2018 – Page 9 – Health Research BC

Re-establishing cognitive function in models of mental illness by boosting neural activity in the prefrontal cortex

The frontal cortex (FC) of the brain plays a critical role in higher cognitive functions including attention, working memory, and planning future goal-directed actions. Cognitive deficits arising from deceased neural activity within the FC (hypofrontality) are features of many forms of mental illness, including schizophrenia, attention-deficit hyperactivity disorder, dementia and addiction. Neurochemical, physiological and pharmacological research implicates reductions in the function of key neurotransmitter systems: catecholamines, glutamate and GABA.

Dr. Axierio-Cilies and team have developed a novel compound that alters key subtypes of glutamate receptors. Using optogenetic (light) stimulation of dopaminergic and glutamatergic pathways, this research will assess the usefulness of this novel compound for the treatment of clinical conditions that are attributed to a reduction of neurotransmitter function within the FC as part of a multifaceted drug development program.

JAK-STAT pathway mutations in B-cell lymphomas: Implications for the tumour microenvironment and treatment failure

Lymphoma is a cancer of the lymphatic system where tumours develop from abnormal growths of white blood cells. Non-Hodgkin Lymphomas (NHL) are the fifth most common cancers diagnosed in Canada. Of those, diffuse large B-cell lymphoma (DLBCL) is the most common.

Numerous studies have furthered understanding of the internal chemical mechanisms of communication (signaling pathway) altered in malignant cells. However, the tumour is not only composed of cancer cells; the cancer cells are surrounded by a multitude of other cells and molecules (also known as the tumour microenvironment) that contribute to the development of the tumour. Although some improvement has been made in the treatment of lymphoma, current standard therapies still fail to cure a significant proportion of patients for which novel therapeutic agents have to be developed. More investigations are needed to discover new therapeutic targets that will lead to the development of more effective drugs to improve patient outcomes.

Dr. Viganò aims to fill these knowledge gaps in DLBCL development and treatment. In particular, her research will explore the influence of mutations in the Janus kinase-signal transducer and activation of transcription (JAK-STAT) signaling pathway on the tumour microenvironment. She will also investigate new biological targets to inform the development of novel therapies.

Overcoming antibiotic resistance with anti-biofilm peptides

Antibiotics are arguably the most important and successful medicines. However, the frequent growth of bacteria as biofilms, bacterial communities that grow on surfaces in a protective matrix, is of great concern. Biofilms account for two thirds of all clinical infections and are especially difficult to treat with conventional antibiotics. They are a serious problem in trauma patients with major injuries, as well as individuals with implanted medical devices.

The Hancock lab has developed novel synthetic peptides that have demonstrated a superior ability to combat bacterial biofilms. These agents work against pre-formed biofilms, show synergy with antibiotics, neutralize the universal stress response in bacteria, and work against high-density bacterial abscesses in animal models. These small peptides are promising biofilm-specific agents.

Dr. Pletzer’s research will study the mechanisms of these peptides and how they interact with and aid antibiotics as this novel treatment moves towards clinical development.

Defining the dynamics behind ryanodine receptor function using malignant hyperthermia mutant channel

In order for skeletal muscle to contract, signals alert the muscle cells to release calcium from their internal stores. The skeletal muscle ryanodine receptor (RyR1) acts as the essential gatekeeper for these calcium pools. A single mutation within a person’s RyR1 can result in an unpredictable and life-threatening complication called malignant hyperthermia (MH).

MH is a disease that causes uncontrolled muscle contraction and an extreme increase in body temperature when exposed to general anesthetics. While our understanding of RyR1 is improving, there is still much to learn about the relationship between the protein’s structure and how small molecules like anesthetics alter the channel’s activity.

Dr. Woll’s research will look to identify the binding sites for anesthetics within normal and MH mutant RyR1 in order to determine and compare the interactions and their consequences. To accomplish this, she will employ photoactive analogs of the anesthetics to identify binding sites within both RyR1s and determine the impact of binding on the ion channel’s conformation using cryo-electron microscopy.

Ultimately, this research will provide a strategy for the advancement of scientific methods, further define the transitions that occur within RyR1, and determine how anesthetics impact the channel’s function.

Silent genomes: Reducing health care disparities and improving diagnostic success for children with genetic diseases from Indigenous populations

Health Research BC is providing match funds for this research project, which is funded by the Genome Canada/CIHR Large-Scale Applied Research Project (LSARP): Genomics and Precision Health funding opportunity. Additional support is provided by Genome BC, the BC Children’s Hospital Foundation, BC Provincial Services Health Authority and the University of British Columbia (UBC).

