This year at the 69th Annual American Academy of Neurology Meeting in Boston, thousands of neuroscientists came together to share their research and collaborate. Here we report the latest ALS research findings presented at the meeting by distinguished researchers, who were chosen to speak based on scientific merit. Read more for exciting ALS updates from the meeting.

Dr. John Ravits, Professor of Clinical Neuroscience at the University of California at San Diego, was presented with the Sheila Essey Award in a special platform session devoted to ALS research at the annual meeting of the American Academy of Neurology (AAN) in Boston, Massachusetts, in April. The $50,000 award, which honors the memory of Sheila Essey, was presented by her husband Dick and their son, James. The award recognizes significant research contributions in the search for the cause of, prevention of and cure for ALS, whose recipients are chosen jointly by The ALS Association and the AAN.

Dr. Ravits has led the field in seeking clues from the clinic that shed light on the mechanisms of progression of ALS. His discoveries have shaped the understanding of the ALS disease process as one that spreads within the nervous system, providing a rationale for therapies that interrupt that spread, such as antibodies against key ALS proteins.

Beginning in 2007, Dr. Ravits made a series of seminal observations about the pattern of disease spread, based on both clinical work and post-mortem analysis. He noted that the site of disease onset appears to be highly localized, and random—that is, most people report symptom onset in a specific region of the body, and the region differs from person to person. After that random and focal onset, the disease spreads to adjacent body regions, suggesting the transfer of some pathologic entity from neuron to neuron. And the rate of spread within the nervous system accounts for the rate of disease progression observed in the clinic, he showed.

One implication of these insights is that interrupting the spread of disease between neurons may be beneficial. If the entity that is spreading is a protein, it may be possible to develop an antibody that binds to the protein to prevent healthy neurons from becoming affected. Another implication is that delivery of any localized therapy, such as a stem cell injection, will need to be targeted where it can interrupt or slow the spreading process. “If stem cells are going to work,” Dr. Ravits said, “we will have to choose the site of delivery based on the clinical picture at the time of treatment,” rather than using the same injection plan for everyone.

Gene Editing for ALS

The session also featured several presentations on new treatment strategies for ALS. ALS Association funded Dr. Zachary Kennedy,  in the laboratory of Dr. Robert Brown Jr.,  at the University of Massachusetts Medical School in Worcester, reported on a new technique for “editing” the mutant SOD1 gene. The mutant gene causes an inherited form of ALS and has been the basis for mouse models of the disease for two decades.

The new technique is called CRISPR-Cas9, which combines a small piece of RNA (the CRISPR part) plus an enzyme that can cut DNA (the Cas9 part). In Dr. Kennedy’s work, the RNA is created to match a portion of the SOD1 gene, allowing it to act as a “guide sequence” to deliver the Cas9 to the mutant gene. Once there, the enzyme cuts the mutant SOD1 gene. When the cell tries to repair the broken gene, it usually introduces mistakes that make the gene no longer functional, thus silencing the SOD1 gene permanently. Previous work has shown that shutting down the SOD1 gene is beneficial in mouse models.

The effect is similar to that produced by antisense oligonucleotides, which are being developed for clinical trials in people with ALS, “but that is likely going to require repeated long-term treatment,” Dr. Kennedy said. “CRISPR could permanently alter the genome,” potentially meaning that a single treatment or short series of treatments could be used to treat this form of ALS.

No Benefit from Diaphragm Pacing

Dr. Jonathan Katz, of California Pacific Medical Center in San Francisco, reported on the outcome of a randomized trial of the Diaphragm Pacing System (DPS), a form of electrical stimulation for the breathing muscles that has been approved for ALS. Dr. Katz and colleagues in the Western ALS Consortium enrolled 52 people with ALS whose breathing function had begun to decline, and randomized them to either the recognized standard of care for ALS, or the standard of care plus DPS. “We saw no effect on survival from treatment,” Dr. Katz reported. Unlike results from a European trial called DiPALS, there was no suggestion that treatment with DPS was associated with more rapid decline. “Our results indicate that DPS is not harmful, as previously reported, but we saw no evidence of benefit.”

Interleukin-2 is Explored for ALS Treatment

Dr. Gilbert Bensimon, of Nimes University Hospital in France, reported on a small safety study of interleukin-2 (IL-2), a molecule made by the body’s immune system that stimulates production of “regulatory T cells.” These immune cells are critical for reducing inflammation, an immune process that is thought to contribute to ALS disease progression. “There is a lot of evidence that inflammation contributes to ALS,” Dr. Bensimon said. IL-2 has been used safely in other conditions.

Dr. Bensimon’s study showed that 12 weeks of treatment with IL-2 was safe in people with ALS, and had the expected stimulatory effect on the production of regulatory T cells. “These results support further drug development of IL-2 in ALS,” he said, to determine if increasing the number of these T cells could reduce inflammation, which might slow disease progression.

In a related study, Dr. Cristina Moglia of the University of Turin, Italy, showed that variations in an immune system gene called CX3CR1 influences survival of people with ALS. The gene acts in cells called microglia, which promote inflammation and may be new targets for therapy.

Blood Biomarker May Predict Rate of Progression

Dr. Steven Hahn of the pharmaceutical company Biogen, reported on a study of “neurofilament heavy chain” as a biomarker for ALS progression. A biomarker is a measurable quantity that indicates something important about a disease (cholesterol in the blood is used as a biomarker to predict heart disease risk, for example). Neurofilament heavy chain (NFH) is a protein that provides structure for the long extensions of neurons called axons. As neurons degenerate in ALS, they release NFH into the cerebrospinal fluid (CSF) and the bloodstream. Previous work has shown that NFH in CSF is a good biomarker for ALS severity, but measuring it requires a lumbar puncture. Dr. Hahn and colleagues sought to determine if NFH in the blood might also correlate with important aspects of ALS. They measured NFH in samples collected at the start of the dexpramipexole EMPOWER study, and asked whether they predicted changes in clinical status over the course of the study. They found that higher levels of NFH in the blood correlated with faster decline on the ALS Functional Rating Scale. They are now looking at how NFH measurements changed over the course of the trial. “This work supports the idea of using NFH as a biomarker in ALS clinical trials,” Dr. Hahn said.

Finally, Dr. Pantelis Pavlakis of Weill Cornell Medical College in New York reported on the complex relationship between specific mutations in the SOD1 gene and the clinical features and progression of the person carrying such mutations. This work may help in clinical trials of people with SOD1 mutations, to better detect treatment-related improvements against the background of varying rates of progression.

Together, it was uplifting to witness all the great science currently happening in the ALS field. The collective spirit was collaborative and every participant left the meeting with new ideas and collaborative partners. We look forward to the AAN meeting next year in Los Angeles!