Selected from a pool of more than 200 proposals, three pioneering projects at BWH were recently awarded with Partners HealthCare’s new Innovation Discovery Grants. Partners awarded 10 total projects with $100,000 each to fund research aimed at improving patient care by accelerating the commercialization of emerging technologies and discoveries.
Launched last year, the IDG program has invested $1 million in prototyping, preclinical studies, software development and other approaches that can directly lead to a license and/or a spinoff company based on a device, drug, diagnostic, software or other product based on the researcher’s innovation.
The winning projects at BWH are led by Lynn Bry, MD, PhD, of the Department of Pathology; Vishal Vaidya, PhD, of the Division of Renal Medicine; and Howard Weiner, MD, of the Department of Neurology.
Finding the Recipe for Ending Food Allergies
The word “cure” is not thrown around lightly in science and medicine. But for BWH pathologist Lynn Bry, MD, PhD, director of the Massachusetts Host-Microbiome Center – who studies the gut microbiome’s role in food allergies and other illnesses – a cure is exactly what she has her sights set on.
Bry has collaborated for several years with Tatal Chatila, MD, and other researchers at Boston Children’s Hospital to define which commensal species of microorganisms in the human gut can prevent food allergies from developing in infants or, for adults and children with existing food allergies, which microbes can stop an allergic reaction from occurring.
After identifying approximately 10 types of human microbes that can achieve at least one, if not both, of these two outcomes, Bry and her team put them to the test in mice with a genetic defect that caused a severe allergy to eggs. In short, the treatment worked. Mice that received the oral regimen of the microbes had no reaction when exposed to eggs two months later.
“Clinically, we were able to cure the mice of the food allergy,” Bry said. “These microbes can alter what the immune system is doing – in this case, skewing from an allergic reaction to one that is now tolerant of the food antigen.”
Bry and her team are currently testing the same mechanisms with peanut and other allergens and seeing similar results. She says that this work, combined with the fact that they have already identified the human microbes responsible for adjusting the immune system’s response to certain foods, is encouraging in terms of being able to soon develop a long-term therapy for people.
“Immunomodulation – or the way the immune system becomes altered – doesn’t happen overnight. We know it takes time for the body to respond and evolve,” Bry said. “If we can give patients a regimen that would last for a couple months – that can potentially cure a lifelong affliction – that’s still a big success if it’s effective.”
The Innovation Discovery Grant will help support preclinical trials and the formation of a startup company, Consortia Therapeutics, which will develop the therapies used for clinical trials in humans. Bry hopes to start the first phase of clinical trials as early as next year.
The mice studied, developed by Chatila’s lab at Children’s, had a genetic defect in their interleukin 4 (IL-4) receptors, a protein that influences the behavior of the immune system. The defect is found in some humans with food allergies. The mutation sensitizes the mice, priming them to have an allergic reaction to common food allergens, such as egg. However, when the researchers administered a cocktail of specific microbes, the mice’s T cells didn’t stimulate the production of molecules responsible for producing allergic reactions, immunoglobulin E (IgE). Instead, the microbes induced regulatory T cells that support responses tolerant of these food antigens.
“We want to understand how long these administered microbes persist and if we’re altering the underlying structure of the gut microbiota for the longer term,” Bry said. “We’d also like to answer: Are we further enhancing beneficial species? Are we knocking down ones that contribute to an imbalance in the gut microbiota? We’d like to find out exactly what the microbes in our cocktail are doing to protect against food allergies.”
Stopping Kidney Disease in Its Tracks
Despite the prevalence of kidney disease worldwide, diagnostic methods and treatments have not advanced much over the years, says Vishal Vaidya, PhD. Dialysis treats the symptoms, not the disease, while biopsies, which are inherently invasive, have been the traditional means of diagnosing kidney fibrosis.
About three years ago, Vaidya’s lab identified several genes prevalent in fibrotic kidney tissue, but one eventually stood out: secreted modular calcium-binding protein, also known as SMOC-2.
“It’s not a very new protein – it has played a role in cancer biology and matrices in other organs – but nobody had looked at it in the kidney,” Vaidya explained. “We found that the protein is always very highly expressed in patient kidneys if they have fibrosis. We were also able to show that not only is it elevated in the kidneys, but it is also elevated in the urine of patients with fibrosis. It can serve as a biomarker of fibrosis.”
