2021 Virtual

endMS Summer School

Taking MS Research Off the Grid

June 7-9, 2021

Hosted by the University of Saskatchewan

2021 endMS Summer School Agenda

Start time is 9:00 am Saskatchewan time for all 3 days. British Columbia is 1 hour behind = 8 am, Alberta is the same time = 9 am Manitoba is 1 hour later = 10 am, Ontario and Quebec are 2 hours later = 11 am New Brunswick and Nova Scotia are 3 hours later = 12 pm Newfoundland is 3.5 hours later = 12:30 pm

Last update June 4, 2021 1

Monday, June 7th 2021 – Times are in SK Time Zone (CST)

9:00-9:15 am Welcome & Introduction – Dr. Charity Evans, Dr. Darcy Marciniuk, Dr. Christina Wolfson Morning sessions will be moderated by Dr. Valerie Verge

9:15–10:15 am

Dr. Bogdan Popescu: Iron in multiple sclerosis - Describe shortly the pathology of multiple sclerosis and how it relates to disease stages. - Describe what is known about the role of iron in the pathogenesis of multiple sclerosis. - Describe how iron is visualized in tissues. - Describe how the synchrotron works, specifically related to techniques that are used to image

iron and other chemical elements. - Describe the pathological heterogeneity of active lesions in multiple sclerosis - Describe the iron heterogeneity in active lesions and its implications - Describe the distribution and quantification of iron in smoldering, inactive and remyelinated

plaques.

10:15– 10:30 am

Break

10:30– 11:45 am

Dr. John Gordon: Regulatory dendritic cell therapy for immunologic disease This talk will address use of regulatory dendritic cells to induce tolerance in immunologic disease, using both multiple sclerosis and aero- and food-allergen sensitivities as prototypical examples. The audience will gain an appreciation for dendritic cell and T cell regulation of immune responses and immunopathology, and for the possibilities presented by use of these cells in preclinical models and in the clinic. Cole Libner: Antibodies to the RNA binding protein heterogeneous nuclear ribonucleoprotein A1 contribute to neurodegeneration in in vitro and in vivo models of multiple sclerosis. Loss of neurons and axons, collectively known as neurodegeneration, is characteristic of multiple sclerosis (MS) and is thought to underlie permanent disability. Historically, autoimmunity in MS was thought to primarily target myelin components contributing to demyelination, but recent data implicates an autoimmune response to neurons contributes to neurodegeneration. MS patients make autoantibodies to the RNA binding protein heterogenous nuclear ribonucleoprotein A1 (hnRNP A1), a protein over expressed in neurons. Using in vitro and in vivo models we show that anti-hnRNP A1 antibodies enter neurons and exacerbates hnRNP A1 dysfunction in the form of its nuclear cytoplasmic mislocalization and the formation of cytoplasmic stress granules, ultimately resulting in increased neurodegeneration. Objectives: 1. To understand the contribution of neurodegeneration to MS. 2. To understand how RNA binding protein dysfunction contributes to neurodegeneration. 3. To demonstrate how antibodies to the RNA binding protein hnRNP A1 contribute to

neurodegeneration in in vitro and in vivo models of MS. Nataliya Tokarska: Acute Intermittent Hypoxia (AIH) slows progression in an MS preclinical model Efficient repair of demyelinated lesions is one of the major challenges of multiple sclerosis (MS).

2

Conventional therapies tend to focus on immune response modulation responsible for the

generation of these lesions. While this alleviates symptoms and mitigates damage, it alone does not

tackle the fundamental problem of remyelinating damaged areas of the central nervous system

(CNS). In MS, demyelination can be followed early on by efficient remyelination, supporting that

endogenous repair mechanisms exist. Our lab focuses on therapies that enhance these intrinsic

repair mechanisms following injury. We find that acute intermittent hypoxia (AIH; intermittent

periods of reduced oxygen), a non-invasive therapy, improves spinal cord and peripheral nerve

injured animals, the latter in a manner akin to electrical stimulation. But its potential for repair or

slowing progression in MS is unknown. We hypothesized that AIH treatment would enhance repair of

the demyelinated CNS and mitigate disease progression in the MOG35-55 experimental autoimmune

encephalomyelitis (EAE) mouse model of MS.

