The year 2013 saw major developments in new therapy approaches for genetic forms of ALS, especially for the most common genetic cause of the disease, mutations in the C9ORF72 gene. Association-funded scientists made progress in understanding important elements of the disease’s pathogenesis, which will guide the search for new treatments. The Association also sponsored several meetings to advance both understanding of the disease and the more rapid development of clinical trials.
Improving Clinical Trials
The entire ALS community was disappointed in the negative results from the dexpramipexole trial. However, major lessons were learned in the design and execution of the trial, which will translate into improvements in similar trials in the future. Taking the lead in the effort to ensure trials are as rapid and efficient as possible, The Association co-sponsored a frank and probing roundtable discussion among experts on strategies to improve clinical trial design. Outcomes from that meeting will be used to improve future trials.
One key agreement among ALS clinical researchers and drug developers is the need for biomarkers to track disease progress and response to therapy. To further that effort, The Association awarded funds to several groups to develop clinically relevant biomarkers that can be used in future trials. In partnership with the American Academy of Neurology, it is providing support through the Richard Olney Clinician Scientist Development Award in ALS to a researcher to further develop immune-system biomarkers of disease progression. The Association also partnered with the Neurological Clinical Research Institute (NCRI) of Massachusetts General Hospital to fund a clinical pilot study of an immune-modifying agent called tocilizumab, which will incorporate biomarker measurement.
The Association is also funding a trial of the drug mexiletine, for treatment of muscle cramps, an important source of discomfort for people with ALS.
Progress on Understanding the C9ORF72 Disease Gene
Mutations in the C9ORF72 gene cause up to 40 percent of familial ALS and up to 6 percent of sporadic ALS. Thus, understanding how these mutations cause disease, and determining how to stop their effects, has the potential to improve the prospects for a large fraction of people with ALS. Association-funded scientists made major strides in both these goals this year, just two years after the discovery of the gene. Key findings announced this year included:
–Gene mutations form sticky aggregates of RNA, which bind other cell molecules. Loss of these molecules may be central to the effects of the mutation.
–The mutation leads to the production of unusual small proteins, called RAN products. The effect of these proteins is unknown and is an active area of research to determine if they contribute to disease.
–“Antisense” therapy against the mutation reduces the amount of aggregated RNA and may be therapeutic, according to experiments in cell culture. In mice, antisense against the mutant gene appears to be safe, setting the stage for development of clinical trials. Antisense against the SOD1 gene has been shown to be safe in people with ALS.
Understanding Disease Pathogenesis
“Pathogenesis” refers to the many steps that lead to disease. By understanding these steps, it is possible to design therapies to interrupt them or mitigate their effects. Key developments in understanding pathogenesis included:
–In work supported by The ALS Association, researchers identified a unique molecular “signature” for a type of immune cell in the brain and spinal cord believed to contribute to ALS.
–Association-funded researchers showed that an ALS-related protein is involved in clearing RNA-containing material that builds up in cells, including neurons. The finding suggests that loss of that clearance ability may contribute to the disease.
–Researchers supported by The Association demonstrated that cells that normally support neurons in the spinal cord instead worsen ALS in an animal model involving the disease.
The Association also sponsored a major scientific meeting on how aspects of evolution and development affect the differential susceptibility of motor neurons. Understanding why some neurons are less vulnerable than others may lead to better strategies to protect those most susceptible to disease.
Major Funding Initiatives to Speed Therapy Development
The ALS Association awarded more than $5,800,000 dollars in new grants this year through its Translational Research Advancing Therapy for ALS program (TREAT ALS™). Awards were made through grants, drug discovery contracts and clinical and research studies, all aimed at finding improved treatments for people with ALS. The Association currently supports a portfolio of over $20 million in research awards.
Educational Initiatives for the ALS Community
Again in 2013, The ALS Association sponsored monthly webinars featuring prominent ALS researchers. Each presenter provided a lay-level overview of their latest research, which spanned the field from new genetic discoveries to the search for biomarkers and development of experimental therapies. Through its partnership with the Northeast ALS Consortium (NEALS), The Association also continued sponsorship of The ALS Clinical Research Learning Institute (CRLI), an intensive program to improve understanding of clinical trials and to train people with ALS and their caregivers to become advocates for ALS research.