Inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis, is increasing in Canada and world-wide. IBD is painful and debilitating. In addition to significantly impacting quality-of-life, IBD is a major economic burden on the Canadian health care system. Current IBD treatment uses anti-inflammatory drugs, which can cause harmful off-target side effects. Therefore, the holy grail is to precisely target IBD drugs to sites of inflammation to improve patient outcomes.
Our team has developed a new strategy to release drugs specifically in the lower gastrointestinal tract, which we call GlycoCage Technology. This approach combines the power of synthetic carbohydrate chemistry with the unique ability of the human gut microbiota to break-down the complex carbohydrates in dietary fiber. GlycoCaged drugs are taken orally and are protected from absorption in the stomach; they are released at the location of disease by specific enzymes made by our gut bacteria.
Previous funding enabled us to do key experiments demonstrating the effectiveness of our GlycoCage technology using a powerful corticosteroid, dexamethasone. We found that we could use lower doses of drugs and eliminate side effects through this approach. In our current project, we will investigate the benefits of GlycoCaging important drug classes that are being used to treat IBD. In the long-run, we aim to establish GlycoCage Technology as a new treatment option to improve current therapies for people with IBD.
Cancer cells develop ways of escaping and hiding from the immune system so that they are not recognized as unhealthy cells. If our immune cells could recognize the abnormal cancer cells growing in the body they would attack and kill the cancer cells. A big problem is that we don’t know enough about how different types of immune cells regulate their response to tumor cells; so we don’t how to manipulate the system to get the immune cells to engage and attack the tumor. One way that immune cells regulate their response to tumor cells is through the binding of sugars, called glycans. Glycans on immune cells and on tumor cells have been shown to be critical in the regulation of the anti-tumor immune response. Recently, we discovered unique glycan on immune cells in the breast tumor microenvironment. Patients whose tumors had high levels of this glycan on immune cells had worse survival outcomes. We think that this glycan controls the immune response and when expression levels are high, it prevents immune cell activation. To study how this glycan regulates the anti-tumor response, we propose to identify the immune cell subsets carrying this glycan and then study how this glycan effects their tumor killing functions. Our work will provide important details to help us understand how to trigger the anti-tumor immune response and may provide a new immune-checkpoint target for therapeutic development.
Chronic skin inflammation (CSI) includes two major groups of conditions: psoriasis, and atopic dermatitis (eczema) that, together, affect up to 6% of the population worldwide. Both diseases are characterized by a chronic and non-curable symptom. White blood cells in both diseases produce signalling molecules that trigger local inflammation. Using mouse models, we found that a human enzyme, neuraminidase 1 (NEU1), may play an essential role in inflammation of the skin.
In this project we will investigate the role of enzyme, NEU1, in chronic inflammatory diseases of the skin. We will investigate the mechanism of inflammation in skin diseases like psoriasis and the role of NEU1 using genetic knock-outs. Using previously developed inhibitors of NEU1, we will test if pharmacological strategies could be used as therapeutics. To learn more about the mechanism of skin inflammation in humans, we will use an in vitro model of human skin to examine the role of the NEU1 enzyme in inflammation. These studies will expand our understanding of the role of glycosylation in mechanisms relevant for in psoriasis and atopic dermatitis and could lead to new clinical strategies for these diseases.
Unlike ‘liquid’ leukemias and lymphomas, most solid tumors are extremely difficult to target immunologically with antibody-based therapeutics. In an effort to overcome this limitation, we identified a novel peptidoglycan on the surface of aggressive solid tumor cells that are present in multiple cancer types. These include breast, ovarian, bladder, colorectal and oral squamous carcinomas as well as glioblastomas. Molecularly, this peptidoglycan is found on the extracellular domain of the cell surface mucin ‘podocalyxin’. Biologically, the emergence of the podocalyxin peptidoglycan is exquisitely tumor-specific and we have demonstrated that it can be successfully targeted immunologically in pre-clinical solid tumor assays in a manner that spares normal cells and tissues. This has been achieved using an antibody drug conjugate against the podocalyxin peptidoglycan that we have developed.
In this project, we will first use genome-wide editing screens to identify regulators of the tumor-specific podocalyxin peptidoglycan using CRISPR Cas9 technology. In preliminary proof-of-principle experiments we have identified twelve potential regulators from four different functionally-clustered intracellular signaling complexes. We will next manipulate such regulators, both genetically and pharmacologically with small molecule inhibitors, to precisely tailor the immuno-oncologic targeting of aggressive podocalyxin peptidoglycan-positive solid tumors. Finally, we will take a glyco-proteomic approach to identify additional tumor-specific peptidoglycans that can also be targeted immunologically. The overarching goal of this project is to develop a pipeline of novel antibody-based immuno-therapeutics that can be used to treat multiple aggressive solid cancers with precision and minimal side effects given that they will, by design, spare normal cells and tissues.
Fungal diseases affect more than a billion people worldwide, yet the responsible pathogens receive little attention and relatively low research support to improve diagnosis and treatment. For example, no vaccines are available for fungal diseases and only a few drugs of limited effectiveness are in clinical use. One of the most important fungal diseases is cryptococcosis, a severe brain infection that occurs in people with weakened immune systems (e.g., individuals suffering from HIV/AIDS). The causative pathogenic fungus is Cryptococcus neoformans and this fungus was recently identified as a pathogen of critical health importance by the World Health Organization. This is because cryptococcosis is responsible for ~19% of all deaths in people with HIV/AIDS. The treatment of cryptococcosis challenging due to the limited number of effective antifungal drugs and emerging drug resistance. To address this challenge, a pan-Canadian leadership team (Drs. Kronstad and Penninger at UBC and Dr. Sheppard at McGill) established a collaboration to develop and apply a new class of hybrid antibodies for the treatment of cryptococcosis. This team has decades of experience in medical mycology, glycobiology, and therapeutic approaches to combat infectious and other diseases. In addition to the leadership team, the experimental team consists of three highly trained personnel at the PhD, postdoctoral fellow, and research associate levels. These scientists each bring valued expertise from microbial, immunological, and biochemical backgrounds to approach this multifaceted project. The PhD student and the postdoctoral fellow will carry out their research efforts on the UBC Vancouver campus in the Life Sciences Institute and the Michael Smith Laboratories. Initial studies have already identified and characterized a collection of hybrid antibodies that are effective at binding to cells of C. neoformans. Further characterization will evaluate the ability of the antibodies to protect against cryptococcosis.
