Developing a viral delivery system that allows doctors to switch a treatment gene on or off using a commonly used, low‑cost drug will create safer, more precise forms of gene therapy.
This project aims to ensure treatments for heart conditions can be adjusted to each patient’s needs while reducing side effects.
Cardiac deliveryIn depth
Adeno-associated virus (AAV) vectors typically deliver a genetic information under a promoter that is either ubiquitous or cell-specific, but with no other means of control.
Controllable systems, which can be used to turn off or titrate gene expression or translation, are critical for accelerating the pace of development and expanding the relevance of AAV gene therapies for cardiac disease. To date, the best control element remains the Tet operon system. However, a secondary transactivator is required to be delivered alongside the AAV vector. Dual control systems such as this are typically not approvable clinically and are considered too “leaky” to safely deliver controlled doses of proliferative, anti-inflammatory or anti-fibrotic transgenes to patients with heart failure.
To address that issue, this project aims to develop a novel AAV viral vector consisting of drug controllable transcript levels suitable for delivery any therapeutic gene. AAV vector with the ability to control the level of transgene translation through the secondary delivery of a clinically FDA approved low-cost drug doxycycline. Using small molecule ligand controllable aptazymes we will design gene therapy control systems that produce transcripts in a tunable manner only in the presence of a small molecule ligand. These control systems will be readily extendable to any AAV capsid, including existing and novel cardiotropic capsids accelerating translation to clinical trial.
Partners
This project is a collaboration with the UKRI Engineering Biology for Advanced Therapeutics Hub.