Biogen Nusinersen application

January 24, 2017 Dear Cure SMA Canada Members, I hope you are doing well. I would like to update you on the latest information to share about Biogen’s Nusinersen application for approval from Health Canada. There are many questions being asked in terms of where we are with the application from a patient’s timeline perspective…

February 5, 2015 Project update for FSMA Canada (Cure SMA) Grant: KT1415 (Feb 1, 2014 to Jan 31, 2016) $50,000 per year

Title: The Non-SMN Mediated Benefits of The HDAC Inhibitor Trichostatin A PI: Rashmi Kothary We have just completed the first year of funding from FSMA Canada. Objective: Our goal was to better understand how a small molecule (TSA) that is a global gene regulator ameliorates the disease symptoms and pathology in a mouse model of…

Arginine Methylation as a Regulator of SMN activities in Motor Neurons

Objective: We will study and obtain more information about the role of a novel protein, called PRMT8, which is present at the surface of the cells that are most affected in SMA, the motor neurons in lower spinal cord.

Research Strategy: We will test the possibility that PRMT8 may be able to make the SMN that is still present in small amounts in SMA patient cells, more active. Preliminary results obtained in our laboratory suggested to us that PRMT8 could regulate the binding of specific proteins to a region of the SMN protein called the Tudor domain in motor neurons.

Significance of the Project: Stimulating the activity of the protein, PRMT8, could potentially have beneficial influence on the activity of SMN that is still present inside SMA cells. Thus our work has the potential to lead to completely new strategies for SMA therapies as well as a greater understanding of how SMN functions specifically in motor neurons.
Progress to Date Made on this Project: Amongst the first things we wanted to confirm for this project to be viable was whether or not this protein, PRMT8, was indeed present at the surface of spinal cord motor neurons, the cells that are most affected in SMA. We are happy to say that we have been able to confirm that PRMT8 is present at the surface of moror neurons, and that at a similar level in SMA spinal cord relative to unaffected animals. We have performed these experiments using various mouse and cell culture models of SMA, and we would still like to confirm this in human motor neurons. We have also demonstrated, using motor neurons grown in a petri dish, that PRMT8, similar to SMN, is playing an important role for the normal function of these cells and for their survival. Confirming that it may indeed represent a good therapeutic target. In a second Research Objective we wanted to investigate in more details ‘how’ PRMT8 might be influencing SMN function. One simple way to look at this is to picture SMN as part of a ‘lock-and-key’ mechanism, where SMN constitutes the ‘lock’ and the ‘key’ would be proteins that are decorated with a special modification or mark called a ‘methyl group’. This is where these enzymes called PRMTs come in, as they are the ones that will add this special mark on proteins, in turn making them a good ‘fit’ for binding to SMN. We have now identified and characterized at the molecular and biochemical level a number of proteins that can be modified by PRMT8 to become better interacting partners for SMN.