Shape Therapeutics, a leader in RNA-based gene therapy, today released two preprint manuscripts detailing major technological breakthroughs that underpin the company's therapeutic editing platform RNAfix®. RNAfix® uses engineered guide RNAs (gRNAs) delivered by Adeno-Associated Virus (AAV) to recruit the natural ADAR enzyme and enable editing of target sites in a patient’s RNA. These new advances overcome longstanding challenges to harnessing ADAR for therapeutic RNA editing, positioning ShapeTX at the forefront of programmable RNA medicines.
The first manuscript, "Generative Machine Learning of ADAR Substrates for Precise and Efficient RNA Editing," introduces DeepREAD (Deep learning for RNA Editing by ADAR Design), one of Shape's custom AI models for gRNA design. Trained on data from high-throughput screens of millions of RNA sequences, DeepREAD generates gRNAs that form highly engineered structures when bound to target RNA. These novel structures redirect ADAR's natural sequence preferences, enabling specific and efficient editing of virtually any target adenosine. "DeepREAD represents a significant advancement in RNA editing gRNA design," said Ron Hause, Ph.D., SVP and Head of AI at Shape Therapeutics. "Our diffusion-based model generates highly efficient and specific guide RNAs for any adenosine in the transcriptome over 10,000 times faster than previous methods, rapidly producing thousands of high quality designs in minutes that outperform existing heuristic design approaches. This dramatically accelerates the development of RNA editing therapeutics for a wide range of genetic disorders."
The second manuscript, "A Novel Engineered U7 Small Nuclear RNA Scaffold Greatly Increases in vitro and in vivo ADAR-Mediated Programmable RNA Base Editing," provides a detailed look at Shape's advanced system for expressing therapeutic gRNAs inside patient cells. By borrowing principles from natural small RNAs and performing deep profiling and additional engineering to enhance efficiency, Shape’s novel scaffold drives high expression of gRNAs at the precise sites in a cell where ADAR activity occurs, leading to unprecedented levels of RNA editing in vitro as well as in the brain of animals given a systemic injection of AAV-delivered gRNA. "Our enhanced U7 SmOPT expression system represents a huge advancement for the therapeutic application of RNA editing, particularly in areas like the central nervous system where AAV delivery is often constrained to low doses per cell," said Adrian W. Briggs, Ph.D., Chief Technology Officer at Shape Therapeutics.
The advances described in the two new manuscripts provide a blueprint for a breakthrough gene therapy pipeline. “By combining AI-powered gRNA design with our optimized expression system, we can now precisely and efficiently edit RNA targets that were previously out of reach and at an efficiency unmatched by other editing platforms. This opens up exciting possibilities for treating a wide range of genetic disorders in the CNS and beyond," said Dr. Briggs.