Over the next several years, Renal fellow Casimiro Gerarduzzi, PhD, who is part of Vaidya’s team, worked with several mouse models to validate that early discovery. The first group of mice had an abundance of SMOC-2 in their bodies; they developed very severe kidney fibrosis. The following group was genetically engineered to be devoid of any SMOC-2; none showed signs of kidney fibrosis. The next step was to synthesize and inject a small interfering RNA (siRNA) to disrupt production of SMOC-2. The result: the mouse kidneys were protected from fibrosis.
In addition, eliminating SMOC-2 showed no detrimental effects, Vaidya said. Vaidya explains that this is due to the fact that SMOC-2 only plays a role in pathological – or disease-causing – matrix formation. Eliminating it doesn’t appear to cause any harm.
Vaidya and his team then took mouse fibroblasts – cells responsible for producing connective tissue – and SMOC-2 was able to convert them into myofibroblasts. The latter are responsible for causing kidney fibrosis.
“Myofibroblasts proliferate like crazy, migrate and form scar tissue, and once the scar tissue is formed, the functional cells around it start dying while the scar tissue keeps growing,” Vaidya said. “That’s when the tissue becomes severely fibrotic, to the point of no return.”
The siRNA could prevent the myofibroblasts from activating, but it wasn’t an ideal delivery mechanism for humans due to the likelihood of serious side effects, he explained.
Antibodies, however, seemed like a more viable option. Antibodies are much more precise and selective than siRNA and have been successfully used to treat several autoimmune diseases, including rheumatoid arthritis. The selection committee for the Innovation Discovery Grant awarded Vaidya $100,000 to spend over the next year testing the efficacy of a monoclonal antibody – developed by his lab – to shut down SMOC-2. Once the findings are validated, a startup company would be formed to develop and test a therapy for human use.
“Human trials are far away, but my feeling is one step at a time,” Vaidya said.
Discovering an Off Switch for Cancer in Unlikely Places
The very nature of scientific discovery is to uncover the unknown. Even so, while investigating the mechanisms behind multiple sclerosis, BWH neurologist and neuroscientist Howard Weiner, MD, and Department of Neurology fellow Galina Gabriely, PhD, didn’t expect to reveal a potentially new way to fight cancer.
In their search for improved multiple sclerosis (MS) therapies, Weiner, who is also co-director of the Ann Romney Center for Neurologic Diseases, and Gabriely have spent the past several years identifying a type of regulatory T cell that plays a role in suppressing the immune system in animal models.
“In multiple sclerosis, the immune system is overactive,” Weiner explained. “The immune system thinks your brain and spinal cord are foreign, and it attacks them. We thought we might be able to shut down these attacks by increasing the abundance of this specific type of regulatory T cell.”
These cells can be identified by the expression of latency-associated peptide (LAP) on their surface. Known as LAP-positive regulatory T cells, they have been shown to promote cancer malignancy and immune suppression in many types of cancer, including brain cancer, since they can help cancer cells escape the body’s natural immune defenses against malignancy.
Making the connection between the role these cells could play in either multiple sclerosis or cancer was when the Eureka moment hit, Weiner recalled.
“As we studied these regulatory cells and the LAP structure on their surface, I had this idea: Cancer is exactly the opposite of multiple sclerosis,” Weiner said. “In cancer, you want to attack the tumor but you can’t do it. One of the reasons you can’t do it is there are too many regulatory cells; they’re shutting down the immune system. I just took our finding in multiple sclerosis and turned it around.”
Weiner and Gabriely have since developed a highly specific antibody that targets LAP-positive regulatory T cells and removes them from the body. After testing the antibody to treat glioblastomas in animal models, the results were noteworthy: immune response was restored, tumor growth arrested and survival time increased.
With support from the Innovation Discovery Grant, Weiner and Gabriely are getting ready to publish their results and do the necessary validation for a startup company to translate their findings into a therapy for humans. If the work is successful, Weiner believes the therapy could work with multiple types of cancer – not just brain cancers – and may be about two years away from human trials.
“It’s very exciting to work and discover something that applies to another field,” Weiner said. “When you work with scientists in a different field, it broadens your horizons so that you can learn a lot more – and discover more.”