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Highlights from 24th International ALS/MND Symposium

December 24, 2013

The 24th International Symposium on ALS/Motor Neuron Disease was held in Milan, Italy, December 6-8, 2013, drawing hundreds of researchers and clinicians from around the world. Here are some highlights from the meeting:

Immune System as a Therapy Target
The immune system continues to grow as a target of interest in therapy design.

  • Serge Rivest noted that contrary to some long-held beliefs, there is quite a lot of immune system activity in the central nervous system. But it is has some unique characteristics that may both contribute to the problems in ALS and point the way to development of therapy. Dr. Rivest has worked in Alzheimer’s disease, which shares some important similarities with ALS in terms of neurodegeneration and immune involvement. He has found that stimulating a specific type of immune cell, called an M1 monocyte, helped slow neuronal loss in a genetic mouse model of AD.
  • Kuti Baruchhas shown in a mouse model of ALS that promoting movement of immune cells across a membrane in the brain called the choroid plexus increases survival.

C9ORF72: Gene Modification, Repeat Length Variability
The C9ORF72 gene expansion continues to provide important insights into ALS disease development.

  • In work supported by The ALS Association, Veronique Belzil showed that the mutant gene is chemically modified to reduce the amount of protein made from it. That lack of protein may contribute to disease. The modification, called methylation, is a dynamic process that can be reversed and promoting that reversal may be therapeutic.
  • Marka van Blitterswijk carefully measured the repeat length in various tissues in patients with frontotemporal dementia/ALS and found that the mutation length varied enormously even within a single individual’s tissues. Repeat length in the skin or blood did not correlate with disease subtype, disease duration, or prognosis, meaning that at the moment, it is not possible to make clinically meaningful predictions for individual patients based on the repeat length in tissues that are accessible for sampling.

Discovering New Gene

  • An analysis of genetic variation among more than 13,000 people with ALS has revealed a potentially important new “locus” on chromosome 17 that is linked to the disease. The gene or genes in this region are not yet known, but this finding will likely lead scientists to search in earnest for it. The same team found another potentially important locus on chromosome 18
  • Aaron Gitler presented results from the first genetic analysis of ALS “trios” (a patient and both parents) to search for disease-causing mutations that were not inherited from either parent (“de novo” mutations). He reported finding new mutations in genes that control chromosome structure, a potentially important new function for understanding ALS.
  • Olubunmi Abel provided an update on the ALS Online Genetic Database (http://alsod.iop.kcl.ac.uk), noting the ability of the database to provide comparisons between any pair of ALS-related genes, to predict the disease-causing ability of new mutations and other useful features.

The Importance of Endogenous Neuroprotection
Motor neurons have some capacity to protect themselves from potentially harmful threats. Such endogenous neuroprotective mechanisms are often activity-dependent; that is, the more active the neuron, the greater its capacity to protect itself. Pico Caroni gave an overview of work showing that the most vulnerable motor neurons in ALS are the so-called “fast fatigable” (FF) motor neurons. In the SOD1 mouse model, FF neurons begin to show signs of pathology even before birth. Enhancing their excitability increased their ability to protect themselves against SOD1-mediated toxicity. This neuroprotective ability required a signaling molecule called mTOR, suggesting that this protective pathway may be an important one for further therapeutic exploration.

Robotic Analysis for High-throughput Screening
The search for new treatments often relies on a “high-throughput” screen, a test of hundreds to thousands of chemicals to find the small handful that have the desired effect. At the Milan meeting, Steven Finkbeiner provided an overview of a robotic screening system that analyzes treatment effects on motor neurons. In this system, induced pluripotent stem cells (iPS cells) derived from ALS patients are differentiated into motor neurons, which are then grown in culture. The robotic system allows tracking of individual motor neurons (as opposed to averaging results for large groups of them) over time, to observe disease progression and the effects of treatment. Recently, Dr. Finkbeiner and colleagues used the system to assess the ability of an experimental compound to rescue ALS motor neurons from the toxic effects of TDP-43, a protein that misfolds and accumulates in almost all forms of ALS (http://www.ncbi.nlm.nih.gov/pubmed/24336168).

Biomarkers and Treatments
Recently, several groups have made progress on finding biomarkers that can track disease progression.

  • In work supported by the North Carolina Jim “Catfish” Hunter Chapter of The ALS Association, Benjamin Brooks showed that an easily measured protein in blood serum, called creatinine, declined over the course of the disease. The decline correlated with decline in the ALS Functional Rating Scale, the current gold standard of disease progression and predicted loss of ambulation, a clinically significant milestone in the disease. Further work may allow serum creatinine to be used as a biomarker in clinical trials to determine response to therapy.
  • Tirasemtiv has been developed for symptomatic treatment of ALS. It promotes calcium release from muscle, increasing the force produced by muscle contraction. It has been shown to be safe and effective in single and multiple doses in ALS patients.  Jeremy Shefner presented an interim report on an ongoing trial of more than 700 ALS patients randomized either to placebo or 250 mg tirasemtiv given twice per day. He noted that dizziness is the most common adverse event and usually resolves within a week of the start of treatment. Complete results are expected in mid-2014.
  • The ALS Association sponsored a study of the costs of care at 18 multidisciplinary clinics in the United States that adhere to the treatment guidelines for ALS created by the American Academy of Neurology. Adherence to practice parameters was very high, except that only half had advance directives in place for patients. Patient satisfaction was high. Cost of salary and benefits paid per clinic day was about $500 per patient, with a range from $258 to $806. The study was not able to capture all costs of care, the authors noted.

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