Award Partner: Genome BC

Platform for Regulatory Science, Innovation, and Equitable Health Systems (PRISm)

Canada’s life sciences sector is poised to turn research into health solutions for addressing health threats. There is a central challenge: existing practices, policies, and processes slow patient access to new technologies.

 

With support from Genome BC’s Immunoengineering Strategic Initiatives (GISI) and Health Research BC, a new initiative aims to change that.

 

The Platform for Regulatory Science, Innovation, and Equitable Health Systems (PRISm) will position British Columbia—and Canada—as a global leader in regulatory science. By engaging communities and tapping into BC’s robust data ecosystem, PRISm will make sure that new health discoveries reach patients sooner.

 

Led by Dr. Dean Regier, Director, Academy of Translational Medicine, University of British Columbia and Senior Scientist at BC Cancer, PRISm brings together scientists from different fields to collaborate in an innovative way, driving systems change. This research will:

1. Simplify data capture and access, finding new ways to share crucial information across health systems.

2. Fast track product development, producing clinical, economic, and equity evidence that makes downstream healthcare decisions easier.

3. Quickly transition innovations to the market and to health systems, focusing on equity, safety, value, and sustainability.

4. Mentor students and new researchers, building the next generation of experts.

 

Community engagement is central to PRISm. Together, we will ensure that the evidence we produce responds to the needs of diverse populations. Collaborations with governments and industry will make our research findings policy-relevant and immediately actionable.

 

Through inclusive research, training, and decision-making, PRISm will help build a learning health system for Canada—one that is equitable, evidence-driven, and resilient in the face of health threats.

“DeCIDE” – short for “Designer Cellular Immuno-Engineering for Infectious Disease Elimination”

The Zandstra and Levings research groups are excited to receive matching funds from Health Research BC to support our Immunoengineering Strategic Initiative from Genome BC. This funding will support our vision to incorporate cell-based immunotherapies into British Columbia’s pandemic response preparedness.

 

This project is led by Dr. Peter Zandstra, director of the School of Biomedical Engineering at UBC, and Dr. Megan Levings, Investigator and Lead, Childhood Diseases Theme, BC Children’s Hospital. We are pleased to collaborate with Amgen, BioCanRx, Breakthrough T1D, CCRM, and CIHR on this exciting study.

 

The COVID-19 pandemic highlights the need to complement vaccine development with cell therapies. For the clinically extremely vulnerable (~200,000 people in BC), the risk of viral infection is a daily reality. Among people living with a transplant, mortality approached 20% early in the pandemic, and many (>50%) are unable to mount good antibody responses even after receiving two-dose vaccination. Other immune suppressed individuals and older adults also have poor vaccine responses. Poor viral control can also trigger new diseases, such as long COVID, multiple sclerosis, and Lupus, all characterized by inflammation and tissue damage.

 

Our vision is to harness advances in stem cell biology, genome engineering, and biomanufacturing to produce modular immune cell therapies that can be delivered quickly anywhere in Canada. Such “off-the-shelf” cell therapies will: 1) have immediate applications for immune-compromised people and those at-risk of, or experiencing, severe infection-related complications; and 2) be poised to be rapidly pivoted to pandemic response.

Microbiota for Pandemic Interventions and Exploration (MiPEx)

This project is supported by the Genome BC Immunoengineering Strategic Initiative (GISI), with funding from Genome Canada and matching funds through Health Research BC. It is a BC-based initiative with national and international collaborations. 

 

Dr. Carolina Tropini, the BC Principal Investigator from the University of British Columbia, leads a multidisciplinary team alongside co-leaders Dr. Bruce Vallance and Dr. Lisa Osborne. Together, they are tackling a serious health threat: antimicrobial resistance (AMR). AMR makes infections harder to treat and is expected to cause 10 million deaths per year globally by 2050. Many of these infections begin in the gut, where harmful bacteria can thrive when the body’s natural defences are weak. 

