Research Location: International Collaboration on Repair Discoveries

Cerebrovascular burden and cognitive impairment after spinal cord injury

Spinal cord injury (SCI) is a complex pathophysiology, characterized not only by paralysis but also severe autonomic cardiovascular dysfunction. After SCI, strokes are 300 – 400% more likely to occur compared to non-disabled individuals.

One potential explanation for this is autonomic dysreflexia (AD), a life-threatening condition whereby persons experience sudden, transient episodes of high blood pressure. Such volatile swings in blood pressure in individuals with SCI result in structural and functional changes within peripheral blood vessels and lead to the deterioration of peripheral organs, including the brain. In the general population, chronic hypertension is a key risk factor for cerebrovascular dysfunction (increased stroke-risk and cognitive impairment). However, it is currently unclear whether the cumulative load of AD plays a similar role in cerebrovascular and cognitive impairment in persons with SCI.

Using the latest technological advances in magnetic resonance imaging, Dr. Nightingale’s research will examine differences in the structure and function of micro-vessels in the brain between two groups of SCI participants with different durations of SCI (and thus AD exposure), relative to an able-bodied age-matched control group. The results of this research will lead to a better understanding of AD in SCI individuals, and potentially improve treatment to better prevent the occurrence of stroke.

Development of a novel biophotonics method to improve treatment and neurological outcomes in acute spinal cord injury

Acute spinal cord injury (SCI) is a devastating neurological condition resulting in permanent morbidity and impaired quality of life. In spite of advancements in the acute treatment of SCI, preventing neurological deficits in affected patients is highly limited. The hemodynamic management of acute SCI patients to maintain blood supply and maximize oxygenation of the injured spinal cord tissue is currently one of the few aspects of critical care in which clinicians can improve neurologic outcomes. However, optimizing the hemodynamic management in acute SCI is limited and challenging due to the lack of a real-time means for monitoring spinal cord blood flow, oxygenation, and hydrostatic pressure.

The overall objective of Dr. Shadgan's research is to develop a novel optical method, using an implantable optical sensor and system that work based on near-infrared spectroscopy (NIRS) to provide real-time measurements of spinal cord hemodynamics in acute human SCI. Such a tool would provide information to guide clinicians in their treatment decisions and allow them to personalize the hemodynamic management of acute SCI patients to optimize neurologic outcomes. This program includes a sequence of preclinical studies aimed to translate this approach to human SCI patients. Dr. Shadgan's research program will also include the training of highly qualified personnel, intellectual property protection of the method and system, and knowledge translation.

Servo-controlled device to maintain physiological functioning

300,000 individuals live with spinal cord injury (SCI) in the US alone, of which 180,000 suffer from orthostatic hypotension, sudden falls in blood pressure upon standing. Such dysregulated blood pressure can also be caused by multiple sclerosis, autonomic failure, autonomic neuropathy, or neurological cancers. A high quality, efficient, and cost effective method is needed to help these individuals regulate their blood pressure.

Dr. Krassioukov has developed a device and algorithm for controlling autonomic processes in patients using electrical stimulation, based on the surprising discovery that electrical stimulation of the spinal cord circuitry caudal to SCI can control the activity of disconnected sympathetic circuitry to regulate blood pressure. The device can be individualized, and electrical output may increase or decrease based on the information received from the patient’s physiological monitor.

Dr. Krassioukov’s product may improve patients’ control of autonomic functions such as dysregulated blood pressure due to SCI or other injuries or diseases, improving their quality of life and ability to manage symptoms, at a lower cost and with improved effectiveness than current methods.

Near infrared spectroscopy for the hemodynamic monitoring of acute spinal cord injury

One of the only treatments that could potentially improve paralysis in patients who have suffered an acute traumatic spinal cord injury (SCI) is the elevation of the mean arterial blood pressure (MAP) to provide enough blood supply to the injured spinal cord. It is, however, difficult to know what the MAP target should be for a given patient to optimize their neurologic recovery.

Currently there is no measurement tool that provides real-time information about the spinal cord blood supply and oxygenation, and allows them to know if their efforts to elevate blood pressure are actually improving (or worsening) the injured spinal cord. Such a tool would provide information to guide clinicians in their treatment decisions and allow them to personalize their care and optimize neurologic outcomes.

