New enzymes and processes for the removal of cell surface antigens from red blood cells to generate ‘universal donor’ O type blood for transfusion

Human blood comes in four major "types" — A, B, AB and O — which differ in the sugars on their red blood cells (RBCs). Correctly matching blood types before transfusions is essential to avoid immune responses that can be fatal. O type blood is known as a universal donor since RBCs from an O type person can be transfused into A, B, AB or O type individuals without harm. It is used in emergencies when there is no time to type the patient or the correct type is unavailable. Type O blood is often in short supply.
A and B type blood can be converted to universal O type blood by using specific enzymes to clip off the extra sugars: once clipped the original sugars are not reformed since mature RBCs have lost that ability. However the enzymes available have not been efficient enough. The Withers lab recently discovered efficient enzymes for this within the human gut microbiome. In conjunction with the Centre for Blood Research, they have proven their efficiency and converted whole units of blood. This proposal is primarily to carry out the pre-clinical evaluations needed, and in conjunction with Canadian Blood Services, move this technology forward. This will open up access to universal donor blood, thereby helping alleviate shortages.

3D printing of hydrogel tubing via reactive hydrodynamic focusing to replace single-use plastic medical tubing

Single-use plastic medical tubing is widely used in hospitals. Although practical, plastic tubing has a potentially life-threatening problem in that blood cells and proteins can deposit on the tubing to form clots. There are also problems with being unable to dispose of the plastic tubing in an environmentally-friendly manner. Commercially available plastic tubing has seen little change over the last 30 years.

We propose replacing plastic tubing with a 3D printed tube made from compostable materials. Our tubes are based on a substance called a hydrogel, have excellent mechanical and fluid movement properties, and are bio-compatible (do not cause reactions in people). Our approach is technically and economically feasible for scale-up. We target MSFHR health priority #3. We will provide on-demand printing of hydrogel tubing, replacing existing plastic tubing used, e.g. dialysis, to allow clinicians to rapidly customize tubing shape, size, and composition to adapt specific treatment needs. At the end of its life-cycle, our tubing is compostable, which will reduce single-use plastic and open up new pathways for environmentally-friendly disposal.

Novel carbon fibre breast positioning device (CARA) for reducing toxicity in breast radiotherapy

Radiation therapy is used to reduce the chance of breast cancer recurrence after surgical removal of the primary cancer in approximately 2,000 British Columbian patients and approximately 2 million women around the world annually.  Because the breast is a mobile organ sitting over the lungs and heart, these organs and other normal tissues may receive unwanted radiotherapy dose leading to serious side effects. Our group has designed a carbon-fibre device suitable for breast positioning in radiotherapy to optimize the position of the breast during treatment to reduce these side effects. Initial tests in our clinic are very promising. To bring this device into widespread use for patients, further work is required to improve the quality of the device to meet the highest standards for patient care and those set by Health Canada. Carbon fibre devices are very challenging to make when complex shapes are required, as is the case for this breast support. We will work with a research group specializing in carbon fibre to find the best materials and manufacturing process for the device, and then get  the improved device into the hands of leading experts in breast cancer treatment for further evaluation in the clinic.

Cytology-based DNA measurement for oral cancer screening

Oral cancer (OC) presents a global burden on society and the healthcare system with remarkably high incidence rates and poor prognosis. Despite the oral cavity being easily accessible for visual assessment and diagnostic procedures, it remains to be detected at an advanced stage when the prognosis is poor and radical interventions are necessary. An invasive biopsy of a clinically suspicious lesion is the current standard of care for OC diagnosis and lesion monitoring; however, repeated biopsies may not be feasible.

This study aims to provide a non-invasive, objective, and accurate OC diagnostic test using high throughput DNA-based cytometry. This test incorporates the OralGetafics platform, which combines artificial intelligence software with a commercially available and affordable scanner, which has been widely used in China and India for OC screening. We recently showed that the system could detect cancer or normal cells with sensitivity of 100 percent and specificity of 86.7 percent with minimal input from the cytotechnician. Potentially, this new technique can be used in remote communities with limited access to care and provides a significant benefit in early detection of at-risk oral lesions and reduction in OC burdens.

Automated body composition analysis for precision medicine applications

There is growing evidence showing that the amount of muscle and fat one has in the body influences various aspects of cancer such as carcinogenesis (formation of cancer), response to chemotherapy drugs (to decide on the optimal dosage to the patient to destroy cancer cells while avoiding damage in other organs), death resulting from complications due to surgery, and overall survival outcomes. Conversely, cancer also causes loss of muscle mass. Accurate and easily available tools are thus needed to measure muscle and fat in an individual in the context of cancer treatment decisions. CT images are almost universally acquired in cancer diagnosis and treatment planning, and these directly show muscle and fat in the body. But in order to extract measurements, manual intervention (which is tedious) or automated tools are needed. We are developing a fully automated 3D method to measure the amount of muscle and fat from 3D CT images available in the cancer clinic. The availability of these measurements will enable correct chemotherapy treatment dosage to be determined for each individual based precisely on their body composition, resulting in better health outcomes.