Indigenous populations in Canada and around the world face unique health challenges, inequities, and barriers to healthcare. As a result, they typically have poorer health outcomes than non-Indigenous groups.

The health disparity gap widens when it comes to Indigenous populations’ access to the technology and research involved in genomics – the study of the complete set of human genes – which have advanced health care by allowing medical treatments to be tailored to the specific needs of individual patients through precision medicine, routinely available to other Canadians.

Dr. Laura Arbour, a clinical geneticist at BC Children’s Hospital and Island Health, and a professor in UBC’s Department of Medical Genetics, is working to address the growing genomic divide – particularly the lack of background genetic variation data for Indigenous populations – through the Silent Genomes project. The four-year project aims to improve health outcomes by reducing health disparities, enhancing equitable access to diagnosis, treatment, and care for Indigenous children with genetic diseases. Arbour is joined on the project by the University of Northern British Columbia’s Dr. Nadine Caron, and Dr. Wyeth Wasserman from UBC and the BC Children’s Hospital Research Institute, where the research will be conducted, along with BC Women’s Hospital + Health Centre.

The Silent Genomes research team will work with First Nations, Inuit and Métis partners across Canada to establish processes for Indigenous-led governance of biological samples and genome data, leading to policy guidelines and best practice models for genomic research and clinical care.

The project will also create an Indigenous Background Variant Library (IBVL) of genetic variation from a pool of 1,500 First Nations Canadians that will improve the accuracy of genomic diagnosis by providing necessary reference data for Indigenous populations living in Canada and globally. Researchers will also assess the effectiveness of the IBVL to lower health care costs, and plan for long-term use of the IBVL for Canadian Indigenous children and adults needing genetic/genomic health care.

End of Award Update – July 2024

Results:

The Silent Genomes Project (SGP) successfully achieved four main objectives:

Established Indigenous-informed policies for Indigenous governance over biological data through the S-GIRDD Steering Committee.
Developed a comprehensive Background Variant Library (IBVL) using genomic data from First Nations participants, that was operational in January 2024, allowing internal testing with potential for expansion with more genomes from Indigenous participants.
Conducted whole genome sequencing for Indigenous patients with suspected genetic diseases, with standard analysis completed for 89 patients/families and ongoing analysis for unresolved cases.
Provided research training for Indigenous students in precision diagnosis and health economics over a six-year period. With the scholarship support of Life labs, the project team ensured the participation of over 30 students in the first 5 SING Canada workshops.

Impact:

Governance within the Silent Genomes Project ensured development of policies and operational guidelines for Indigenous involvement in genomic research. The Silent Genomes Indigenous Rare Disease Diagnosis Steering Committee has developed the processes for variant release which were implemented for the IBVL, protocols for clinical research applications planning to use the IBVL, and review process for the manuscripts where IBVL was used for the variant selection. The process of transformation of the advisory S-GIRDD Steering Committee into the sustainable IBVL Governance Committee is underway. The project leadership and the S-GIRDD committee members participated in the 2nd “DNA on Loan” conference organized by CIHR, where gaps in currently existing guidelines, that the team was exposed through the SG lifetime, have been discussed. Internationally, utilizing the mechanism approved by the S-GIRDD (online restricted access to frequency of Indigenous variants) within accepted upon ethical frameworks (CARE principles), was reviewed and is under consideration by two other jurisdictions (Australia and New Zealand).
Efforts were made to enhance the capacity of healthcare providers, Indigenous patients, communities, and students to engage with genomics research and health care. Five SING Canada workshops were conducted by Dr. Tall bear and her team, with the support of SG team members. Additionally, two Indigenous graduate students have either completed or are nearing completion of their studies. Educational materials developed by Activity 1 are available on the Silent Genomes website, along with regularly updated content on Genetics and Genomics research best practices.
The first release of the Indigenous Background Variant Library (IBVL) is undergoing testing and will be available for clinical use within the next few months. Once completed, this effort will enable assessment of how genomic variant knowledge impacts diagnostic clarity for Indigenous patients with rare diseases. The SGIRDD Steering Committee is actively involved in developing sustainable IBVL usage processes beyond the project’s duration. Internationally, the pipeline and user interface developed within the project have been shared with the Varoomed Project (Aotearoa/New Zealand), for testing or partial adoption.
Aims to increase access to genetically based diagnoses and care involved closing enrollment and engaging National Clinical Network (NCN) teams across 11 Canadian sites, with ongoing discussions to address limitations in Canadian TCPS2 Chapter 9 guidelines. Efforts were made to raise awareness among healthcare providers regarding barriers to accessing clinical and research genomics post-project. The Culturally Informed Genetic Counselling Guide, provided to each site, has been published on the SG Best Practices website for wider dissemination. The NCN continues to work on breaking down barriers to access to clinical and research genomics.

