Enhancer-AI - AI-driven modelling and design of cell type specific enhancers for gene therapy

From 01-10-2023 to 30-09-2027

Description

Gene therapy offers the promise of an efficient, single-dose therapeutic solution for many incurable diseases. In reality, despite large efforts of the scientific community and a strong industrial interest, bringing gene therapy to the market has proven challenging. The major hurdles faced by gene therapy come in the form of its safety and efficacy with off- target effects caused by low specificity or inappropriate transgene expression levels. The use of well-designed synthetic regulatory regions, called enhancers, could provide a solution to reach cell type-specificity and high levels of transgene expression. This SBO project proposes to develop new computational and experimental tools, and combine them in a pipeline to identify enhancers in complex tissues. This pipeline will exploit recent advances in single-cell multi-omics, gene regulatory network (GRN) inference, and deep learning. We will use this pipeline to design enhancers that are specifically active in three chosen brain cell types that are of high relevance for gene therapy. Practically, we will: 1) use mouse and human brain samples to generate a single-cell multi- omic atlas; 2) select unique regulatory regions to each cell type and train enhancer models; and 3) design and validate synthetic enhancers in vivo, using massively parallel reporter assays. As a clinically relevant case study, we will focus on microglia enhancers in the context of Alzheimer’s disease. In parallel, we will use the AI-based GRN and enhancer models to interpret and prioritize regulatory variation in whole genome sequences, in order to improve diagnosis and prediction of risk and progression for neurodegenerative disease. Our project will yield licensable enhancers, software tools, and diagnostic AI models with direct industrial applicability, and will demonstrate our ability to interpret and generate enhancers specific to any cell type, which can find application in a wide range of diseases, even beyond the scope of our project.

Team

• Stein Aerts, Coordinator (External)
• Yves Moreau, Promoter

Financing

Funding: FWO - Research Foundation - Flanders

Program/Grant Type: FWO SBO - FWO Projects Strategic Basic Research