Objectives:

- To use the EAE model to examine the effect of AIH treatment on clinical score outcomes

- To use the EAE model to examine the effect of AIH treatment on mitigating disease progression.

The following parameters are examined:

a. Myelin

b. Axon protective phenotype

c. Oligodendrocyte precursor cell (OPC) recruitment

d. Inflammation

e. Immune cell polarization

Dr. Julie Pétrin: Access to Health Care for Canadians with Multiple Sclerosis This presentation will focus on providing the audience with a broad overview of access to healthcare for Canadians with MS. The health care access experiences of Canadians with MS, the main barriers they encounter in att empting to manage their conditions, as well as their prioritized access concerns, will be highlighted. I will conclude the presentation by discussing the current implementation science project being developed to address prioritized concerns.

11:45 am–12:30 pm

Dr. Scott M Rosendahl: MS Research Opportunities Utilizing the Canadian Light Source

The Canadian Light Source (CLS) at the University of Saskatchewan is a national research facility producing the brightest light in Canada, millions of times brighter than even the sun. Annually, the CLS hosts more than 1000 scientists from around the world who conduct ground breaking health, agriculture, environmental and advanced materials research using synchrotron light.

This talk will provide an overview of techniques available at several beamlines at the CLS, highlighting applications in biological research and how researchers can access these capabilities.

Infrared spectromicroscopy will be specifically discussed as a particularly well-suited technique for studying biological processes, due to the diversity of biological molecules which absorb light in the mid-infrared spectral region. Further, it is a non-destructive and highly selective technique that is compatible with histology, allowing for straightforward incorporation into existing research protocols. When combined with imaging, the high brightness of synchrotron infrared light at the CLS enables diffraction limited spatial resolution across the mid-infrared energy range. This capability has potential applications in measuring oxidative stress on tissues and cells and will be explored. Objectives: - Understand the research opportunities available at the CLS. - Learn the application process to utilize the CLS in your research programs.

3

- How Mid-Infrared Spectromicroscopy can be used as a tool for studying biological processes.

12:30–1:15 pm Lunch

1:15–2:15 pm

Session will be moderated by: Cole Libner Presenter: Dr. Michael Levin: How RNA binding proteins contribute to the pathogenesis of neurodegeneration and disability in MS and relevant MS models Participants will: • Gain a greater understanding of the role of neurodegeneration in pathogenesis of MS. • Understand the role of RNA binding proteins in the pathogenesis of neuronal dysfunction and neurological disease. • Be introduced to in vitro & in vivo models of disease used to examine RNA binding protein biology in MS. • Understand how RNA binding protein dysfunction mechanistically contributes to the pathogenesis of neurodegeneration in MS.

2:15-3:00 pm

Breakout Sessions – Summer School Trainees will be placed in small breakout rooms

Breakout A: Dr. Bogdan Popescu Neuropathology of inflammatory demyelinating diseases.

Describe the pathology of various types of white matter lesions seen in multiple sclerosis (active lesions, inactive lesions, smoldering lesions, remyelinating lesions).

Describe the pathology of various types of cortical demyelinating lesions.

Contrast lesions of multiple sclerosis with those of other inflammatory demyelinating diseases (neuromyelitis optica, acute disseminated encephalomyelitis, acute hemorrhagic leukoencephalitis).

Breakout B: Dr. Michael Levin Seq and ye shall find! A comprehensive, experimental approach to CLIPseq, RIPseq and RNAseq of nervous system tissues.

(Blue) lights, camera, action! How to use optogenetics to discover mechanisms of protein dysfunction with molecular fluorescent real-time imaging.

