21EBTA Engineering Biology for Cell and Gene Therapy Applications

Cell therapy and gene therapies (CGTs) are interrelated areas of biomedical research and treatment that aim to treat, prevent, and potentially cure diseases. Cell therapy aims to treat diseases by restoring or altering certain sets of cells or by using cells to carry a therapy through the body. Gene therapy aims to treat diseases by replacing, inactivating or introducing genes into a patient's cells. Both cell and gene therapies overlap in that they necessitate the transfer of new genetic material to cells to produce what could be thought of as "living medicines". The most commonly used cell therapy at present is Chimeric Antigen Receptor (CAR) T-cell therapy for treating blood cancers. This involves genetic modification of patient's own T-cells to express a CAR specific for a tumour antigen, following by ex vivo cell expansion and re-infusion back to the patient enabling to the engineered T Cell to identify cancer cells and destroy them.
The global cell and gene therapy manufacturing market size was valued at USD 13.1 billion in 2020 and is expected to expand at a compound annual growth rate (CAGR) of 20.3% from 2021 ($17B) to 2028 ($57.4B). Despite their promise, these therapies are limited providing little control over their dosage, timing, or localization and are often prohibitively expensive. These shortcomings can be overcome by using Engineering Biology to create the next generation of cell and gene therapies. We will use our unique automated facilities to develop new engineering biology tools, and solutions for the bottlenecks in the production CGTs and enable new, inexpensive and safe therapies for future clinical applications. The research will be split into four Engineering Biology Work Packages:1. Genetic Devices for Control in CGTs, 2. Delivery Mechanisms, 3. Standardisation of Cell Lines and 4. Responsible Research and Innovation.

Despite their promise, to date, first-generation Cell and Gene Therapies (CGTs) are still confined to narrow applications against B-cell cancers and rare genetic disorders with a single-target and a constitutively expressed therapeutic and they are also extremely expensive. In order to make CGT more broadly available and applicable to more diseases there are two overarching CGT challenge areas:

1.Biological challenges - engineering the CGTs to work specifically and safely and 2.Translational challenges - enabling the CGTs to move to the clinic quickly and cost effectively.

The work proposed in this transition award aims to address these challenges by using Engineering Biology to create the next generation of cell and gene therapies using engineering biology tools, and solutions for the bottlenecks in the production CGTs and enable new, inexpensive and safe therapies for future clinical applications.
We will develop 1. Genetic devices for control of CGTs including synthetic superenhancers, synthetic lethal switches, Synthetic sensing circuits and RNA based switches and circuits. These systems will enable us to better programme in control mechanism into CGTs. This is of great interest to industry and ultimately will lead to more precise, effective and safe therapeutics for patients. Such circuits will also be of immense value to fundamental biological research aiding the learning by building approach to address biological questions. 2. Improved and novel delivery mechanisms including enhanced AAV production, exosome based systems and Synthetic nucleosome arrays. 3. Foundation of an Edinburgh human iPSC progenitor cell bank that will produce a standardized quality controlled cell bank of iPSC progenitors that can be broadly shared with academic and industrial researchers enabling more labs to work with these cell types