21EBTA Engineering Biology for Cell and Gene Therapy Applications
Lead Research Organisation:
University of Edinburgh
Department Name: Sch of Biological Sciences
Abstract
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.
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.
Technical Summary
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
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
Organisations
Publications

Bhaskar H
(2023)
Live-cell super-resolution imaging of actin using LifeAct-14 with a PAINT-based approach.
in Protein science : a publication of the Protein Society

Cabrera A
(2022)
The sound of silence: Transgene silencing in mammalian cell engineering
in Cell Systems

Caringella G
(2023)
Recent advances, opportunities and challenges in cybergenetic identification and control of biomolecular networks
in Current Opinion in Biotechnology

Davies J
(2023)
Synthetic morphology with agential materials
in Nature Reviews Bioengineering

Davies JA
(2022)
Synthetic Morphogenesis: introducing IEEE journal readers to programming living mammalian cells to make structures.
in Proceedings of the IEEE. Institute of Electrical and Electronics Engineers


Gidden Z
(2023)
Imaging Proteins Sensitive to Direct Fusions Using Transient Peptide-Peptide Interactions.
in Nano letters

Greenhough B
(2024)
Amphibious ethics and speculative immersions: laboratory aquariums as a site for developing a more inclusive animal geography.
in Scottish geographical journal

Description | 1. Engineering Genetic Devices for Control of Cell and Gene Therapies. Tissue specific promoters have been developed and tested in cell lines. Prof Pollard is in the process of patenting and spinning out a company. This technology is also featured in the new engineering biology mission hub which has been funded recently. We have developed a RNA aptazyme based switch controlled by a small molecule. A manuscript is in preparation. 2. Set up the Edinburgh human progenitor cell bank to produce cryopreserved iPSC-derived wild-type and isogenic CRISPR-engineered progenitors cells poised to differentiate into mature cell types. This is in process and has received additional BBSRC funding. 3. Delivery Mechanisms Engineering of HEK293 cells for enhanced AAV production was begun. This has resulted in Fujifilm Diosynth Biotechnologies funding a studentship to begin in October 24. |
Exploitation Route | Cell bank will be used by academics and industry scientists. The promoter work is the basis of a spin out. There is a great deal of company interest in engineering of producer cell lines for AAV for gene therapy applications. |
Sectors | Healthcare Manufacturing including Industrial Biotechology Pharmaceuticals and Medical Biotechnology |
Description | Establishment of a cryo-bank of lineage-committed neural progenitor cells produced from engineered human pluripotent stem cells |
Amount | £199,933 (GBP) |
Funding ID | NC/X002144/1 |
Organisation | National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) |
Sector | Public |
Country | United Kingdom |
Start | 02/2023 |
End | 12/2025 |