Potential Influence:

The lessons learned while establishing a National Clinical Network will be used to break down barriers in access to clinical and research genomics for Indigenous peoples.
Further collaborations are needed to fill the existing gaps in policies and guidelines related to Indigenous involvement in genomic research.
The S-GIRDD Steering Committee is currently focused on developing processes for sustainable use of the IBVL beyond the Silent Genomes project, with the goal of independent continuous seamless governance and technical support during the lifetime of the IBVL.
The international “Be FAIR and CARE” meeting gathered international Indigenous Genomics specialists from around the world, which conceived an idea of creating an International Indigenous Genomics Advisory and Research Consortium which would provide the necessary skills and knowledge for the development of stipulations for Indigenous data sharing processes globally. If similar projects are using comparable pipelines and user interface (e.g. the ones developed within the project), it may technically ease global data sharing processes.
The Health Economics study developed a set of practical and collaborative approaches for qualitative research when working with Indigenous People and communities to provide opportunities to advance Indigenous governance, capacity, and equity approaches.

Next Steps:

Building upon the original SGP, the new extended work is intended to catalyze longer-term efforts that could be sustained under healthcare systems (as the reference data provided by the IBVL becomes standard of care for diagnostic testing), funded by grants such as an anticipated Genome Canada health competition, directly supported through federal allocation, or a mixture of these models. Over the next 5 years, there are four key foci. First, developing sustained funding for the IBVL as an integrated reference data source for clinical diagnosis of rare disease. Second, achieving broader inclusion of Indigenous communities in the IBVL to enable the reference data to be of equitable utility for all Indigenous peoples of Canada. Third, to build upon emerging capacity to substantially increase the number of Indigenous researchers, research leaders, and genetic/genomic health care providers. Fourth, to identify and develop new health-related applications requiring reference data that are of priority to Indigenous peoples.

Cellular resolution OCT for clinical ophthalmology

Two of the leading causes of irreversible vision loss in developed countries are age-related macular degeneration (AMD) and diabetic retinopathy (DR). These diseases lead to the death of photoreceptors, the light-sensitive cells in the retina located at the back of the eye.

Treatments are currently available for “wet” AMD and DR, but there are currently no effective treatments for “dry” AMD. The key to preserving sight is early diagnosis, and monitoring the effects of the novel therapies in development.

The current technologies for non-invasive retinal imaging systems include flood illumination fundus photography, confocal scanning laser ophthalmoscopy (SLO) and optical coherence tomography (OCT). The resolution attainable with these techniques doesn’t permit visualization of the photoreceptor mosaic. The limiting factor to this ability is the eyes themselves—the cornea and lens that focus light onto the retina do not have microscopic abilities.

Dr. Sarunic has developed a novel instrument combining wavefront sensorless adaptive optics (SA) with OCT to correct ocular aberrations. This novel SAO OCT can achieve cellular resolution imaging of the retina, visualizing the individual photoreceptors that form a mosaic pattern on the retina (akin to looking at the pixels in a camera). This SAO OCT design is compact and clinically friendly, and with further investigation and commercialization, could lead to improved diagnosis and treatment for those with vision loss.

An advanced wearable robotic exoskeleton for assisting people with lower limb disabilities

Human locomotion is influenced by many factors, including neuromuscular and joint disorders that affect the functionality of joints and can cause partial or complete paralysis. Reduced mobility is estimated to affect over 1.5 million people in the United States alone. Many individuals require mobility assistive technologies to keep up with their daily life, and the demand for these devices increases with age.

A wearable robotic exoskeleton is an external structural mechanism with joints and links corresponding to those of a human body. It is synchronized with the motion of a human body to enhance or support natural body movements. The exoskeleton transmits torques through links to the human joints and augments human strength.

Dr. Arzanpour has developed a novel wearable robotic exoskeleton for assisting people with lower limb disabilities, such as spinal cord injury patients. The robot is highly versatile and capable of guiding the lower limb joints to perform all normal and complex movements. The technology is light, modular, portable, programmable and relatively inexpensive, and is particularly innovative in its versatile hip, knee and ankle joint mechanism, such that the normal range of motion of the natural joints is preserved.

So far, a proof-of-concept prototype of the proposed lower limb exoskeleton has been fabricated and successfully tested on an anthropomorphic test dummy. With further progress this technology could help people with lower limb disabilities to walk again and greatly improve their quality of life.