The long-term goal of research in the Levin Lab is to better understand the cause of neurodegeneration, a salient feature and cause of permanent disability in MS. My team focuses on the role that neuronal RNA binding proteins (RBPs), specifically heterogeneous nuclear ribonucleoprotein A1 (A1), play in the pathogenesis of neurodegeneration in MS.We were the first to show nucleocytoplasmic and nuclear depletion of A1 and its colocalization with stress granules in neurons in the brain of an MS patient, which we replicated, demonstrating that A1 neuronal mislocalization is a dominant feature of MS cortical pathology. Considering these neuropathologic findings of RBP dysfunction, we modeled A1 dysfunction using in vitro and in vivo models of disease. Using neuronal cell lines, we showed that pro-inflammatory cytokines and autoantibodies to A1 reproduced the findings we observed pathologically as well as altered RNA metabolism of the cells. Using the in vivo model experimental autoimmune encephalomyelitis (EAE), we found that both cellular - and antibody – mediated autoimmunity induced neuronal A1 nucleocytoplasmic mislocalization and nuclear depletion, and SG formation and increased neuronal death. Taken together, these data implicate dysfunctional RBPs as contributors to novel mechanisms of neurodegeneration in MS.

3:00–3:15 pm Break

4

3:15-4:00 pm Breakout Sessions (Groups will switch breakout rooms) Breakout C: Dr. Bogdan Popescu (see Breakout A above) Breakout D: Dr. Michael Levin (see Breakout B above)

4:00 pm Wrap Up

Tuesday, June 8th 2021 - Times are in SK Time Zone (CST)

9:00-9:15 am Introduction to the Day – Dr. Charity Evans Morning sessions will be moderated by Dr. Michael Levin

9:15–10:15 am

Dr. Valerie Verge: Boosting the intrinsic ability of the focally demyelinated nervous system to repair itself Multiple Sclerosis (MS) is characterized by segmental demyelination of axons that can be spontaneously and efficiently remyelinated early in disease. Thus, endogenous mechanisms exist for repair that can be targeted. We aim to gain a better understanding of MS neuropathology and design therapies that enhance intrinsic repair mechanisms of the injured nervous system; therapies that can be used to improve CNS remyelination, resolve inflammation and protect demyelinated axons. We find that electrical nerve stimulation (ES) significantly improves nerve regeneration and remyelination. We are currently investigating acute intermittent hypoxia (AIH) therapy (intermittent periods of reduced O2), as a non-invasive approach to improve outcomes in spinal cord and peripheral nerve injured animals. Notably, AIH has a similar molecular signature to ES likely due to AIH’s ability to also increase neural activity. Thus, it holds great potential for repair in other pathologies, such as MS. Participants will: • have an understanding of the various indices of repair that can be assessed; • understand the ability of increased neural activity to enhance intrinsic repair; • be introduced to a novel non-invasive way to boost the intrinsic ability of the demyelinated nervous system to repair - acute intermittent hypoxia (AIH); • understand the potential of AIH to significantly impact multiple indices of repair at near peak disease in preclinical MS models.

10:15– 10:30 am

Break

10:30– 11:45 am

Dr. Mohan Babu: Mapping Pathological Interaction Connectivity Landscape in Mitochondrial Disorders Dr. Ekaterina (Kate) Dadachova: Radioimmunotherapy (RIT) of MS as a new approach to its treatment Pre-Session Reading The objectives of the presentation will be:

1) To learn about radioimmunotherapy (RIT) and its current applications in cancer treatment. 2) To understand the approach of targeting PD-1 on activated T cells with RIT. 3) To get informed about the ongoing work on RIT of MS.

Dr. Josef Buttigieg: Effects of a trimeric protein on immune cells in a model of MS. Currently there are few treatment options for MS, with many not treating the disease itself and focusing on symptom management. Those therapies that do treat the immune system, work by suppressing the entire immune system, thus rendering the patient susceptible to infections by pathogens. In conjunction with iProgen, we have developed an approach that specifically targets autoimmune cells. By removing the cells that cause the disease, it is hypothesized that this will allow the central nervous system to repair itself. Thus improving the quality of life for patients and reducing the

5

burden on the healthcare system. In this talk, we will discuss the theory behind autoimmunity, how our trimeric protein is proposed to work, and current stage of investigation.

11:45 am–12:30 pm

Dr. Scott Napper (VIDO): Vaccine Development in the Midst of a Pandemic I will discuss the efforts within the Vaccine and Infectious Disease Organization (VIDO), as well as global efforts, to develop a vaccine for SARS-CoV-2 and the lessons learned as we start to think about future pandemics.

