A research team at the Krembil Research Institute has inked a deal with a multinational pharmaceutical company that could accelerate the development of a potential disease-modifying drug for Alzheimer’s disease.
French drug company Servier has announced a new strategic research partnership agreement with Toronto-based Treventis Corp.—a biotech company founded by Krembil Director Dr. Donald Weaver—to co-develop a promising new therapeutic treatment already underway at UHN.
“This is a very big deal,” said Dr. Weaver, a medicinal chemist, University of Toronto Professor, Canada Research Chair and neurologist who treats dementia patients at Toronto Western Hospital.
“Drug discovery is a tremendously competitive field and this partnership demonstrates the ability of Krembil and UHN to achieve a level of excellence on the world stage. It also helps cement our place as one of the leading neuroscience research facilities in Canada.”
As part of the collaborative agreement, researchers in Paris and Toronto will jointly develop compounds that target two key proteins known to play a role in Alzheimer’s disease. Those proteins, called tau and beta-amyloid, are believed to have a deleterious effect on brain function when they misfold.
“We all have these proteins in our brains. When they misfold they become toxic to brain cells. They kill brains cells,” said Dr. Weaver. “We have identified a class of compounds that we believe prevent beta-amyloid and tau from doing this.”
Dr. Weaver’s team has spent nearly two decades searching for a therapeutic strategy to slow or stop the neurodegenerative disease that affects more than 500,000 Canadians. There are currently no disease-modifying drugs for Alzheimer’s on the market.
In 2013, Treventis was awarded $4.7-million in funding from the prestigious Wellcome Trust to investigate compounds, with the goal of designing a drug that can safely and effectively treat people with chronic neurological dementias, such as Alzheimer's. Funding from the Wellcome Trust, a British-based independent charity, is extremely competitive, difficult to obtain and is traditionally awarded to researchers in the U.K.
“The Wellcome Trust funding allowed us to get to the point where we have a molecule that works, but needs some fine-tuning,” said Dr. Weaver. “Partnering with a major pharmaceutical company like Servier is the next logical step.”
Dr. Weaver is quick to also credit other funding agencies that have played a significant role in advancing the fundamental research to its current stage of applied drug discovery. Among the most generous contributors, he said, are the Alzheimer’s Society of Canada, Canadian Institutes of Health Research, Toronto General & Western Hospital Foundation, The W. Garfield Weston Foundation, BrightFocus® Foundation and Krembil Foundation.
For its part, Servier has indicated that it is excited to partner with Treventis in taking this research to the next level.
“We very much hope that this new collaboration will allow us to answer the huge unmet patient need for disease-modifying treatment of Alzheimer’s disease, thanks to Treventis’ unique and innovative technology,” Christian de Bodinat, the Director of Servier’s Center of Therapeutic Innovation in Neuropsychiatry, said in a statement. “We are very excited to be part of one of the first programs employing a dual approach in this field.”
As part of the agreement, Servier will fund all research costs and maintain worldwide rights to develop and commercialize drugs advanced during the partnership.
Dr. Weaver and his team are thrilled to partner with one of the most innovative pharmaceutical companies in the world.
“I think it says that Servier has faith that we have a sound approach, excellent molecules and that there is a good foundation already in place,” said Dr. Weaver. “This allows us to optimize and fine-tune the molecule and perform more elaborate biological evaluations.”
Next steps for the research team include ramping up work in the laboratories at the Krembil Discovery Tower and JLabs, and attempting to identify a candidate for a Phase 1 clinical trial.
Dr. Weaver will discuss his research and this latest development on the January 23, 2018 edition of CBC’s Ontario Today.
A research project focused on the use of nanoparticles to improve the treatment and visualization of tumours received $6.6 million in funding from the Terry Fox Research Institute. The project will receive five years of funding through the New Frontiers Program and will be led by Dr. Gang Zheng (PM Senior Scientist and Techna Core Lead), Dr. Brian Wilson (PM Senior Scientist and Techna Core Lead), and Dr. Jonathan Irish (Techna Core Lead), together with Dr. Christine Démoré and Dr. Stuart Foster at Sunnybrook Research Institute.
The research team will advance the development of two Canadian technology platforms: porphysome nanoparticles, which are small injectable particles that accumulate within tumours; and photoacoustic imaging, which uses short pulses of laser light to produce high resolution images of tumours. The researchers will examine a treatment strategy involving the use of nanoparticles that absorb light and can convert it into heat energy that selectively destroys tumour tissue.
This project will focus on prostate and thyroid tumours—two cancers that lack minimally-invasive treatment options. Current treatments for these tumour types involve either a ‘watch and wait’ approach or the use of aggressive surgeries to remove the cancer. These surgeries can have unwanted side effects and impair quality of life for patients.
“The majority of prostate and thyroid cancers won’t kill you, but some will need treatment,” explains Dr. Zheng. “If we can avoid invasive surgery for most patients, we can eliminate harmful side effects—and the economic burden for Canada will be decreased by this as well.” With this funding, the researchers will focus on fast-tracking these new technologies to the clinic so that they can help patients.
