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Virtual Keystone Symposia
Drug Discovery
By Shannon Weiman
Here at Keystone Symposia we are accustomed to hosting luminaries and Nobel Prize winners, but every once in a while a new face comes along that really knocks our socks off. This year that face was Dr. Francisco Quintana, who spoke and session chaired at multiple eSymposia, and showcased his transformative work developing innovative new treatments against a multitude of diseases, from multiple sclerosis, to inflammatory bowel disease, and beyond!
Vaccinating Against Multiple Sclerosis
One of the greatest challenges to treating neuroinflammation and neurodegenerative diseases is physically getting treatments past the blood brain barrier, and into the CNS itself. Dr. Francisco Quintana of Harvard Medical School and The Broad Institute, has devised a clever solution to this perplexing problem. Instead he has designed a way to re-educate the immune system from the outside, targeting peripheral dendritic cells as master-regulators of T-cells, which then travel throughout the body and into the brain. Quintana shared this transformative work at the joint eSymposia on "Neurodegenerative Diseases: Genes, Mechanisms and Therapeutics" and "Neuroimmune Interactions in Health and Disease" in June.
In the context of autoimmune diseases like multiple sclerosis (MS), this approach is a powerful way to reprogram immune responses that are wrongly attacking host tissues. Quintana uses nanoparticles similar to those used in vaccines, but in this case redesigned to suppress immune responses against a particular antigen, instead of activating them.This is accomplished with two key ingredients: 1) a special molecule that triggers immune-suppressive transcriptional programing and 2) any antigen of interest. These nanoparticles are ingested by dendritic cells within lymph nodes, inducing a tolerogenic phenotype that instructs T-cells not to attack cells with that antigen.
In mouse models of MS, the nanoparticle treatment not only induced regulatory T-cells that traveled to the brain, but once there, these T-cells orchestrated the transformation of the local microenvironment, correcting the pathological behavior of astrocytes and microglia that were driving neuroinflammation. Miraculously, the approach both prevented and even reversed disease progression.
Quintana has adapted the versatile platform to treat a variety of autoimmune diseases with great success, including MS and type-I diabetes, and even inflammatory conditions like inflammatory bowel syndrome and rheumatoid arthritis. Many of these candidates are now ready to enter clinical trials, offering hopes of a cure for diseases that have challenged modern medicine for decades.
Watch the full length KSQA exclusive interview here: https://youtu.be/-suYqViJLCA
Read more in the PNAS publication:
Tolerogenic nanoparticles suppress central nervous system inflammation
Bioengineering Yeast to Sense and Treat IBD & Beyond
Quintana also spoke about another innovative project in his lab at the eSymposia on "Synthetic Biology: At the Crossroads of Genetic Engineering and Human Therapeutics" in May, describing genetically engineered yeast as a probiotic treatment for inflammatory bowel disease (IBD).
Quintana’s synthetic yeast can not only sense inflammation in the colon or small intestine, they respond by degrading the inflammatory signal eATP, thereby dampening immune responses. The resulting suppression of intestinal inflammation reverses IBD pathology like fibrosis, and promotes recovery of a healthy gut microbiome in various mouse models of colitis and enteritis.The engineered yeast even out-perform FDA-approved treatments for IBD, without the adverse side effects of systemic immune suppression. Ultimately this innovative approach could transform treatment options and quality of life for patients suffering with various intestinal diseases driven by eATP, including IBD, as well as irradiation-induced intestinal fibrosis in cancer patients, and even graft versus host disease in transplant patients.
The idea was born six years ago on a flight from Boston to Vancouver, BC, where Quintana was seated next to colleague Dr. Sergio Peisajovich. The two were on their way to a Keystone Symposia meeting on Inflammatory Diseases, and spent the flight brainstorming about how they might combine their expertise in molecular immunology and protein engineering to correct pathological immune signaling. Now their “pie in the sky” ideas have become a reality. Passing pre-clinical studies with flying colors, the synthetic yeast are now ready to launch into clinical trials.
Designing and developing a novel treatment from inception to clinic is an accomplishment that most scientist can only hope to accomplish by the end of their career, but for Quintana, this is just the beginning. He envisions adapting the platform against many other diseases, “simply” by engineering the yeast to sense different signals and/or respond with different actions, targeted to each disease case. It may not be so simple, but the highly modifiable yeast platform is suited for the challenge.
The yeast might even be engineered to treat diseases outside the gut itself. With an avid interest in the gut-brain axis, Quintana is eager to develop probiotics that trigger signals in the gut that will act to modulate activities in the brain, for the treatment of multiple sclerosis and other CNS disorders.In light of the recent explosion of evidence pointing to the gut’s central role in educating systemic immune responses, this yeast probiotic platform is a powerful tool for modifying gut signaling to correct immune pathology throughout the body and in the context of diverse diseases. From autoimmune diseases to chronic inflammatory conditions, these innovative immune-modulating yeast have vast potential across all fields of medicine.
Hear more about this new frontier in synthetic biology and medicine in the full length KSQA interview: https://virtual.keystonesymposia.org/ks/sessions/14002/view
Read more in the Nature Medicine publication:
Self-tunable engineered yeast probiotics for the treatment of inflammatory bowel disease
Transformative Technology: Tracing Single-Cell Interactions in the CNS with Viral Barcoding
Quintana is not only broaching new therapeutic horizons, but also pioneering transformative new research technologies. In another project, he has repurposed the rabies virus as a tracer for single-cell interactions in the brain. Not only can this innovative approach show which cells physically contact each other in the CNS, it can also unveil how those interactions influence transcriptional programing in neighboring cells, thereby altering their behavior.
This powerful new tool enables researchers to examine how glial cells interact with neurons, and vice versa, to reveal underlying pathology behind neuroinflammatory, neurodegenerative and even neuropsychiatric disorders.Read more in the Science publication:
Barcoded viral tracing of single-cell interactions in central nervous system inflammation
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