U of T researchers use a self-driving lab to advance mRNA treatment for cystic fibrosis

By developing and using a self-driving lab (SDL), University of Toronto researchers have discovered new lipid nanoparticles (LNPs) that can help deliver mRNA medicine into the lungs through inhalation, with potential applications in gene-editing therapies for cystic fibrosis (CF). 

“This research demonstrates that AI-driven LNP design can enable the successful delivery of gene-editing RNA (ribonucleic acid) to the lungs,” says Bowen Li, an associate professor in the Leslie Dan Faculty of Pharmacy, who leads the LUMI-lab (Large-scale Unsupervised Modeling followed by Iterative experiments). “While gene-editing therapy for CF is an emerging field, these new LNPs and our new delivery method open a potential treatment avenue for patients.” 

An inherited disease, CF primarily affects the lungs and digestive system. A faulty protein disrupts the movement of salt and water in and out of cells, causing thick mucus to build up that obstructs a person’s airway or digestive tract. According to Cystic Fibrosis Canada, about 4,400 Canadians live with CF, which is the most common fatal genetic disease affecting children and young adults in Canada.

While prescription drugs, like Trikafta, are effective for many people with CF, approximately 10 per cent of patients have mutations that do not respond to currently available medications. This treatment gap makes Li’s research and the work of the LUMI-lab particularly relevant to this population. 

LNPs (tiny droplets of fat, albeit chemically complex) help carry RNA to lung cells, delivering genetic instructions that enable cells to produce gene-editing enzymes. 

“Once you identify a mutation, like a genetic mutation that causes disease, a nucleic acid can be designed to address that specific disease, but the problem is always delivery,” says Li. “Most RNAs accumulate in the liver, so getting them to other organs, like the lungs, has been a challenge. This is the bottleneck that limits their translation to clinical use.” 

By overcoming this delivery challenge, the LUMI-lab's discoveries have the potential to impact research beyond cystic fibrosis. The ability to deliver mRNA to different organs throughout the body could lead to new treatments for a wide range of diseases.

Li is the inaugural recipient of the Acceleration Consortium’s Translation Grant, which encourages researchers to develop self-driving labs, or use AI and automation to accelerate scientific discovery. The grant provides up to $500,000 in funding over two years with the possible addition of $300,000 for equipment. 

Based at U of T, the AC is a global community of academia, industry and government accelerating the design and discovery of new materials. 

The AC grant gave Li the resources to develop the LUMI-lab, which is driven by an AI model trained on more than 28 million molecular structures. In its quest to improve mRNA delivery, the lab automatically selected, synthesized and tested over 1,700 LNPs, among 221,000 synthesizable candidates in the virtual library, including several that outperformed approved benchmarks. Notably, after testing less than one per cent of the candidates, the AI model independently discovered that adding bromine into the lipid tail – a previously unexplored molecular feature - improved mRNA delivery.

An automated liquid handler, a piece of lab equipment purchased with the AC grant funds, was also instrumental in helping Li and his team develop the new inhalable LNP formulations. 

“Our AI model can generate new design knowledge, rather than just help us analyze the data,” says Li. “It’s like a brain, and the AC funding helped give it its robotic arms that supported this breakthrough.” 

Li and his team’s mRNA therapeutic treatment, delivered through these new LNPs, is at the preclinical stage, where its safety and efficacy are being evaluated. This milestone is estimated to have been achieved nearly 100 times faster than the average research and development timeline from initial discovery to testing.  

Li and the LUMI-lab team are also working to expand the application of LNPs to surgical and vaccine delivery, in addition to protein engineering. 

Related research findings have been published in the journals Cell, Nature Materials and Science.

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Thumbnail image: A robotic arm, a liquid handling system and other scientific instruments inside the LUMI-lab at U of T. Photo credit: Steven Southon

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