Dr. Kwon will explore the potential of near-infrared spectroscopy (NIRS) as a monitoring tool to provide this information, with the explicit goal of developing this technology into a device that can be commercialized to be used in SCI patients. NIRS works by shining near-infrared (NIR) light through tissues and then recording how much light is transmitted versus how much is absorbed by molecules within the tissue. By measuring near infrared light absorption in tissue, NIRS can measure how much oxygen and blood is being delivered, potentially informing us of whether cells within the tissue are being irreversibly injured due to oxygen deprivation.

Dr. Kwon’s research will translate a promising technology (NIRS) into a clinical application for acute SCI patients. His initiative is focused on providing a tool that will assist clinicians in their hemodynamic management of acutely injured patients during a time when their efforts greatly impact patients’ neurologic outcomes.

End of Award Update: February 2023

 
Most exciting outputs

Product/technology – Near Infrared Spectroscopy (NIRS) Biosensor for the Spinal Cord. We managed to bring the technology forward to the point of implanting an NIRS sensor into a human spinal cord injury (SCI) patient.
 

Impact so far

We are still very early in our human testing, and from our first patient have identified the need for sensor refinement and further safety/performance testing (which this award is helping us to conduct).
 

Potential influence

We will ultimately change how the hemodynamic management of acute SCI is conducted.
 

Next steps

Right now, the most pressing issue is to get our newly refined sensors (arriving soon) and then conduct further safety/performance testing.

A novel therapeutic for inflammatory skin diseases

Granzyme B (GzmB), an immune-secreted serine protease, is abundant in skin conditions characterized by excessive inflammation (such as burns, blisters, or scarring) at the hair follicle or at or just under the epidermis, and has been identified as a therapeutic target for autoimmune and chronic skin diseases. 

Studies have defined a role for GzmB at the interface between the outermost (epidermis) and inner (dermis) layers of skin known as the dermal-epidermal junction (DEJ). In fact, many of the key proteins that anchor these two layers together are proteolytic substrates of GzmB. Given that it is well-documented that GzmB accumulates in the DEJ in many autoimmune conditions associated with separation of these layers (e.g. blistering and skin peeling conditions), it is plausible that GzmB-mediated cleavage of such anchoring proteins would contribute to disruption of the DEJ leading to blistering. In support of this concept, when human GzmB is added to freshly obtained human skin, complete separation of the DEJ ensues. 

Dr. Granville has developed a topical first-in-class inhibitor of GzmB and have identified a condition known as Discoid lupus erythematosus (DLE) as our lead indication to enter the clinic. DLE is a rare, autoimmune skin condition that is usually triggered by sunlight. DLE lesions are characterized by DEJ inflammation, scarring, alopecia, and microvascular damage. Importantly, GzmB levels are highly elevated in this form of cutaneous lupus. 

The aim is to obtain first approval of our GzmB inhibitor for DLE followed by subsequent approvals for other skin conditions. This project will generate further proof-of-concept data to support the clinical development and commercialization of a topical GzmB therapeutic for inflammatory skin conditions.

The acute impact of spinal cord injury on cardiac function, and novel hemodynamic management in SCI patients

Following acute spinal cord injury (SCI), one of the only presently available neuroprotective strategies is to try and optimize management of spinal cord blood flow. This treatment specifically aims to immediately increase blood flow to the injured spinal cord tissue to prevent the spread of injury to surrounding spinal cord tissues.
Currently, vasopressors are administered to increase blood pressure to a similar threshold in all patients; however, its efficacy in improving neurological outcomes has not been consistent, and in some patients has been found to actually worsen outcomes. A more optimized and individualized approach to blood flow management in SCI patients is needed.

High-thoracic SCI immediately impairs the brainstem and neural control of the heart. Our pilot data suggest this decentralization of the heart immediately impairs cardiac function, which could have significant implications for the acute management of blood flow in SCI patients. Dr. Williams will investigate the immediate and acute cardiac responses to high-thoracic SCI, and determine whether improvements to cardiac function can improve spinal cord blood flow and neurological outcomes in SCI patients.

Dr. Williams will conduct translational studies utilizing a porcine model of SCI. She will test the efficacy of potential novel management strategies, including restoring cardiac function alone or in combination with vasopressor therapy. A simultaneous study will look at acutely injured individuals with SCI at Vancouver General Hospital, examining heart function during the first three days after injury.