 

The MiPEx project focuses on strengthening those defences by harnessing the human gut microbiota—the collection of helpful microbes that live in our digestive system. Some people naturally carry beneficial microbes that help fight off harmful bacteria. This research aims to identify and develop those helpful microbes into “live biotherapeutics,” a new kind of treatment that uses good bacteria to block infections. 

 

The team will use advanced lab techniques and models that mimic the human gut, including gut-on-a-chip technology and germ-free mice, to test how well these microbes work. In the future, this approach could help protect vulnerable individuals, reduce the need for antibiotics, and strengthen Canada’s preparedness for future pandemics. 

 

By developing innovative, sustainable treatments, MiPEx contributes to BC’s health care and biotechnology sectors and supports healthier outcomes for all Canadians. 

 

A Pathogen-ready Arsenal of Next-generation lipid nanoparticle (LNP) messenger RNA (mRNA) therapeutics

RNA-based genetic medicines have enormous potential to transform disease prevention and treatment. However, RNA molecules are very unstable, and the analytical methods available to assess them can’t accurately predict how effective a new genetic medicine will be. A lot of time and money is therefore spent on testing each RNA in labour-intensive functional experiments, slowing drug optimization efforts. 

 

This project titled A Pathogen-ready Arsenal of Next-generation lipid nanoparticle (LNP) messenger RNA (mRNA) therapeutics (PAN-RNA) funded by Genome BC Immunoengineering Strategic Initiative aims to develop two new genetic medicines (for autoimmune disorders and cystic fibrosis), and a comprehensive analytical platform designed to accelerate their development and optimization. We will screen viral genomes to identify sequences that increase RNA stability and expression in specific target cell types, such as lung cells for the cystic fibrosis drug. We will then experimentally assess the functional performance of therapeutic RNAs that incorporate these viral elements. In parallel, we will use advanced imaging-based measurement techniques to comprehensively characterize genetic medicines containing different RNAs. Correlating the resulting data with our functional data on the same RNAs will allow us to develop sophisticated mathematical models that can predict the effectiveness of RNAs using our analytics methods alone, vastly reducing the amount of time and money spent on functional testing. 

 

The immediate outcomes of the project will be two new candidate genetic medicines for further development, a validated analytics platform, and mathematical models to predict genetic medicine performance. However, our work will also serve as proof-of-concept that can be rapidly applied to the development of numerous other genetic medicines. These outcomes will help the biotechnology and pharmaceutical sectors accelerate their genetic medicine development pipelines, ultimately creating new medicines to fight pandemics and help Canadians living with autoimmune disorders, cystic fibrosis, cancer, and other diseases. Our work will also help create new Canadian biotechnology and pharmaceutical industry jobs, companies, and revenue streams, providing additional economic benefits. 

 

The BC-based PAN-RNA project is led by UBC co-directors Eric Jan (Life Sciences Institute, Department of Biochemistry and Molecular Biology) and Sabrina Leslie (Michael Smith Laboratories, Department of Physics). PAN-RNA has assembled a team of expert leaders including Pieter Cullis, a world leader in LNP delivery technology and Laura Evgin, an ECR-expert in CAR-T therapies, Leonard Foster, a proteomics/mass spectrometry expert with extensive experience running a core platform, and collaborators Selena Sagan (molecular virologist), Sarah Hedtrich (lung epithelial gene therapy), Marco Marra (world leader in genomics), and Robin Coope (high-throughput instrumentation). The PAN-RNA project is co-funded by CIHR and NSERC. 