AAPLE-Walk: A novel gait-mimicking exercise machine for cardiovascular fitness and rehabilitation

Heart disease and diabetes are just two of many conditions that can occur in people after a spinal cord injury (SCI). Exercise can play a significant role in mitigating the risks associated with these conditions, but typical exercise options for people with SCI or other lower limb disabilities are usually limited to seated upper body exercise (for example, wheeling or hand cycling). Physical activity guidelines have been proposed for SCI, and although conventional exercise confers some cardiovascular (CV) benefits, the current options may not be enough to prevent widespread health decline post-injury.

Hybrid exercise, in which passive leg exercise is combined with active arm exercise, represents an under-explored area with significant clinical promise to improve CV outcomes over and above what is possible with arm exercise alone. In parallel, research is emerging about the benefits of upright walking therapy on recovery of neurological function and improvements in the secondary complications that accompany SCI, such as neuropathic pain. However, this type of therapy currently necessitates the use of expensive machines and/or trained personnel at specialized rehabilitation centres.

Dr. Borisoff has developed a new exercise machine, called AAPLE-Walk, that aims to provide arm-driven, walking-like leg movements while standing and exercising. This machine would provide comprehensive benefits to CV fitness and elicit lower limb muscle activity, potentially improving the secondary conditions of multiple diseases.

Dr. Borisoff has developed a proof-of-principle prototype of this machine, and next steps include further refining this prototype so the usability and health impacts can be evaluated.

It is clear that better exercise methods are needed for those with disabilities. These methods should challenge the heart better than simple, arm-only exercise, as well as beneficially impact an array of secondary complications. AAPLE-Walk may be an answer. The ultimate goal for this device is a product suitable for home use—or, with additional features, a device suitable for high-volume use at clinics. If successful, this would be low cost and offer more comprehensive benefits compared to expensive therapy machines currently on the market.

Novel infection resistant coating for indwelling urinary devices

Urinary catheters are polymer tubes inserted into the bladder to drain urine. Over 25% of patients in hospital are fitted with a catheter during their stay. These tubes are a major cause of infection in hospitalized patients and result in longer hospital stays with skyrocketing health care costs and may result in death. In fact, infections acquired in hospitals are the fourth leading cause of death in hospitalized patients.

Currently, antibiotics are our only method of attempting to deal with these infections, but they do not work well. Bacteria form large communities, known as biofilms, on the surface of the catheter, which can render antibiotics ineffective. Additionally, bacteria have developed ways to inactivate antibiotics and become resistant, making them difficult to kill.

Dr. Lange has developed a breakthrough technology based on a special coating for catheters. The coating is inspired by nature—it’s very similar to what marine mussels use to attach to surfaces—and prevents bacteria from attaching to the catheter surface without killing the bacteria, which would induce resistance. Instead, by preventing bacteria from attaching to surfaces, we leave them exposed for our immune system to kill.

Dr. Lange’s preliminary studies have shown that this new coating prevents the attachment of different types of bacteria to the catheter surface in test tubes and in a realistic urinary environment in animal models. The coating doesn’t break down over time and can be used to cover many different types of materials.

The next steps for this technology will be producing catheters with this coating, including testing its effectiveness over long periods of time in larger animals, ensuring it cannot be rubbed off, and that it stays active under conditions it would face in medical environments. Although this project is specifically looking at catheter infections, the data that Dr. Lange will generate will provide a general method for preventing infections associated with other medical devices, another major problem in hospitals.

Engineered T regulatory cells to treat Crohn’s disease

Inflammatory bowel disease (IBD) is an incurable disease that affects about 230,000 Canadians. People with IBD suffer from diarrhea, abdominal pain, weight loss, intestinal blockages, and other complications. Current treatments can control symptoms in many people, but they are not curative, and can have side effects like increased risk of infections. The causes of IBD are so far unknown.

People with IBD appear to have abnormal immune responses to the bacteria (microbes) that normally live in the intestine. This response involves blood cells, called helper T cells, that react to microbes, especially when they are not suppressed properly by another type of T cell that inhibits inflammation (known as T-regulatory cells, or Tregs).

Dr. Levings will develop a new IBD treatment that captures the natural ability of Tregs to control inflammation, using a new technology called Chimeric Antigen Receptors (CARs) which has shown promising results in cancer studies. The technology changes Tregs in such a way that they treat intestinal inflammation without affecting the rest of the body’s immune system.

Dr. Levings has validated this technology in a laboratory setting, and the next steps include testing it in animal models, creating new versions of the specific CAR she has developed, and interviewing and surveying physicians and patients to find out how receptive they would be to using CAR Treg therapy for IBD.