Researchers at U of T Engineering have successfully utilized an AI framework to redesign a crucial protein involved in the delivery of gene therapy. The study, led by Professor Michael Garton (BME) and recently published in Nature Machine Intelligence, describes new work optimizing proteins to mitigate immune responses, thereby improving the efficacy of gene therapy and reducing side effects.
“Gene therapy holds immense promise, but the body’s pre-existing immune response to viral vectors greatly hampers its success. Our research zeroes in on hexons, a fundamental protein in adenovirus vectors, which –– but for the immune problem –– hold huge potential for gene therapy,” says Garton.
“Immune responses triggered by serotype-specific antibodies pose a significant obstacle in getting these vehicles to the right target; this can result in reduced efficacy and severe adverse effects.”
To address this issue, Garton’s lab used AI to custom-design variants of hexons that are distinct from natural sequences.
“We want to design something that is distant from all human variants, by extension, unrecognizable by the immune system,” says Suyue Lyu (BME PhD candidate), lead author of the study.
Traditional methods of designing new protein often involve extensive trial and error as well as mounting costs. By using an AI-based approach for protein design, researchers can achieve a higher degree of variation, reduce costs and quickly generate simulation scenarios before homing in on a specific subset of targets for experimental testing.
Although numerous protein-designing frameworks exist, it can be challenging for researchers to properly design new variants because of the lack of natural sequences available and how large hexons can be –– on average, these proteins consist of 983 amino acids. With this in mind, Lyu and Garton needed to come up with a completely different AI framework.
Dubbed ProteinVAE, this model can be trained to learn the characteristics of a long protein using limited data. Despite its compact design, ProteinVAE exhibits a generative capability comparable to substantially larger models available on the market.
“Our model takes advantage of pre-trained protein language models for efficient learning on small datasets. We also incorporated many tailored engineering approaches to make the model suitable for generating long proteins,” says Lyu.
“We intentionally designed ProteinVAE to be lightweight. Unlike other, considerably larger, models that demand high computational resources to design a long protein, ProteinVAE supports fast training and inference on any standard GPUs. This feature could make the model more friendly for other academic labs.”
“Our AI model, validated through molecular simulation, demonstrates the ability to change a significant percentage of the protein’s surface, potentially evading immune responses,” says Lyu. “Our next step would be to move on to wet lab experimental testing.”
Garton believes this AI-model can be utilized beyond gene therapy protein design and could likely be expanded to support protein design in other disease cases as well.
“This work indicates that we are potentially able to design new subspecies and even species of biological entities using generative AI, and these entities have therapeutic value that can be used in novel medical treatments,” says Garton.