In this proposal, Dr. Kothary and his team seek to explore the role of SMN protein in aging. Recent advances in SMA research, such as the FDA approval of Spinraza, are likely to increase lifespan and dampen SMA motor symptoms, leading to a shift of the severe infantile SMA patient population towards a milder SMA adult patient population. Such lifespan extension may reveal new, previously unknown issues arising with age in SMA.

Dr. Kothary and his team recently generated a new mouse model that will allow for the investigation of whether defects related to SMN-depletion occur during aging. Furthermore, challenging this new model in different conditions such as exercise or diet will reveal whether some subclinical defects might be present in aged SMN-depleted tissues. Altogether, this study will shed light on future potential obstacles that may be faced by SMA patients receiving an SMN-upregulating therapy. Being proactive in understanding such impairments will ensure timely development of additional therapeutics and ensure sustained quality of life for SMA patients throughout their lifespan.

Meet Dr. Kothary

Who are you?

My name is Rashmi Kothary and I am the Deputy Scientific Director at the Ottawa Hospital Research Institute. My lab develops mouse models of SMA and we use them for preclinical studies.

How did you first become involved with SMA research?

My introduction to SMA research was in 1999 when Dr. Christine DiDonato joined my laboratory as a postdoctoral fellow. She had the SMA genetics expertise and we had the mouse modeling expertise. Together, we worked on generating a novel mouse model of SMA that we have uses to get a better understanding of the multi-organ nature of the disorder.

What is your current role in SMA research?

We are exploring the multi-organ nature of SMA. In particular, we are studying the potential of immune function problems.

What do you hope to learn from this research project?

This study will expand our understanding on defects that are present in less severe SMA patients (Type IV), and inform us about possible defects that may arise during aging in both the motor unit compartment and in non-neuronal organs.

How will this project work?

We will take advantage of a new mild mouse model of SMA that has been generated in our laboratory to perform these studies.

What is the significance of your study?

The proposed studies will help us to gain insight into several aspects of canonical SMA features in addition to non-neuronal and muscle defects seen during aging in a SMA context. This is particularly important as underlying defects may be masked by the current short lifespan of untreated SMA patients and could arise later in life. Therefore, as SMA type IV or SMA treated patients age, they may still be inflicted with findings in neuronal or non-neuronal compartments. Being proactive in understanding such impairments will ensure timely development of additional therapeutics.

Basic Research Funding

This grant to Dr. Kothary is being co-funded through Cure SMA – Canada and is part of $1,325,000 in new basic research funding that we’re currently announcing.

Basic research is the first step in our comprehensive research model. We fund basic research to investigate the biology and cause of SMA, in order to identify the most effective strategies for drug discovery. We also use this funding to develop tools that facilitate SMA research.

Dr. Parks and his team are exploring the use of exosomes, small particles released from all cells, as potential biomarkers for SMA. They have shown that SMN protein is naturally released in exosomes from all cell types examined. Furthermore, when using a mouse model, the quantity of SMN protein contained in the serum-derived exosomes correlated with the disease status of the animal, with progressively less protein in the carrier and SMA affected animals compared to wildtype mice. In humans, SMN protein was also easily detectable in exosomes isolated from human serum, with a reduction in the amount of SMN protein contained in exosomes from a patient with Type 3 SMA compared to a healthy control.

Taken together, these results indicate that the amount of SMN protein contained in exosomes correlates to the level of SMN protein within the originating cell in both patients and mouse models, and suggests that analysis of exosome-derived SMN protein may serve as an effective biomarker for SMA. In this proposal, Dr. Parks and his team will build upon these exciting preliminary results, and further explore the utility and accuracy of analyzing SMN protein levels in serum-derived exosomes as a biomarker for SMA.

Meet Dr. Parks

Who are you?

I am a Senior Scientist at the Ottawa Hospital Research Institute in Ottawa, Ontario, Canada, as well as a Full Professor at the University of Ottawa. I serve as the Co-Director of the University of Ottawa Centre for Neuromuscular Disease, which brings together over 60 basic scientists and clinical researchers that work on various aspects of neuromuscular disease. Work in the Parks laboratory is primarily directed towards studying aspects of virus biology (specifically adenovirus, a common cold virus) as it pertains to its use as a gene delivery vehicle in gene therapy applications. More recently, our work has evolved into other “nanotechnologies” like exosomes. Exosomes are small particles released from all cells and can be easily isolated from blood or serum samples. Analysis of protein or DNA contained in exosomes can frequently provide insight into the “health” of the cell from which they are released – so studying exosomes isolated from the blood of patients is a simple method that can potentially provide insight into the health of the patient.

How did you first become involved with SMA research?

Ottawa has one of the highest concentration in the world of basic and clinical researchers working on neuromuscular diseases such as SMA. Many years ago, Dr. Rashmi Kothary, an Ottawa-area expert in SMA, sought our help to investigate gene therapy approaches to treat SMA. As someone who primarily studies viruses, I had little knowledge of what SMA was. I became more involved with local patients and families affected by neuromuscular disease, and became inspired to try to help however I can. As I learned more about SMA, my lab started to ask our own research questions, and realized that perhaps we had something to offer to the field. We hope that our work will uncover new insight into SMA disease and, hopefully, uncover new strategies to treat the disorder.

What is your current role in SMA research?

