Vaccines can provide both short-term and long-term protection from deadly pathogens. This was demonstrated during the COVID19 pandemic, which saw the rapid production of lipid nanoparticle (LNP) mRNA vaccines. LNP-based mRNA vaccines are easy to produce in large quantities with a great degree of quality control on a relatively short time scale. These vaccines generally rely on passive uptake by antigen-presenting cells (APCs) to initiate priming of B and T cells, which are both required for a robust humoral (antibody) response. While LNP-based mRNA vaccines induce robust antibody responses, there are still questions about the durability of the immunological memory induced by these vaccines. Such a factor is a critical feature of a vaccine that keeps people protected over the course of years to decades. In contrast, many pathogens and viruses are actively taken up by glycan-binding proteins expressed on our immune cells that recognize host-derived glycans. Therefore, passive uptake of LNP-based mRNA vaccines misses out on this natural route of uptake. We hypothesize that targeting LNPs to immune cells, particularly APCs, may help improve the efficacy of vaccines. To do so, we will target sialic acid binding immunoglobulin-type lectins (Siglecs) that are carbohydrate-binding cell surface receptors found on immune cells. Siglecs are an ideal target for delivery because of their endocytic properties, their selective expression on immune cell subsets, and the availability of high affinity and selective glycan ligands for targeting. Here, we propose three aims to test this main hypothesis. In Aim 1, we will synthesize next-generation carbohydrate-based Siglec ligands for improved targeting. In Aim 2, we will formulate LNPs with ligands targeting Siglec-1, Siglec-3 (CD33), or Siglec-7/E to direct LNPs to macrophages, monocytes, and dendritic cells, respectively. Successful targeting will result in enhanced uptake of LNPs and increased expression of encapsulated mRNA in the cell type of interest. In Aim 3, we will examine the ability of Siglec-targeted LNPs to induce robust primary antibody responses directed at the spike protein of SARS-CoV-2, as well as memory responses following a boost. In summary, this project will develop Siglec-targeted LNPs to enhance immune responses as an improved vaccination approach.
Year: 2024
GlycoCaged N-heterocycles for improved treatment of inflammatory bowel diseases
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.
Modulating Immune Cell Glycosylation as a Strategy to Improve the Anti-Tumor Response
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.
Human neuraminidase enzymes as therapeutic targets in skin inflammation
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.
Regulating A Tumor-Specific Cell Surface Glycopeptide Epitope For Precision Immuno-Oncology
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.
Use of novel hybrid lectibodies to fight cryptococcosis
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.
Establishing a Patient-Centred Collaborative Research Model to Inform Research Priority Setting within Fraser Health’s Mental Health and Substance Use Services Program
The Mental Health and Substance Use (MHSU) program at Fraser Health recently formed a research unit to provide strategic oversight and direction for the conduct of research. In order to foster a collaborative model that considers the perspectives of people with lived;living experiences (PWLLEs) in the identification of MHSU’s research priorities, we aim to convene a diverse group of PWLLEs, clinicians, and researchers. We will work with BC SUPPORT Unit and a patient engagement expert to facilitate the recruitment of diverse PWLLEs. These PWLLEs will work closely with two clinicians and the Research Lead to form the priority setting group and set a research agenda for the program. The group will meet monthly for a 9-month period to discuss and prioritize research ideas and ad-hoc requests submitted to the research unit. Following the initial 9-month period, we will conduct interviews with members to evaluate the priority setting process, including potential barriers and facilitators to PWLLE engagement. The proposed activities will act as a proof-of-concept model for patient-centred research and priority setting at MHSU, with the potential for continued, long-term adoption by the MHSU leadership team if found to be successful.
Planning for Implementing a 2SLGBTQIA+ Liaison Nurse Role in the BC Health System: Promoting Equity in Our Communities
It is well-established that Two-Spirit, lesbian, gay, bisexual, trans, queer, intersex, and asexual (2SLGBTQIA+) people are subject to discrimination within healthcare settings, leading to poor health outcomes. In fact, these instances of discrimination are growing in context of rising hate toward the 2SLGBTQIA+ community. In response, the Island Health Authority has recently launched a revolutionary role: the 2SLGBTQIA+ Liaison Nurse. This Liaison Nurse works directly with 2SLGBTQIA+ patients in the healthcare system to support: navigating the system, advocating for services, ensuring a safe and respectful healthcare encounter, and accessing gender-affirming care. Our larger project will involve scaling up and implementing this role across additional healthcare sites in BC, and evaluating the role to ensure safe, quality, and equitable care for 2SLGBTQIA+ people across the province. Funding through a C2 grant will support bringing together health authority, community, and researcher representatives to develop a comprehensive research plan for implementing and evaluating this role. In particular, funds will support a 2-Day Intensive in Vancouver to support necessary conversations in support of the project’s next steps.
Co-creating a research roadmap for an innovative virtual health delivery model to recruit and retain health workforce in rural, remote, and Indigenous communities.
People living in rural, remote, and Indigenous (RRI) communities face a disproportionate burden of chronic diseases yet have limited access to healthcare services. Often, this is due to shortages of healthcare workers in such areas. A rapid shift towards virtual care is markedly influencing how people access healthcare. However, adoption of digital technologies without consideration for health equity risks creating further disparities in health outcomes. Two novel virtual health programs have deployed ‘hybrid’ approaches to health service delivery by blending in-person and team-based virtual care. These services honour relational virtual support built on collaboration, empathy, and cultural safety. A group of researchers, and research-users have formed the Hybrid Care Research Collaborative with the goal of integrating research within ‘hybrid care’ programs to understand the needs of healthcare providers and community members in RRI areas. This data-driven approach will enable the development of interventions and policies incorporating local knowledge and cultural perspectives. Our proposed planning activities will advance interprofessional rural health research and inform a long-term research agenda with community partners.
Seizing the Window of Opportunity: Co-creating an Enhanced Prenatal Care Program to Build Resilience among Socially Vulnerable Populations
Being pregnant can bring extra challenges, especially for people who are struggling financially and socially. It can make them feel stressed and less able to respond to catastrophic events such as pandemics, family illness and climate change.
Caring for this population is especially challenging now with fewer maternity providers in the province. There is currently no specifically designed program for socially vulnerable pregnant people. Around the world, programs supported by Community Health Workers (CHWs) have made it easier for people to get healthcare, help them stay healthy, and improve their social situations, but less is known about how they could be used in BC.
This project unites researchers, providers, CHWs and pregnant individuals with diverse identities, especially multiethnic and low-income, including new immigrants and refugees in Vancouver.
Together, we will explore:
What are the most important areas to include in a CHW-supported prenatal and postnatal program?
What could improve the delivery and satisfaction of the program?
How could success be measured?
We wish to hear what is important to people to create programs that can elevate the experience of pregnancy for those facing challenging social situations.