Once the stuff of science fiction, using DNA and RNA to treat genetic disease inside our cells themselves is now science fact. One type of such genetic medicine are antisense oligonucleotides (ASOs), which are short pieces of single-stranded DNA that can bind to specific molecules of RNA to block or alter their abilities. By blocking the RNA that encode for diseased proteins, ASOs can target the source of diseases at the molecular level.
ASOs are an FDA-approved treatment method and are currently in use. However, their utility is limited because our cell membranes are designed to keep invaders, even helpful ones like ASOs, out. This means that currently, anyone receiving ASO treatment needs to take weekly injections containing astronomical amounts of ASOs at an exorbitant cost to see a therapeutic effect. Simply put, this delivery bottleneck is the main challenge to the success and accessibility of this treatment.
That’s where Dr Leo Chou, assistant professor at the University of Toronto’s Institute of Biomedical Engineering, hopes he can make a difference using self-driving lab (SDL) technology.
Using a technique called DNA origami, Dr Chou and his team will fold DNA into custom shapes that will help get it past the cell membrane and into the cell. DNA origami offers a unique value add to solve the delivery challenge because nanoparticles are known to be able to enter cells better by virtue of their nanoscale size. By using a nanoparticle that is made of DNA itself, this method also avoids adding larger molecules such as lipids and polymers, which most mature nanoparticle delivery systems currently use.
To further improve or enhance the folded DNA, these nanoparticles are also decorated with synthetic peptides, known as peptoids, that will help the folded DNA permeate the diseased cell and repair it.
“Since there are an infinite number of combinations of DNA origami and peptoids, we need the technology of a self-driving lab to help us find the right combinations to treat these diseases,” said Dr Chou. “By using an SDL to find the right combinations, we can more quickly realize our goal of reducing the dose and frequency of treatment for patients which will reduce its financial and physical burdens.”
Dr Chou’s team received a 2023 Accelerate Seed Grant from the Acceleration Consortium to support their work. Accelerate Seed grants build accelerated discovery capacity at the University of Toronto by helping faculty enter the field or collaborate with those already doing accelerated discovery.
In this case, Dr Chou is working with Dr Helen Tran, assistant professor in the department of Chemical Engineering and Applied Chemistry at the University of Toronto and Acceleration Consortium Scientific Leadership Team member. Dr Tran is creating peptoids and has ways of creating combinatorial peptoid libraries.
“We have put a great team together,” said Dr Chou. “Dr Tran and I will be working on the material design part of this project. Together with Dr Yun Li from the Peter Gilgan Centre for Research and Learning at SickKids we will measure how effective the material is in reducing the expression of the disease gene in the cell. All of that information then goes into an algorithm run by Dr Michael Garton from U of T’s Institute of Biomedical Engineering so it can be fed back into material synthesis to test it again.”
That is the power contained within the closed loop of an SDL; material science is combined with the power of artificial intelligence, robotics, and advanced computing, to autonomously and rapidly design and test new materials.
“Our goal is to discover new treatment delivery systems faster and faster using an SDL,” said Dr Chou. “That’s the most important thing about thing about using an SDL- the more information we give it, the more it learns and can develop successful new DNA origami and peptoid combinations.”
These treatment methods have the potential to help a wide variety of diseases and disorders that affect the brain.
“ASOs are an example of a programmable therapy and it can be used to treat a variety of diseases, if we can figure out the delivery bottleneck,” said Dr Chou. “Once we do that, we can help treat diseases like dementia, Alzheimer’s, Parkinson’s and seizures. And we’ll be able to do it faster than ever before.”
The next round of Accelerate Seed Grant applications will open in the spring of 2024!
