Targeting the pathological processes underlying neurodegenerative disease with effective therapies remains one of the greatest yet most important challenges facing neuroscientists today. Among other conditions, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Amyotrophic lateral sclerosis (Lou Gherig’s disease) and frontotemporal dementia ravage the cognitive and motor functions of their victims. While these diseases have unique genetic or environmental origins, they have one common neuropathological signature: aberrant accumulation of proteins – such as amyloid-β, tau, α-synuclein, huntingtin or SOD1. Because of this commonality, immunotherapy–by targeting the proteins implicated in disease onset and progression–is a promising candidate for treating a host of neurodegenerative diseases.
On Wednesday, November 16 at the 2016 Society for Neuroscience conference, Dr. Eliezer Masliah, of the National Institutes of Health, will present the latest research on the use of immunotherapy for various neurodegenerative diseases, in his talk Capturing Immune Responses to Understand and Treat Neurodegenerative Disease. In this Q&A, Dr Masliah explains the state of immunotherapy for neurodegenerative disease.
ER: Why do immunotherapies hold more promise for treating neurodegenerative disease than other treatments? How have clinical trials so far supported their efficacy?
Dr. Masliah: The advantage of immunotherapy is that it can work via several mechanisms and can be very specific. Multiple mechanisms of action include blocking propagation, targeting oligomers, modulating immune responses, reducing toxicity, reducing inflammation, stimulating clearance, lysosomal clearance autophagy pathways, etc. Recent anti-amyloid phase III trials show some promise in post-hoc analysis. Synuclein immunotherapy has been shown to be safe and early preliminary studies show promise.
ER: What are the main challenges that immunotherapies face?
Dr. Masliah: Most recent studies have shown that new approaches are safer and more specific. Potential challenges are cost in particular with passive immunotherapy.
ER: Do you expect that immunotherapies would be as effective against intracellularly accumulating proteins as against extracellular proteins? For example, would a tau or α-synuclein antibody be as effective as an amyloid-β antibody?
Dr. Masliah: Yes, there is extensive evidence that antibodies enter cells and target abnormal intracellular proteins; however, it is worth noting that most proteins such as amyloid-β, tau synuclein, are actually secreted and propagate from cell to cell. There are many opportunities and mechanisms for antibodies to target abnormal aggregated proteins. In fact, the more toxic forms might be those secreted.
ER: There is uncertainty as to whether preventing protein accumulation can stop progression of some neurodegenerative diseases. For instance, some trials that effectively lower amyloid-β levels have failed to show cognitive effects. Are there certain diseases, which we are confident are in fact caused by toxic protein accumulation, that may be better targets for immunotherapy than others?
Dr. Masliah: The trials you refer to were in patients with mild to moderate Alzheimer’s disease that for practical purposes represent full blown disease, not good examples. Primary and secondary prevention trials such as A4, DIAN-TU and others are underway in patients with pre-clinical Alzheimer’s disease or Mild Cognitive Impairment. Results won’t be known for a few more years.
Image credit https://www.flickr.com/photos/nihgov/
Any views expressed are those of the author, and do not necessarily reflect those of PLOS.
Emilie Reas received her PhD in Neuroscience from UC San Diego, where she used fMRI to study memory. As a postdoc at UCSD, she currently studies how the brain changes with aging and disease. In addition to her tweets for @PLOSNeuro she is @etreas.