Developing Educational Tools for Neonatal Intensive Care Staff Regarding Rapid Genome-wide Sequencing

The Neonatal Intensive Care Units (NICUs) at BC Women’s Hospital and Victoria General Hospital care for >2000 critically ill babies each year. Many of these babies are sick because they have genetic conditions which can be very difficult to diagnose (the disorders are rare and many of these babies are premature). There is a new test called genomic sequencing (GS) that looks at a baby’s entire genetic code and can detect a change that may be responsible for the baby’s medical problems. This test has revolutionized the ability to diagnose babies with genetic disorders and is ordered for many babies in the NICU. The results can be difficult to interpret for the doctors who order the test (often it is not clearcut as to whether the change is causing the disorder and sometimes medical problems can be discovered that are not part of the baby’s condition (e.g., risk for cancer). The NICU team is composed of doctors, nurses and other healthcare workers (but not genetic counsellors). We conducted a study of the NICU staff that showed they are not comfortable ordering GS, interpreting the results and want more education about GS. In this project, we will develop educational tools to help the NICU staff look after babies who have had GS.

Genetic Lipid Disorders and Premature Atherosclerotic Cardiovascular Disease: Raising Awareness to Save Lives

Familial Hypercholesterolemia (FH) and elevated lipoprotein(a) [Lp(a)] are two of the most common genetic lipid disorders: 1 in 311 Canadians have FH and 1 in 5 have high Lp(a). Affected individuals have a higher risk for heart disease and stroke, but both diseases remain underdiagnosed and undertreated. To improve care, increased awareness through education, engagement and dissemination of research findings is vital. The goal of this event is to organize an Educational Patient Engagement Forum focusing on recent developments in the screening, diagnosis and treatment of FH and high Lp(a), and management in specific populations (Indigenous communities and children). The forum will include lectures by those with lived experiences, clinician-scientists, Indigenous researchers, allied health providers, and an interactive session with patients’ testimonials. FH and Lp(a) Canada Registry members will also discuss identification of individuals with inherited lipid disorders, initiatives and resources for patients and health care professionals. The forum will empower patients to become advocates, increase awareness of these diseases, and recognize the importance of screening for early identification, treatment and heart disease reduction.

Targeting amyloid propagation in Alzheimer disease: Structures, immunology and extracellular vesicle topology

Dr. Neil Cashman is one of five BC researchers supported through the British Columbia Alzheimer’s Research Award. Established in 2013 by the Michael Smith Foundation for Health Research (MSFHR), Genome British Columbia (Genome BC), The Pacific Alzheimer Research Foundation (PARF) and Brain Canada, the goal of the $7.5 million fund is to discover the causes of and seek innovative treatments for Alzheimer’s disease and related dementias.

 

As the incidence of Alzheimer’s disease (AD) continues to increase worldwide, a treatment or prevention for AD is a top priority for medical science. One of the main hallmarks of the disease are protein plaques that form inside the brain, and are believed to be the primary cause of brain cell (neuron) death. Research has shown that the protein, amyloid-β (A-beta) is the main component of these plaques.

 

While there are many forms of A-beta produced by brain cells, the specific one that causes AD is hotly debated by scientists. Dr. Neil Cashman, a neuroscientist and neurologist at the University of British Columbia (UBC) has discovered a novel way of identifying a unique form of A-beta that can become toxic and inflict the damage associated with AD.

 

Cashman, who holds the UBC Canada Research Chair in Neurodegeneration and Protein Misfolding, and his team have discovered immunological compounds that specifically recognize the potentially toxic form of the A-beta protein, and can exclusively detect this form in the brains and spinal fluids of AD patients. Furthermore, Cashman found that normal, healthy control patients did not have this dangerous form of A-beta. It was also found that some healthy people naturally develop immune responses against their A-beta oligomer-specific target.

 

Cashman’s team will exploit this knowledge and their unique tools to learn how toxic A-beta proteins can spread from cell-to-cell and region-to-region in the brain causing AD. The discoveries by Cashman’s lab may provide an effective early diagnostic tool for the disease, and ultimately could lead to the development of a preventative vaccine to neutralize the toxicity of abnormal A-beta, potentially slowing or stopping the spread of neurodegeneration in the brain.