The project, titled The Terry Fox New Frontiers Program Project in Nanoparticle-Enhanced Photoacoustic Imaging for Cancer Localization and Therapeutic Guidance, is a renewal of a previous project funded by the same program.
It’s impossible to predict how the present will affect the future. Case in point: when World War II soldiers were given a drug to prevent malaria, a deadly tropical disease that was causing more deaths than the enemy, no one could have predicted that the drug would also be a safe and effective treatment for a lesser known autoimmune disease known as systemic lupus erythematosus (lupus).
Lupus is a disease in which the immune system attacks a number of organs including the skin, joints, lungs and kidneys. About 80% of those afflicted with the disease develop skin rashes on sun-exposed areas of their body.
It was during the war that doctors noted that rashes associated with lupus cleared up when soldiers were treated with an antimalarial drug. Since the discovery, several studies have gone on to show that antimalarial agents also prevent organ damage and improve survival in patients with lupus.
Krembil Emeritus Scientist Dr. Murray Urowitz’s latest study provides further evidence of the safety and efficacy of antimalarial agents in treating lupus.
The five-year study investigated some of the long-term effects of antimalarial agents on lupus outcomes in three patient groups: those who took antimalarial drugs more than 60% of the time; those who took antimalarial drugs less than 60% of the time; and those who did not receive antimalarial drugs. The three groups were regularly assessed for lupus symptoms, rates of disease flare ups, antimalarial drug related toxicity and the use of steroids to manage their symptoms.
The study results revealed that patients who consistently took antimalarial drugs had fewer lupus symptoms compared to those who did not. These patients also had noticeably fewer flare ups and needed lower cumulative doses of steroids. Importantly, only two study participants experienced adverse effects as a direct result of the antimalarial treatment.
Explains Dr. Urowitz, “Our study highlights the importance of consistent intake of antimalarial agents early in the course of lupus. It builds upon the discovery that was made decades ago, which first identified the benefits of antimalarial therapy in treating lupus.”
This work was supported by the Lou and Marissa Rocca, the Lupus Foundation of Ontario and the Toronto General & Western Hospital Foundation.
Pakchotanon R, Gladman DD, Su J, Urowitz MB. More Consistent Antimalarial Intake in First 5 Years of Disease Is Associated with Better Prognosis in Patients with Systemic Lupus Erythematosus. J Rheumatol. 2017 Nov 15. pii:jrheum.170645. doi: 10.3899/jrheum.170645.
An international team of researchers have shown—for the first time—that mutation of the KRAS gene can promote the development of abnormal blood vessels in the brain, increasing a person’s risk of hemorrhagic stroke.
During a hemorrhagic stroke, a blood vessel in the brain leaks or ruptures, spilling blood into the brain and damaging surrounding tissues. This damage can lead to a variety of complications including difficulty speaking, paralysis and even death. Approximately 40% of all stroke-related deaths are attributed to hemorrhagic stroke.
Particular regions of the brain’s vasculature can be more susceptible to ruptures or leaks. For example, up to 20% of hemorrhagic strokes in children are located in brain arteriovenous malformations (BAVMs), consisting of tangles of abnormal blood vessels. BAVMs are present in 15 out of every 100,000 people and are most often found in patients with no family history of them. Beyond this, very little is known about BAVMs, including how they develop or why they are prone to rupture or leak during a hemorrhagic stroke.
“Even if they don’t bleed, BAVMs can cause seizures or other stroke-like symptoms,” says Krembil Scientist Dr. Ivan Radovanovic. “Patients aren’t always good candidates for the few treatments that are available for BAVMs such as surgery or radiation. So it’s really a condition that requires new therapeutic options, and understanding its cause will open the door to other possibilities.”
Dr. Radovanovic and TGHRI Senior Scientist Dr. Jason Fish, along with researchers in Finland and Switzerland, co-led a study that provides new insight into the biology of BAVMs. Their findings were recently published in the prestigious New England Journal of Medicine.
As part of the study, the research team examined the genetic content of BAVM tissue that was surgically excised from patients. They found that BAVMs from 45 of 72 patients (~60%) contained a mutated version of the KRAS gene, best known for its role in promoting the growth and survival of cancer cells. The altered gene was specifically located in the cells lining the inner surface of the BAVMs’ blood vessels, where it dysregulated the cell’s behaviour and structure. Importantly, it weakened the ‘glue’ that holds the cells together to form blood vessels, potentially making the vessels more likely to leak or rupture.
The findings of the study not only reveal that KRAS plays an instrumental role in the development of BAVMs, but also identify new therapeutic targets to treat them. “Fortuitously, there are already cancer drugs used in clinical practice that dampen KRAS’s effects on cells. The next step will be to test whether these drugs can reverse the effects of mutated KRAS in experimental models of BAVMs,” says Dr. Radovanovic.
This work was supported by the Swiss Cancer League; Novartis; the European Research Council; the American Heart Association; the Canadian Institutes of Health Research; the Canada First Research Excellence Fund; the Canada Foundation for Innovation; the Ontario Ministry of Research, Innovation and Science; the Natural Sciences and Research Council of Canada; the Brain Aneurysm Foundation; the Department of Surgery and Division of Neurosurgery at the University Health Network; and the Toronto General & Western Hospital Foundation. JE Fish holds a Tier 2 Canada Research Chair in Vascular Cell and Molecular Biology. M Tymianski holds a Tier 1 Canada Research Chair in Translational Stroke Research.
