Selective knockdown of misfolded SOD1 as a therapy for amyotrophic lateral sclerosis

Project Overview

In some cases of ALS, it is clear that specific inherited genetic changes (called mutations) can not only cause the disease, but can do so by creating a protein (the end product of genes that actually does a function in our cells) that has an abnormal, toxic function resulting in motor neuron degeneration. For years scientists attempted to understand what this secondary toxic function was so that they could develop treatments to stop it. However, as technology advanced, the capability to simply selectively reduce (called knockdown) the amount of the toxic protein that exists in motor neurons and other important cells in ALS became a reality and the concept of this as a potential treatment to slow down the disease process was born. However, while all of the techniques to date have shown promise, including one method using substances called antisense oligonucleotides (ASOs) that is in clinical trial, there is definite room for optimization of methods to more effectively reduce toxic SOD1 proteins and for easier delivery of the treatment to people. A team led by Dr. Jiming Kong, professor at University of Manitoba will use a very novel and newly patented technique aimed at knocking down the levels of SOD1, first in motor neurons in the laboratory and then in ALS model mice. The process involves intravenous (IV – through the bloodstream) delivery of a small compound that can enter the brain and spinal cord and selectively tag misfolded SOD1 with something that targets it to a disposal mechanism called the lysosome. Provided the mechanism works well in an ALS mouse model, the team will work to advance the system for application to perform early stage clinical trials. Ultimately, the proof-of-concept for this CT4-directed method may not only provide a more optimal strategy for treating people living with SOD1-mediated ALS, but may also be adaptable to other forms of ALS or other diseases where reduction of toxic proteins can be beneficial.

Partners and Donors

ALS Society of Canada