for conferees was the design of clinical trials of experimental treatments for ALS. A number of interesting ideas were proposed.
Trials should be thought of as “diagnostic” tests, not for the presence of disease but for the effects of a treatment.
- Questions in trials must be clearly defined, and the trial must be designed to answer those questions.
- The main question to be answered by phase 2 trials should be whether or not to move to a phase 3 trial.
- “Futility” trials, whose end point is that the drug is unlikely to have benefit, can be useful in some situations.
- Trials that are too small or otherwise poorly designed can actually slow the research process.
Clinical trial results
Results of some recent clinical trials were announced at the symposium.
CK-2017357, an experimental drug designed to enhance muscle contraction, has shown “evidence of effect” in a phase 2a trial in ALS. The drug is in development by the South San Francisco company Cytokinetics.
KNS-760704, also known as dexpramipexole, has shown promise in a phase 2 study and likely will be taken into a phase 3 study this year. The experimental drug, in development by Pittsburgh-based Knopp Neurosciences, is designed to improve energy production and provide protection to neurons under stress.
Talampanel, an investigational drug designed to interfere with signaling by the potentially toxic chemical glutamate, failed to slow disease progression in a phase 2 trial in ALS. The drug was being tested by the Israeli company Teva Pharmaceuticals.
Pioglitazone, a drug marketed as Actos in the United States, United Kingdom and Germany for the treatment of type 2 diabetes, was being tested in ALS but the trial was stopped early when it became clear that participants taking a placebo were doing better than those taking the drug. Pioglitazone makes tissues more sensitive to insulin and had shown promise in animal models of ALS. Investigators are further analyzing the results and hope to figure out why the drug was not effective and perhaps harmful in ALS.
To find out about open clinical trials, go to www.clincialtrials.gov, and search the database.
Several investigators presented their work in experimental therapies for ALS. Among the intriguing reports of strategies in development:
- the ongoing design of artificial viruses at the University of Sheffield in the United Kingdom that are designed to deliver therapeutic genes safely and effectively to the central nervous system;
- the creation of “induced pluripotent stem cells” from ALS patients’ skin cells at the South San Francisco biotech iPierian, as model systems in which to study the disease and the effects of various therapies; and
- a plan to transplant stem-cell-derived astrocytes into people with ALS, by approximately the year 2014, as a joint venture of the University of California, San Diego, the Salk Institute and the Carlsbad, Calif., company Life Technologies.
Want to know more about what happened at the 21st MNDA International Symposium? See the “Highlights and Insights Blog” and Abstract Book 2010 on the Motor Neurone Disease Association website.