Nikolaev SI, Vetiska S, Bonilla X, Boudreau E, Jauhiainen S, Rezai Jahromi B, Khyzha N, DiStefano PV, Suutarinen S, Kiehl TR, Mendes Pereira V, Herman AM, Krings T, Andrade-Barazarte H, Tung T, Valiante T, Zadeh G, Tymianski M, Rauramaa T, Ylä-Herttuala S, Wythe JD, Antonarakis SE, Frösen J, Fish JE, Radovanovic I. Somatic Activating KRAS Mutations in Arteriovenous Malformations of the Brain. N Engl J Med. 2018 Jan 3.
‘Tis the season for coughing, sneezing and runny noses. Winter is the time of year when Canadians are most susceptible to the common cold, which is caused by viruses that infect the nose and throat. Cold viruses are typically harmless and removed by the immune system within a week or two. However, in some people, they can persist and cause problematic infections in other organs.
Cold viruses, along with other several other viruses, can infect the heart causing a condition known as myocarditis. This condition is characterized by inflammation of and damage to the heart muscle, compromising its ability to pump blood. In some cases, the damage is so severe that it leads to heart failure, which occurs when the heart can no longer pump enough blood to meet the body’s needs.
Not much is known about viral myocarditis, the immune response in the heart or the mechanisms underpinning the transition from infection to heart failure. These knowledge gaps have precluded the development of specific and more effective treatments for viral myocarditis.
To address this, TGHRI Scientist Dr. Slava Epelman led a study examining dendritic cells (DCs), a type of immune cell, in the heart and their role in viral myocarditis. DCs reside in a variety of other organs, such as the lungs, liver and kidneys, where they initiate the immune response to eliminate disease-causing viruses.
Dr. Epelman and his colleagues discovered that the heart contains at least five different kinds of DCs, the two most abundant of which are referred to as CD103+ cells and CD11b+ cells. Using an experimental model of viral myocarditis, they found that both CD103+ and CD11b+ cells—like DCs in other organs—are crucial for triggering an immune response to eliminate viruses infecting the heart. The absence of these cells, especially CD103+ cells, not only suppressed the anti-virus response, but also led to significant heart damage that impaired the organ’s pumping action, an early warning sign for heart failure.
Dr. Epelman says, “Our findings suggest that CD103+ and CD11b+ DCs are required to prevent the progression of a mild infection to full blown heart failure by triggering an effective immune response to the virus.”
This work was supported by the Canadian Institutes of Health Research, the Heart and Stroke Foundation, the March of Dimes Canada, the Ted Rogers Centre for Heart Research, the Heart & Stroke/Richard Lewar Centre of Excellence in Cardiovascular Research, the Peter Munk Cardiac Centre, the National Institutes of Health and the Toronto General & Western Hospital Foundation. M Cybulsky holds a Tier 1 Canada Research Chair in Arterial Wall Biology and Atherogenesis.
Clemente-Casares X, Hosseinzadeh S, Barbu I, Dick SA, Macklin JA, Wang Y, Momen A, Kantores C, Aronoff L, Farno M, Lucas TM, Avery J, Zarrin-Khat D, Elsaesser HJ, Razani B, Lavine KJ, Husain M, Brooks DG, Robbins CS, Cybulsky M, Epelman S. A CD103(+) Conventional Dendritic Cell Surveillance System Prevents Development of Overt Heart Failure during Subclinical Viral Myocarditis. Immunity. 2017 Nov 21. doi: 10.1016/j.immuni.2017.10.011.
Following a four-month search, a UHN search committee comprising key researchers and leadership have selected Dr. Milos Popovic as the next Director of Research at the Toronto Rehabilitation Institute (TRI).
Dr. Popovic has been active in rehabilitation research and held a research appointment at TRI for over 15 years. He received an MSc and diploma in Electrical Engineering from the University of Belgrade, followed by a PhD in Mechanical Engineering from the University of Toronto. He is currently a professional engineer in Ontario, a Senior Scientist and Associate Scientific Director at TRI and a Professor at the University of Toronto.
His scientific accomplishments are outstanding. These include the development and creation of a start-up company called MyndTec, which uses neuromodulation for the restoration of voluntary upper limb function in severely disabled stroke patients. He has also developed and implemented neuroprostheses for reaching, grasping and walking and these devices played an enormous role in his exploration of neuroplasticity and neurorecovery. Recently, he successfully launched, along with Dr. Taufik Valiante, the CRANIA project, which will bring transformational new infrastructure to TRI and Krembil to support research in neuromodulation—an approach that involves changing the function of specific brain regions or nerves as part of advanced new therapies.
UHN would like to thank the outgoing Director of Research at TRI, Dr. Geoff Fernie, for his many years of service. His many accomplishments have helped to position TRI as a world-leading rehabilitation research institute—a legacy that has been recently recognized when he was named a Member of the Order of Canada.