 

End of Award Update

Source: CLEAR Foundation

 

What did we learn?

We know that Abeta oligomers, a “seeding species” in Alzheimer’s disease, are predominantly spread in the brain via naked protein aggregates, and not through extracellular vesicles.

 

Why is this knowledge important?

The development of oligomer-specific antibodies (Acumen, ProMIS Neurosciences) has enabled selective immunotherapies for Alzheimer’s disease that target the toxic molecular species of AD, while sparing precursor protein (APP), Abeta monomers, and Abeta fibrils in the form of plaques. Binding to any of these non-oligomer molelcular species of Abeta lead to adverse effects, most prominently plaque-disruption linked ARIA – a form of neurovascular brain edema.

 

What are the next steps?

Dr. Cashman is now the full-time Chief Scientific Officer of ProMIS Neurosciences, which is conducting IND-enabling studies of the oligomer-specfic antibody PMN310. Human phase 1 trials are set for late 2022 or Q1 2023.

 

Publications

Preclinical development of a disease modifying small molecule therapy for Alzheimer disease

Dr. David Vocadlo is leading one of five BC researchers leading teams supported through the British Columbia Alzheimer’s Research Award. Established in 2013 by the Michael Smith Foundation for Health Research (MSFHR), Genome British Columbia (Genome BC), The Pacific Alzheimer Research Foundation (PARF) and Brain Canada, the goal of the $7.5 million fund is to discover the causes of and seek innovative treatments for Alzheimer’s disease and related dementias.

 

Alzheimer’s disease (AD) is a debilitating and progressive neurodegenerative disease, accounting for almost two-thirds of all dementias in Canada, and in BC affects up to 70,000 people. Symptoms include memory loss, behaviour and personality changes, and a decline in cognitive abilities.

 

Current AD medications treat symptoms of the disease, but none exist that can stop or even slow the progression of AD which starts in the brain many years before it manifests. The need for AD therapies that treat underlying progression of the disease is paramount for the aging population, in particular because of the projected increase in the number of AD patients.

 

Dr. David Vocadlo, a professor in Chemistry and Molecular Biology & Biochemistry and Canada Research Chair in Chemical Biology at Simon Fraser University (SFU), aims to address several key challenges that would clear the way for a promising new AD therapeutic target.

 

The two biological hallmarks of Alzheimer’s disease in the brain, neurofibrillary tangles and amyloid plaques, are caused by the dysfunction and abnormal accumulation of specific proteins that can kill brain cells over time, progressively impairing brain function.

 

Vocadlo and a multidisciplinary group of research teams from SFU, the University of British Columbia (UBC) and the University of York in the UK, are pioneering their new approach that has been shown to block disease progression in animal models of AD by blocking the toxicity of the brain proteins that form the tangles within brains. Their approach centres on a specialized sugar unit called O-GlcNAc. Clumps of protein from AD brains have almost none of this sugar attached to them because the O-GlcNAcase enzyme continues to remove this sugar modification.

 

Vocadlo’s therapeutic goal is to use small molecules to block the activity of the O-GlcNAcase enzyme, and in this way increase the levels of O-GlcNAc in the brain to prevent this protein from clumping together and becoming toxic. Vocadlo’s team is currently advancing this therapeutic target in order to advance it into the clinic.

Locally produced brain insulin in memory and Alzheimer’s disease: A multi-disciplinary approach to a key question

Dr. James Johnson is one of five BC researchers leading teams supported through the British Columbia Alzheimer’s Research Award. Established in 2013 by the Michael Smith Foundation for Health Research (MSFHR), Genome British Columbia (Genome BC), The Pacific Alzheimer Research Foundation (PARF) and Brain Canada, the goal of the $7.5 million fund is to discover the causes of and seek innovative treatments for Alzheimer’s disease and related dementias.

 

Alzheimer’s disease (AD) – the most common form of dementia – is a fatal, progressive and degenerative disease that destroys brain cells, causing thinking ability and memory to deteriorate.