12:30–1:15 pm Lunch

1:15–2:15 pm

Session will be moderated by: Nataliya Tokarska

Dr. Robert Laprairie: The endogenous cannabinoid system and multiple sclerosis: intersections and evidence. This talk will summarize the normal function of the endogenous cannabinoid system and evidence for how this system is dysregulated in multiple sclerosis. The limited evidence for cannabinoids as therapeutics for multiple sclerosis will be reviewed. Objectives: (1) Know the major components of the endogenous cannabinoid system and major constituents of cannabis. (2) Understand how the physiological functions of the endogenous cannabinoid system relate to the pathophysiology of multiple sclerosis. (3) Review the limited evidence concerning cannabinoids as therapeutics for multiple sclerosis. Dr. Sarah A. Morrow: Evaluating cognition in the MS clinic: why do we care? Cognitive impairment in MS is common and is considered an invisible symptom. Yet, it will remain invisible if it is not measured as part of a clinical MS assessment. This presentation will discuss why it is important to assess cognition clinically as well as how research to date has supported the importance of measuring what cannot be seen.

Dr. James J Marriott: Clinical Trials in MS: New Therapies & Approaches Objectives: - To review established MS clinical trial design - To explore stem cell therapies for MS - To explore novel methods to conduct future MS trials

2:15-3:00 pm

Breakout Sessions - Summer School Trainees will be placed in small breakout rooms

Breakout A: Dr. Valerie Verge Assessing repair in the focally demyelinated nervous system – multiple tools at your disposal Dr. Verge and her research team have over 4 decades experience in assessing repair of the injured nervous system, with Dr. Verge being one of the pioneers in how to quantitatively assess histopathological changes in response to perturbations and treatments. In the past decade they have shifted some of their focus toward gaining a better understanding of how therapies they use to repair the injured nervous system may be applied to demyelinating pathologies and how to best assess outcomes. This will be the focus of this breakout session. Participants will: • have a better understanding of the challenges of reliably and consistently assessing histopathological and behavioural outcomes in tissue sections and animal models of MS; • be introduced important factors in generating unbiased reproducible quantitative outcomes; • be introduced to the multiple indices of repair that can be assessed at the histopathological and behavioural levels;

6

• understand the limitations and strengths of these approaches when thinking about translation

Breakout B: Dr. Sarah J Donkers and Dr. Katherine B Knox A focus on rehabilitation: clinical, community, and research initiatives

Drs. Sarah Donkers (physiotherapist, PhD) and Katherine Knox (physiatrist, MD) will provide an

interactive overview of some of their current physical rehabilitation projects. This workshop will be

broken into 3 components: clinical, community, and research. ‘Clinical’ will include a virtual tour of

the Saskatoon MS Clinic and a glimpse into some of the assessments a patient living with MS may

experience when visiting the clinic. ‘Community’ will highlight the NeuroSask: Active and Connected

initiative. ‘Research’ will focus on how neurophysiological measures (e.g. fNIRS) are being used to

evaluate an intense MS balance and walking rehab intervention aimed at promoting functional

neurorecovery.

Objectives:

To experience part of a virtual visit to the Saskatoon MS Clinic, Department of Physical Medicine and

Rehabilitation

To expose attendees to existing resources with regards to MS

To provide an experiential learning opportunity regarding research in MS physical rehabilitation.

3:00–3:15 pm Break

3:15-4:00 pm Breakout Sessions (Groups will switch breakout rooms) Breakout C: Dr. Valerie Verge (see Breakout A above) Breakout D: Dr. Sarah J Donkers and Dr. Katherine B Knox (see Breakout B above)

4:00 pm Wrap Up

Wednesday, June 9th 2021 Times are in SK Time Zone (CST) 9:00-9:15 am Introduction to the Day – Dr. Charity Evans

9:15–10:15 am

Session will be moderated by Dr. Sarah J Donkers Dr. Katherine B Knox: To stem the tide of progression in MS: A call for team effort and a whole person approach Objectives: a) Describe disability progression in MS b) Illustrate an example of multidisciplinary team work and individualized care in MS c) Share collaborative efforts for synthesizing best evidence and the gaps in MS care and research Description: Despite the advent of disease modifying therapies in multiple sclerosis, the majority of

people living with MS experience disability progression over their lifetime. This presentation will

summarize the natural history of MS progression, which may begin even before MS diagnosis. This

talk will briefly illustrate how a multidisciplinary approach may delay or reduce the impact of

disability in MS and will share how an evidenced-based platform (msbest.ca) may allow more rapid

synthesis of new evidence to guide future best practices.

