Leveraging RNA nanotechnology for next-generation gene delivery systems

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Can we built efficient gene delivery systems to target the brain? Gene therapy offers the promise to effectively revert the cause of inherited and acquired brain diseases. However, the brain is arguably the most challenging organ to target with therapeutic agents, especially large-size gene therapeutics. This is due to the existence of the blood brain barrier (BBB) - a highly selective border separating the blood circulation from the brain, formed by a continuous layer of sealed endothelial cells embedded in the capillary basement membrane. The BBB physiologically protects the neurons from neurotoxic factors present in the bloodstream, but also prevents exogenously administered medications to reach their target of action. Non-targeting brain therapies could not only result in poor efficacy of the treatment, but also in side effects due to the accumulation of toxic drugs in other organs, encumbering the life of the patient. Lipid nanoparticles were thought to cross the BBB, thanks to their charge and size by abortpion mediated endocytosis or transcytosis. But this approach failed to provide efficient delivery, testified by the lack of approved gene therapies targeting the brain.Can we use nucleic acids as gene delivery systems to target the brain? Nucleic acids are unstable natural polymers that degrade by nucleases upon intravenous injection and thus far were considered unsuitable for use as drug delivery vehicles. Yet, they have inherent properties to accommodate spatially arranged molecules and controlled stoichiometry for precise shape and size nanoparticles, crucial for an efficient tissue and cell targeting. The new approach involves the introduction of nuclease stable RNA nanoparticles, based on Sixfold's Ltd patent portfolio for the exploitation of DNA and RNA-based nanoparticles and targeting molecules including, but not limited to, aptamers, for the delivery of selected gene therapeutics. In preliminary studies, these particles have shown to accumulate in the brain. The research programme focuses on the assessment of the causal relationship between RNA nanoparticles charge, lipophilicity and size; to tissue/cell targeting. The nature of repetitive units (nucleotides) of nucleic acids, allows for precise design of the delivery systems in silico and prediction of the nanoparticle behaviour using Machine Learning. This offers a high degree of flexibility to create an on-demand platform for tissue targeting and reduce the physical experimentation. A toolbox of methods allowing for the nanoparticles stoichiometric characterization and biodistribution monitoring imaging will be developed. Preclinical demonstrators of the platform will be assessed thanks to the engagement of pioneering research groups working on animal models on neurodegenerative diseases including Parkinson's and Kennedy's (spinal bulbar muscular atrophy) diseases.