 

One percent of AD is the early-onset type that runs in families. While extensive studies of these forms of the disease have revealed the genes that cause them, the most common, late-onset forms of AD are understudied and poorly understood at the level required for therapeutic intervention.

 

Studies have shown links between Alzheimer’s disease and obesity, altered fat metabolism, insulin and diabetes, with diabetes increasing the risk of suffering from AD by 30-65 percent. Scientists have also found the brain produces a small amount of insulin with reduced levels in the brains of AD sufferers. While the function of brain insulin is a mystery, evidence suggests reduced brain insulin could play a role in Alzheimer’s disease.

 

Dr. James Johnson, a professor in the Departments of Cellular and Physiological Sciences and Surgery at the University of British Columbia (UBC), further found in preliminary studies that high-fat diets reduced brain insulin production. The goal of Johnson’s continuing research is to answer the key question: is the loss of brain insulin alone enough to cause cognitive impairment? Johnson will test the hypothesis that brain-produced insulin is a critical factor for the survival and function of brain cells in the context of both a genetic change that increases Alzheimer’s risk and a diet that increases Alzheimer’s risk. Using mice models lacking brain insulin, Johnson’s team will assess their ability to learn and study how their brains are reprogrammed. Insulin will be correlated with Alzheimer’s-like changes in human brains.

 

Information on the role and mechanisms of brain insulin through Johnson’s pioneering research has the potential to advance understanding of AD and contribute to an eventual cure. Identifying the link between diet, insulin and Alzheimer’s disease could also enable earlier diagnosis and inform strategies for Alzheimer’s prevention. Furthermore, the findings may shed light on much-needed new drug targets for Alzheimer’s disease or possibly re-purposing existing diabetes drugs.

Novel retinal biomarkers for Alzheimer’s disease

Dr. Faisal Beg is one of five BC researchers supported through the British Columbia Alzheimer’s Research Award. Established in 2013 by the Michael Smith Foundation for Health Research (MSFHR), Genome British Columbia (Genome BC), The Pacific Alzheimer Research Foundation (PARF) and Brain Canada, the goal of the $7.5 million fund is to discover the causes of and seek innovative treatments for Alzheimer’s disease and related dementias.

 

Millions of people worldwide are afflicted with Alzheimer’s disease (AD). In the absence of a complete understanding of the disease, therapeutic trials have been unsuccessful and there remains no cure. Detecting the onset of AD is difficult as the changes in behavior are subtle and hidden. Biomarkers that can reliably detect AD at the earliest possible stage are essential for disease monitoring and treatment to improve the quality of life for patients.

 

Imaging shows that the brain has a protein called amyloid, which accumulates beyond normal amounts in AD. However, brain imaging exams for amyloid are expensive, can be invasive, and not easily available, and as a result, cannot be used for general screening. Studies suggest that amyloid also accumulates in the retina of individuals with AD, but this has not been proven.

 

Dr. Faisal Beg, a biomedical engineer and professor in the School of Engineering Science at Simon Fraser University (SFU), is leading a multi-disciplinary team of researchers from SFU, the University of British Columbia (UBC) and McGill University to find the connection between the eye and AD by investigating it as a potential source for the earliest biomarkers for the disease.

 

The team is developing computational tools and image processing technologies to examine chemical biomarkers, structural degradation, and functional loss in the eye that may be associated with AD. This work could be the basis for a new retina imaging device using laser light that can show the presence of amyloid in the retina. The technology would improve understanding of the disease mechanisms underlying the accumulation and serve as an early indication that the protein is also accumulating in the brain.

 

Beg’s research could lead to an inexpensive, non-invasive retina exam for use in clinics to screen everyone on a regular basis for the earliest signs of amyloid. Besides having the potential to aid in the early diagnosis of the disease, the imaging techniques may also be able to track the progression of AD and assess the efficacy of treatments under development.