Dr. Janine Brown: Multiple sclerosis and medical assistance in dying This presentation will review the legislated parameters of Bill C-14, outlines some of the complex care considerations of end-of-life, MAID, and MS care, and outline a research proposal that explores individuals living with MS and their families' perspectives on MAID. By the end of the presentation,

7

participants will be able to: 1) Explain the legislative parameters and safeguards of MAID that are embedded in Bill C-14 2) Describe the complexities of care where EOL, MAID, and MS intersect. 3) Critique a qualitative research proposal exploring individuals living with MS and their

families' perspectives on MAID. Dr. Ilia Poliakov: An overview of MS Management during the COVID-19 pandemic Objectives:

1) Discuss the switch to the virtual patient care model. 2) Discuss the interactions of MS, MS treatment, and COVID-19 morbidity and mortality. 3) Discuss the interactions of MS, MS treatment and COVID-19 vaccinations.

10:15– 10:30 am

Break

10:30– 11:30 am

Lived Experience Panel Moderated by: Dr. Katherine B Knox To provide trainees with insight into the experiences of those living with or affected by MS.

11:30 am–12:30 pm

endMS SPRINT Team Presentations Moderated by: Dr. Christina Wolfson SPRINT Team Presenters: Emily Kamma, Wendy Lasisi, Cole Libner, Huah Shin Ng

SPRINT Mentor: Dr. Jason Plemel

CNS macrophages in progressive MS: characteristics, neurodegeneration, and therapeutics

While there are over 15 disease-modifying drugs approved over the last 20 years for the treatment

of relapsing-remitting multiple sclerosis (MS), there is only limited treatment options available for

progressive MS. The development of new drugs for the treatment of progressive MS

(primary/secondary progressive) remains challenging as the pathophysiology of progressive MS is

poorly understood. Macrophages/microglia serve central roles in all stages of MS, and they are

largely the basis to define lesion types in MS. Given the enrichment and activation of

macrophages/microglia throughout MS and during all disease stages, many mechanisms may define

their contribution to neurodegeneration in progressive MS. We conducted a review to describe the

clinical aspects of progressive MS and the roles of central nervous system (CNS)

macrophages/microglia in progressive MS and neurodegeneration. We also reviewed the types of

drugs approved for progressive MS and other potential treatments in which involvement of

macrophages/microglia have been documented.

*** SPRINT Team Presenters: Monique Almeida, Maria-Elizabeth Baeva, Brian M Lozinski, Simon Thebault SPRINT Mentor: Dr. Sarah J Donkers “ASK” about physical activity in MS: a toolkit for MS clinics The importance of exercise and other types of physical activity in MS is increasingly recognized. MS health care providers play an important role in addressing physical activity behaviour. This presentation will provide an overview of our SPRINT project - a multi-step mixed methods knowledge translation (KT) initiative. We surveyed MS specialized clinics across Canada to inform the development of a tailored KT ‘toolkit’. A preliminary toolkit was designed based on the identified beliefs, behaviours, current practices, and needs with regards to physical activity promotion. An

8

overview of the toolkit development and its contents will be provided. ‘ASK’: A toolkit supporting health care providers to Assess current physical activity, Support individuals with MS by providing tailored recommendations, and encourage people with MS to Keep it up through routine monitoring. Objectives re: presentation: - Highlight the established evidence supporting the importance of physical activity for people with

MS, and the need to support the clinical translation of addressing physical activity behaviour in the routine management of MS.

- Present the results of our needs assessment survey of Canadian MS clinics with regards to physical activity promotion

- Describe the development of our evidence-based, practical ‘toolkit’ for physicians to address identified needs and knowledge gaps.

