Intelligent Gene Control

Expression of the therapeutic protein in a gene therapy cassette can cause severe side effects. Off-target effects in the liver, kidneys and motor neurons in particular have been highlighted by the FDA as a major concern. Such side effects are difficult to address, particularly because the ability to control gene therapies after administration is limited. Gene control systems provide a means of precisely controlling gene therapies, for example in response to tissue type or via the administration of drugs by clinicians.

Concinnity is developing modular, multi-functional, RNA-based gene control systems that form part of the gene therapy cassette. They are inserted into the 3’ UTR and become active after transcription of the cassette to mRNA. These control systems are programmed to respond to internal or externally provided molecules and control gene expression in a defined manner by modulating the amount of gene therapy mRNA in the patient’s cells.

Such control systems have huge potential, allowing a gene therapy to recognise the disease state of the patient and dynamically adjust its activity to keep within defined safe/efficacious boundaries, to recognise tissue type and thus avoid off-target effects by ensuring activity is restricted only to the desired tissues, or adjusting activity in response to clinically administered FDA-approved drugs.

RNA-based control systems have a number of advantages, including no requirement for additional genetic components, their small size of <150 bp (freeing up space for the therapeutic payload) and their applicability across a broad range of therapeutics, most notably mRNA therapeutics where conventional DNA-based control systems (e.g. synthetic promoters) cannot be used.