Exosomes are small microscopic particles released from all cells, almost like little bubbles, and they are found in high numbers in blood. Exosomes contain a sampling of the proteins that were in the cell, and thus they are an easy way to assay the “health” of the cell. We found that SMN protein is also released from cells in exosomes, and the level of SMN protein in exosomes isolated from patients is less than what we see in samples from unaffected individuals. We are investigating whether we can use a simple blood assay to monitor responses to therapies that act through increasing SMN protein levels in the cell.

What do you hope to learn from this research project?

Our objective is to develop a novel assay, based on a simple blood sample, that can be used to characterize spinal muscular atrophy disease severity and response to treatment.

How will this project work?

We will obtain blood samples from patients with SMA before and during treatment with Spinraza and monitor the levels of SMN protein in small vesicles within the blood termed exosomes. In response to therapies that act through increasing the expression of SMN protein, we should see an increase in the amount of SMN protein in these vesicles isolated from blood.

What is the significance of your study?

Successful completion of our work will lead to the development of a simple, minimally-invasive assay that can be used to monitor the response of patients with SMA to therapy, which would enhance our ability to monitor response in clinical trials.

Basic Research Funding

This grant to Dr. Parks was funded through Cure SMA – Canada and is part of $1,325,000 in new basic research funding that we’re currently announcing.

Basic research is the first step in our comprehensive research model. We fund basic research to investigate the biology and cause of SMA, in order to identify the most effective strategies for drug discovery. We also use this funding to develop tools that facilitate SMA research.

Cure SMA Canada has awarded a $140,000 research grant to Joceyln Côté, PhD, at The
University of Ottawa, for his project, “Investigating the mechanism by which SMN
regulates translation: identification of novel therapeutic targets.”
Understanding the function of the SMN protein is vital to understanding SMA and serves
to aid in the development of therapeutics. In this grant, Dr. Côté and his team plan to
build upon their prior work which describes a new function for SMN in the regulation of
protein production, called translation. They propose to perform experiments to gain a
better understanding of how SMN goes about doing this new function, and also to
determine what might be the consequences of losing this function in cells from SMA
patients.
This work will provide crucial insights into a novel function for SMN that is misregulated
in SMA. This will lead to a more complete understanding of disease mechanism. In turn,
identification of the molecular mechanisms and the various players/regulators involved
in this process may yield novel therapeutic targets for the treatment of SMA.
This grant was funded byCure SMA Canada .
Meet Dr. Côté
Who are you?
I am a biochemist and molecular biologist by training with specific expertise in the field
of RNA metabolism. I obtained my PhD from the University of Sherbrooke in the
province of Quebec, Canada. I then pursued my training as a postdoctoral fellow at
Washington University in St. Louis, Missouri and at McGill University in Montreal,
Quebec, Canada.I started my independent research group at the University of Ottawa in
2004 and I am now a Full Professor in the Department of Cellular and Molecular
Medicine.
How did you first become involved with SMA research?
Coming from a biochemical background, I initially started working on SMA because I
identified SMN, or more specifically a part of the SMN protein called the Tudor domain,
as a domain capable of ‘sensing’ arginine methylation in proteins. Following this
discovery, we reasoned that these ‘methylated’ proteins might represent a major subset
of proteins that would stop functioning normally in the absence of SMN in SMA patients,
and that studying these proteins might help us gain a better understanding of what SMN
does in spinal cord motor neurons and how loss of these activities leads to SMA.
Although it started primarily as a scientific question, after I first attended the Annual
FSMA Research Conference back in 2002 and met SMA kids and their families, it
became clear to me that I was going to do my best to contribute my expertise towards
increasing our fundamental understanding of this disease in the hope that it would help
one day in the elaboration of novel therapeutic strategies.
What is your current role in SMA research?
My lab uses biochemical, molecular and cell biology approaches, working with various
models of SMA, in order to gain a better understanding of the precise function that SMN
plays in spinal cord motor neurons, and how loss of that function leads to the disease.
For example, we are trying to identify the other proteins and RNA molecules that SMN
interacts with and controls in motor neurons. Doing so should give us some insights into
what SMN is actually doing in this cell type. Then, we assess if these SMN interacting
partners could represent valid targets that might be easier to manipulate than SMN itself
to improve disease.
What do you hope to learn from this research project?
From this project we hope to learn about a new function for SMN in the regulation of
protein production. We want to gain a better understanding of how SMN goes about
doing this new function, and how loss of this function in motor neurons contributes to
SMA.
How will this project work?
We propose to use a series of biochemical, molecular and cellular approaches that will
allow us to:
1. determine the composition of the regulatory complex(es) in which SMN functions to
regulate protein production in motor neurons;
2. identify the subset of messenger RNAs that are regulated by SMN at the level of protein
production and determine whether these are misregulated in SMA; and
3. explore the therapeutic potential of increasing the levels and/or activity of regulators of
SMN function in SMA cells in order to compensate for loss of SMN. For these
experiments we are using cell culture and mouse models of SMA, but also validating
our results using SMA patient cells to insure that our findings are relevant to the human
condition.
What is the significance of your study?
The current proposal will provide crucial insights into a novel function for SMN in spinal
cord motor neurons. Identification of the targets that are misregulated due to loss of this
novel SMN function in SMA should lead to a more complete understanding of disease
mechanism and has the potential to identify new therapeutic targets.