Multispectral RNA Mango: Synthesis of new multicolour fluorogens for incorporation into pathogen detection and identification kits

With the increasing prevalence of viral pathogens as exemplified by COVID-19, reliable and inexpensive detection is of increasing importance. Rapid testing allows appropriate and immediate treatment, which can have a profound effect on the treatment outcome. Early on-site detection is also greatly beneficial for hospitals and clinics since it would allow patients to be rapidly screened before entering the system.

Viruses and bacteria contain unique RNA fingerprints that can be used to identify their exact species. Recently, we have developed RNA Mango technology that can specifically and rapidly detect extremely low levels of RNA and that outcompetes the previous standard for RNA-based pathogen detection (RT-PCR) in terms of speed, while maintaining sensitivity. A limitation of our current technology is that it is not yet as reliable as it needs to be, since it is lacking controls for reaction failure — an important aspect for pathogenic detection and identification. In this application, we will further develop our RNA-detection technology into a rapid, multichannel, colour-based test that will allow us to quickly and reliably detect and identify multiple pathogens and expand its commercial in vivo applications.

eSense: an online psychological intervention for women’s health

Sexual dysfunction affects up to 1/3 of women across ages, cultures, and social conditions. The World Health Organization recognizes sexual health as a fundamental part of general health and quality of life. Our research shows that face-to-face cognitive behavioural therapy (CBT) and mindfulness (MBT) are effective for treating women’s sexual concerns. Yet these treatments reach only a small segment of women, and are accessible primarily to women who have the means to commute to large centres. Access barriers disproportionately affect women of colour, women of Indigenous communities, and women living in rural and remote regions.

We propose that online treatment programs are an effective strategy to solve this problem. In this project, we will evaluate our online program for women’s sexual dysfunction, named eSense, which contains separate modules of CBT and MBT therapy skills. We will then make eSense available to patients seeking healthcare in two Vancouver sexual health clinics and collect user feedback to further improve the program. The longer term goal is to commercialize eSense as a tool to deliver evidence-based skills for improving sexual health in women and improve their quality of life.

Development and application of comprehensive T-cell receptor reactivity profiling technologies to aid in the discovery of novel immune cell therapies

The success of chimeric antigen receptor (CAR)-T cell therapy in the treatment of leukemia has spurred significant effort into developing similar "living medicines" for other cancer types. A large component of this effort is to discover new immune cell receptors that can be engineered into T cells, a specialized subset of immune cells, to function as the guidance system needed to attack and kill specific tumors. However, the difficulty associated with this lies in finding immune receptors that effectively target cancer cells but do not damage healthy tissues. Indeed, multiple clinical trials to-date have resulted in patient deaths due to catastrophic and unanticipated autoimmune reactions. We have developed an innovative laboratory screening method that profiles the reactivity, up front, of candidate T cell therapies against very large sets of possible targets. With this capability, our technology can comprehensively screen candidate cell therapies and predict which ones represent an unacceptable safety risk early in the discovery phase of development. As a result, our platform will increase the likelihood of T cell-based therapies achieving success in clinical trials and becoming approved treatments.

Fucosylation inhibitors for convenient production of fucose-deficient antibodies

Therapeutic antibodies have revolutionized the treatment of cancers. The efficacy of many of these antibodies depends on their ability to recognize and bind to cancer cells. These antibodies then recruit immune cells to kill the cancer cells. Recent interest has focused on the different sugar molecules attached to the antibody and their role in helping or hindering the recruitment of immune cells. Specifically, eliminating one specialized sugar known as fucose from antibodies dramatically improves their ability to recruit immune cells and kill cancers. Industry is therefore interested in ways to prevent this sugar modification and to thereby produce improved anti-cancer antibodies.

We have developed a new family of chemical compounds that block the addition of fucose onto antibodies as they are being produced. We now aim to translate this work to drive the generation of improved therapeutic antibodies. Because the fucose-deficient antibodies are much more potent, it is expected that lower doses of these antibodies can be used leading to a lowered risk of side effects. Additionally, the increased potency should lead to improved efficacy of therapeutic antibodies and outcomes for cancer patients in British Columbia and elsewhere.

3D bioprinting personalized neural tissues for drug screening

Bioprinting can produce living human tissues on demand, opening up huge possibilities for medical breakthroughs in both drug screening and developing replacement tissues. The Willerth lab was the first group in the world to use the cutting edge RX1 bioprinter from Aspect Biosystems to bioprint neural tissues similar to those found in the brain using stem cells derived from healthy patients. Similar tissues can be printed using stem cells derived from patients suffering from Parkinson's disease, recapitulating the disease phenotype in a dish. These highly customized, physiologically-relevant 3D human tissue models can screen potential drug candidates as an alternative to expensive pre-clinical animal models.

This project will bioprint both healthy and diseased neural tissues using our novel bioink in combination with Aspect Biosystems' novel trademarked Lab-on-a-Printer system and evaluate their function. We will then validate these tissue models as tools for drug screening by exposing them to compounds with known toxicity to brain tissues.

Dr. Willerth has over 16 years of experience in the area of biomaterials and tissue engineering, making her the ideal choice to lead this project. This project will lead to better health outcomes for patients suffering from neurological diseases and disorders, which account for 6.7% of the healthcare burden in Canada and improve the quality of life for B.C. residents suffering from such diseases.