News from the AAN Annual Meeting
Common Inflammatory Pathways Identified for ALS Animal Model and Humans With Disease, Suggesting New Therapeutic Targets
ARTICLE IN BRIEF
Investigators identified 19 microRNAs that are common and similarly affected in SOD1 mice and ALS patients. In addition, they found common inflammatory signatures in monocyte samples from ALS and MS patients.
With growing evidence that the immune system and inflammation play a critical role in amyotrophic lateral sclerosis (ALS), scientists at the Brigham and Women's Hospital in Boston used antibodies to target the body's innate immune cells (monocytes) and significantly reduced motor neuron death and increased survival in animal models of the disease.
Based on these results in animals, Oleg Butovsky, PhD, Howard L. Weiner, MD, and their colleagues spent three years collecting peripheral blood from patients with sporadic ALS and familial ALS to peer into their monocyte profile to see whether the events of the human immune system are analogous to what is taking place in the animal models.
According to Dr. Butovsky, a senior scientist at the Center for Neurologic Diseases at the Brigham and Women's Hospital and Harvard Medical School, the inflammatory signature is similar to that of the mouse model of the most common familial form of the disease — mutant superoxide dismutase-1 (SOD1) that leads to the death of motor neurons.
“We think we have a direct link between the animal models and patients,” said Dr. Butovsky, who presented these findings at the AAN annual meeting in New Orleans in April.
Dr. Butovsky explained that the recruitment of inflammatory monocytes seems to play an important role in disease progression. He and colleagues identified a microRNA (miRNA) specific to ALS, which they believe could potentially be used as a biomarker and a therapeutic approach to protect motor neurons in patients with ALS. [miRNAs are non-coding areas of the RNA that play a critical role in regulation of gene expression.]
Dr. Butovsky and Dr. Weiner, the Robert L. Kroc Professor of Neurology at Harvard Medical School and director of the Partners Multiple Sclerosis Center and co-director of Brigham's Center for Neurologic Diseases, are now working on developing methods to specifically target peripheral monocytes in order to modulate their phenotype to help prevent this proinflammatory response.
The clinical trial follows experiments they carried out on the SOD1 mouse where they identified a proinflammatory gene signal in Ly6CHi monocytes, which was reported at the 2011 AAN annual meeting. They found that there was a progressive recruitment of the white blood cell that enters the spinal cord, but not the brain, and damages the motor neuron. The monocytes began appearing in the spinal cord one month before the onset of symptoms. Once they identified markers for this monocyte they used it to down-regulate the proinflammatory monocytes and reduce their numbers getting into the spinal cord. This technique protected the motor neurons from damage and prolonged survival by 16 days.
In their latest study, they measured monocytes from 18 patients with sporadic ALS and four with familial ALS with SOD1 mutation, eight with MS, 13 with Alzheimer's disease, and 33 age-matched controls. They identified a unique miRNA signature — (CD14+/CD16-) — in the blood monocytes of ALS patients, which were analogous to the Ly6CHi in the SOD1 mouse, and that profile was distinct from that obtained from patients with a classic inflammatory disease, MS.
The investigators found 19 miRNAs are common and similarly affected in SOD1 mice and ALS patients.
While there were some dysregulated miRNAs shared in ALS and MS samples, there was no overlap between ALS and the Alzheimer's disease samples.
These findings identify common inflammatory pathways between ALS and MS and further supports a role for inflammation in ALS, Dr. Butovsky said. They also raise the possibility that anti-inflammatory therapies being developed for MS could theoretically be tested in ALS as well.
The Boston researchers are now working on developing a blood biomarker of this inflammatory signature that could help monitor disease progression and response to therapies. They are also testing the benefits of modulating these monocytes as a potential treatment.
“This is an excellent study that provides tantalizing insights into a possible future biomarker for ALS,” said Jeffrey D. Rothstein, MD, PhD, professor of neurology and neuroscience and director of the Robert Packard Center for ALS Research at Johns Hopkins University School of Medicine.
Stanley H. Appel, MD, the Edwards Distinguished Endowed Chair for ALS and director of the Methodist Neurological Institute in Houston, said: “I agree that neuroinflammation and immunomodulation play a significant role in the mouse SOD ALS model as well as in human sporadic ALS. We have evidence of this in our own studies reported in May 2011 in the journal Brain. [See “References.”] The miRNAs they identified provide a unique opportunity to monitor pathogenic pathways in ALS models, and it is a major contribution to have documented that inflammation-related miRNAs are prominent in the mouse SOD1 model, and may also reflect the enhanced inflammation in human sporadic ALS.”
“This novel work provides strong confirmation of the importance of immunomodulation in the pathogenesis of ALS, and presents a significant opportunity for developing relevant biomarkers. The questions that future studies need to address are whether the miRNAs are early or late markers of ALS, do they correlate with the rate of disease progression or disease burden, and can alterations in miRNAs influence disease duration and survival,” said Dr. Appel.