- Explain our plans for future implementation of the toolkit to support physicians in their everyday practices

12:30–1:15 pm Lunch

1:15–2:30 pm

Career Session – Moderated by Dr. Michael Levin Presenter: Tom Brown (Interview Coaching Solutions) Pre-work deadline: May 21st Differentiate yourself in any job interview Learning Objectives: - Professional job interview process overview

2:30 pm Wrap Up – Dr. Charity Evans and Dr. Christina Wolfson

The endMS National Training Program is an initiative of the endMS Network aimed to enhance knowledge and skills relevant to MS research, foster opportunities to conduct MS research in Canada and increase the intent amongst

trainees to pursue MS research for the long term.

The endMS Summer School and endMS Scholar Program for Researchers IN Training (SPRINT) are part of the endMS National Training Program which is funded via a directed grant by the MS Society of Canada’s MS Scientific Research

Foundation.

Special acknowledgment and thank you also go out to:

The University of Saskatchewan for hosting the 2021 endMS Summer School

THANK YOU!

The success of the 2021 endMS Summer School is the result of the hard work of many committed individuals. A grateful acknowledgement goes out to all of the speakers, moderators, mentors and trainee volunteers, as well as to the

individuals living with MS who so generously agreed to share their time and experiences with us.

We also sincerely thank the following individuals. Without you all, this program would not have been possible.

2021 endMS Summer School Planning Committee:

Dr. Charity Evans (Co-Host), University of Saskatchewan Dr. Michael Levin (Co-Host), University of Saskatchewan Dr. Valerie Verge (Co-Host), University of Saskatchewan Dr. Sarah J Donkers, University of Saskatchewan Mr. Cole Libner, University of Saskatchewan Ms. Nataliya Tokarska, University of Saskatchewan Dr. Katherine B Knox, University of Saskatchewan 2021 endMS Education and Training Committee:

Dr. Christina Wolfson (Chair and endMS Program Director), McGill University Dr. Nathalie Arbour, endMS Program Co-Director, Université de Montréal Dr. Marcia Finlayson, endMS Program Co-Director, Queen’s University Ms. Elisea DeSomma, York University Dr. Jacqueline Quandt, University of British Columbia Dr. George Robertson, Dalhousie University Dr. Penny Smyth, University of Alberta Dr. Charity Evans (Co-Host), University of Saskatchewan Dr. Michael Levin (Co-Host), University of Saskatchewan Dr. Valerie Verge (Co-Host), University of Saskatchewan Ms. Anik Schoenfeldt, endMS National Training Program

2021 endMS SPRINT Committee:

Dr. Marcia Finlayson (Chair), Queen’s University Dr. Marjan Gharagozloo, University of Sherbrooke Dr. Sarah Morrow, University of Western Ontario Dr. Christina Wolfson, McGill University Ms. Anik Schoenfeldt, endMS National Training Program

2021 endMS Peer Review Committee:

Dr. George Robertson (Chair), Dalhousie University Dr. Susan Forwell, University of British Columbia Dr. Michelle Ploughman, Memorial University Dr. Christina Wolfson, McGill University Ms. Anik Schoenfeldt, endMS National Training Program

2021 endMS Summer School Review Committee:

Dr. Charity Evans (Chair), University of Saskatchewan Dr. Nathalie Arbour, Université de Montréal Dr. John Fisk, Dalhousie University Dr. Soheila Karimi, University of Manitoba Dr. Michael Levin, University of Saskatchewan Dr. Craig Moore, Memorial University Dr. Jason Plemel, University of Alberta Dr. Roger Tam, University of British Columbia Dr. Lisa Walker, University of Ottawa Dr. E. Ann Yeh, University of Toronto Dr. Valerie Verge, University of Saskatchewan Ms. Anik Schoenfeldt, endMS National Training Program

endMS Summer School Personnel/Volunteers

Ms. Michelle Eisner, UBC MS Connect Education Program

Dr. Michael Levin’s lab team for his Breakout session led by:

Dr. Joseph-Patrick Clarke, University of Saskatchewan Dr. Hannah Salapa, University of Saskatchewan Dr. Patricia Thibault, University of Saskatchewan The MS clinic nursing staff and patient volunteers for the MS

clinic virtual tour

Ms. Anik Schoenfeldt, endMS Program Manager