NeuroDegRNA-Tx · Harnessing cellular resilience through RNA therapeutics in neurodegeneration

NeuroDegRNA-Tx aims to develop and validate a novel mRNA-based therapeutic strategy that enhances intrinsic cellular resilience to treat Alzheimer’s disease (AD). While most current treatments focus on removing the causative protein aggregates, the NeuroDegRNA-Tx approach leverages our recent discovery of a novel stress-resilience mechanism, which we named as SITA (Stress-Induced Transcriptional Attenuation). SITA enables cells to suppress non-essential transcription during the stress of protein misfolding, sparing cellular resources for preserving protein homeostasis. Our data showed that SITA deficiency accelerates disease progression in mouse models of AD. Using genome-wide CRISPR screens, we identified several SITA enhancers (SITAe) as promising therapeutic targets.NeuroDegRNA-Tx will test whether mRNA delivery of SITAe in diseased brains can restore SITA function and reduce disease phenotypes in established mouse models of AD. Using lipid nanoparticle (LNP)-encapsulated mRNA, we will validate hippocampal delivery, assess protein expression, and evaluate behavioural improvements. Single-cell RNA sequencing will confirm target engagement and cell-type-specificity while ensuring therapeutic safety. A lead SITAe candidate will be selected based on efficacy and safety.Commercially, the project will generate critical preclinical data to support patenting, derisk translational development and prepare for follow-up funding through schemes such as EIC Transition. Stakeholder involvement includes academic leaders in RNA therapeutics, neurodegeneration and cellular stress biology, as well as Cambridge Enterprise for IP and commercial strategy.By combining breakthrough mechanistic insights with the enormous potential of RNA-based drugs, NeuroDegRNA-Tx will shift the treatment paradigm from elimination of protein aggregates to improvement in cellular resilience. The project will pave a novel therapeutic avenue in neurodegeneration using mRNA therapeutics.