To date, very little work has characterized the impact of SCI on cardiac function in the initial period following injury. Combining invasive and integrative studies in pigs and humans provides us with the unique opportunity to conduct highly translatable studies that could have an immediate impact on SCI patient outcomes.

 

End of Award Update – July 2022

Most exciting outputs
Our research to date has identified how high-level spinal cord injuries (i.e. at or above the mid-back level) impact the heart immediately after the injury occurs. We found that those injuries impact the heart’s output within the first hours post-injury, and further identified a treatment that could harness the heart to support blood pressure and potentially reduce secondary damage to the spinal cord.

 

Impacts so far
The award has allowed us to examine alternative approaches to treating acute spinal cord injury which could ultimately improve outcomes if that approach is effective in the clinical setting. Moreover, as a trainee this award has provided the critical opportunity for me to expand my skillset in the realms of clinical and pre-clinical research, and apply gold-standard techniques to answer questions about the heart that have traditionally been overlooked in the field of spinal cord injury research.

 

Potential future influence
With the support of this award I have made significant strides in my training toward becoming an established cardiovascular researcher. First, it has allowed me to expand my expertise in the heart and its neural control. Second, I have gained invaluable experience in clinical and pre-clinical research, which truly round out my training as a physiologist. Finally, I have been able to produce and output impactful research across those domains and in doing so built strong collaborations with local and international leaders in these respective fields.

 

Next steps
We have yet to publish additional research that has stemmed from this award, looking at the long-term benefits of heart-focused approaches to treating spinal cord injury, and would like to pursue opportunities to implement such an approach in the clinical setting.

 

Useful links

The maladaptive effects of wood smoke on abdominal aortic aneurysms

Cardiovascular disease is the leading cause of death worldwide. Approximately 80% of all aneurysms that form within the aorta (the major blood vessel that deliveries oxygenated blood to the body) occur in the abdominal region. These are classified as abdominal aortic aneurysms (AAA). AAA is associated with progressive weakening and, ultimately, rupture of the vessel wall, causing rapid and extreme blood loss and a high rate of mortality. Sadly, aneurysm rupture is often the first sign of the disease and many die before reaching a hospital. For those that are diagnosed, treatment is currently limited to open chest or endovascular surgical repair. However, surgical repair of AAA is a risky, complex procedure with a high mortality rate. 

In the past 40 years there has been a worldwide increase in forest fires. Although cigarette smoke is known to induce and advance AAA, the effect of wood smoke on blood vessel remodelling and AAA is currently unknown. Interestingly, firefighters are at a four times greater risk for having a heart attack compared to other emergency response personnel. In fact, firefighters are at a greater risk of dying from cardiovascular disease than from on the job burn injury. Although smoke exposure is thought to play a major role in the majority of firefighter cardiovascular deaths, the processes by which wood smoke may promote cardiovascular disease and AAA is unknown.

Granzyme B (GzmB) is an enzyme that breaks down the protein-based scaffolding between cells that is important in sustaining tissue structure and function. Human and mouse models of AAA have shown that GzmB expression is increased within the blood vessel wall of aneurysms and its degree of expression is directly related with aneurysm rupture. In animal models, drugs that inhibit of GzmB prevent aneurysm rupture and increase survival. Although cigarette smoke is associated with increased GzmB levels in those with lung disease such as COPD, the link between wood smoke, GzmB and AAA is not known.

Dr. Zeglinski will examine the effect of repeated exposure to wood smoke on GzmB expression in the vessel wall and its effect on AAA progression. To explore this relationship, he will use a well-established mouse model of AAA and determine what, if any, effect that wood smoke has on aneurysm formation and rupture. 

The results of this research could lead to the development of new drugs to treat AAA, a devastating disease with few treatment options. Should the results confirm that GzmB is involved in AAA, Dr. Zeglinski will team up with clinicians for a clinical study to assess the levels of GzmB in those who have been diagnosed or have died from an AAA. By translating findings from the bench to the clinic, Dr. Zeglinski will later be able to partner with drug companies to develop a novel therapeutic agent to block GzmB action to slow or stop the progression of AAA and prevent AAA ruptures.