Targeting the drivers of disease with gene therapy
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What is gene therapy?
Gene therapy is a relatively new type of treatment approach that has the potential to modify and even cure diseases by editing the genes responsible for causing illness.
Sometimes at birth, a whole gene, or part of one, is missing. Other times, over the course of a lifespan, genes that were once healthy can mutate and become defective. Depending on the exact problem, it is now possible to use gene therapy to treat a disease by directly repairing a gene in the genome or through delivering an additional copy of the missing gene to express a protein with therapeutic benefits.
Our strategies in gene therapy are two-fold; we leverage CRISPR gene editing techniques to repair broken genes and use adeno-associated viruses (AAV) to deliver therapeutic proteins, new copies of genes, or biologic therapeutics – with the hope of providing long-term treatment for rare or chronic diseases.
What is CRISPR?
CRISPR is a breakthrough approach to editing genetic material in living organisms. At its core, CRISPR acts as molecular scissors that can be used to precisely cut and modify a DNA sequence of interest. Accurate, programmable and adaptable, this technology has found widespread application across several areas of biological and biopharmaceutical research.
CRISPR systems contain two components: the molecular scissors (an enzyme, traditionally spCas9) and a guide RNA (gRNA) that ‘guides’ the enzyme to the part of the genome needing repair. In addition to using CRISPR for genetic therapies, we are exploring its potential to help create cell-based therapies.
CRISPR is the most exciting life science discovery in the last decade. It allows us to identify and validate new targets for medicine discovery, and as a medicine allows us to edit genes to enable the treatment and hopefully cure of many genetic diseases.
Building our CRISPR tool-box
Over the last several years, we have successfully begun to build our CRISPR toolbox – a range of innovative tools such as CRISPR GUARD,1 CRISPR VIVO2 and DISCOVER-Seq.3 These tools help establish how CRISPR can be used as a precise and effective gene therapy in the clinic.
More recently, our CRISPR toolbox has grown with the addition of three new tools and technologies that have the potential to further improve the efficacy and precision of CRISPR-based medicines: Prime Editor nuclease (PEn) technology, 2iHDR, and SpOT-ON (PsCas9).
Prime Editor nuclease (PEn)
In 2022, our scientists developed Prime Editor nuclease (PEn) technology that can efficiently introduce precise genetic insertions through multiple double-stranded DNA repair pathways. In addition to enhancing the efficiency of generating insertions, editing with PEn leads to a reduction of unwanted large deletions, reducing the frequency of off-target effects. This new gene editing approach drives efficient genetic insertions, with a reduced risk of unwanted edits, advancing the potential for therapeutic use.4
2iHDR
Our scientists have developed a strategy called 2iHDR, which aims to improve the success of gene editing by suppressing two pathways of gene repair – called non-homologous end joining (NHEJ) and microhomology-mediated end joining (MMEJ) – that can lead to imprecise gene editing. Using a combination of two inhibitors, we can dramatically improve the efficiency of CRISPR gene editing while reducing the risk of off-target effects. This strategy holds great promise for both cell therapies and gene therapy.5
SpOT-ON
We are constantly striving to improve our CRISPR technology for the treatment and potential cure of genetic conditions. To this end, our scientists have developed an enhanced CRISPR system that utilises an engineered enzyme, SpOT-ON. This enzyme cuts DNA with similar efficiency to the traditional enzyme, SpCas9, with enhanced specificity for the target site in the genome. In a proof-of-concept pre-clinical study of hypercholesterolemia, SpOT-ON successfully targeted the PCSK9 gene, resulting in reduced plasma levels of the associated PCSK9 protein. This recent research emphasises the increasing safety features being built into CRISPR, making it more amenable to therapeutic applications and applying these in vivo for the first time.6
By altering DNA repair pathways with 2iHDR and harnessing a highly specific Cas9 variant with SpOT-ON, we can achieve targeted genetic modifications with enhanced precision and efficacy, driving further advancements in the field.
What are adeno-associated viruses (AAVs)?
Adeno-associated viruses (AAVs) are naturally occurring viruses that are able to enter many different cell types in the body. Importantly, AAVs do not act like a typical virus as they do not replicate and do not cause disease. All viruses, including AAVs, are highly specialised to introduce genetic material into cells, making them ideal for their use as gene therapy. Therefore, we can modify AAVs with the ambition to provide long-term benefits to people living with rare and chronic diseases.
There are two key ways we modify AAVs:
The DNA within an AAV can be engineered to replace its viral genetic material with DNA sequences that encode healthy human genes or other molecules. These other molecules could be a therapeutic protein that is not normally expressed in the body, such as an antibody medicine. Alternatively, synthetic forms of healthy genes can be delivered to compensate for the presence of a defective copy present in a genetic disease.
AAVs can deliver CRISPR gene editing components that then work to correct a person’s own genes.
We can guide AAVs to deliver genes to specific target cells by modifying the outer surface – called the capsid – to improve its delivery properties. By increasing the selectivity for the intended target cells and avoiding other cells, we can optimise both safety and efficacy.
Across our therapeutic programmes we are progressing novel AAVs targeting to the liver, as well as building our capabilities internally and with collaborators to use AAVs to treat disease in other organs such as heart, lung, muscle and brain.
Working together to advance gene therapy
Join us
We welcome committed, talented scientists to join us as we develop new medicines that have the potential to deliver healthcare experiences and outcomes that enable people to enjoy fulfilling lives. We are well-positioned to develop cutting-edge gene therapies to address a range of genetic diseases associated with significant unmet need. By giving our people the resources and support to push the boundaries of science, we are going beyond the ordinary to help improve the lives of patients worldwide.
We are proud of our progress, prepared for the challenges that lie ahead, and confident that gene therapies will help improve the outlook for patients with some of today’s most serious and life limiting diseases.
Collaborating for success
We partner with academia, governments, peer companies, biotechs, scientific organisations and patient groups to access the best science. Our commitment to creating strong, long-term partnerships helps enable us to speed the delivery of innovative and life-changing medicines to the people who need them most.
References
1. Coelho, M.A., De Braekeleer, E., Firth, M. et al. CRISPR GUARD protects off-target sites from Cas9 nuclease activity using short guide RNAs. Nat Commun 11, 4132 (2020). http://doi.org/10.1038/s41467-020-17952-5.
2. Akcakaya, Pinar, Maggie L. Bobbin, Jimmy A. Guo, Jose Malagon-Lopez, Kendell Clement, Sara P. Garcia, Mick D. Fellows, et al. 2018. “In Vivo CRISPR Editing with No Detectable Genome-Wide off-Target Mutations.” Nature 561 (7723): 416–19.
3. Wienert, Beeke, Stacia K. Wyman, Christopher D. Richardson, Charles D. Yeh, Pinar Akcakaya, Michelle J. Porritt, Michaela Morlock, et al. 2019. “Unbiased Detection of CRISPR off-Targets in Vivo Using DISCOVER-Seq.” Science 364 (6437): 286–89.
4. Peterka M, Akrap N, Li S,, Wimberger S, et al. Harnessing DSB repair to promote efficient homology-dependent and -independent prime editing. Nature Communications 2022; March 24th
5. Wimberger S, Akrap N, Firth M, et al. Simultaneous inhibition of DNA-PK and Polϴ improves integration efficiency and precision of genome editing. Nat Commun. 2023;14(1):4761. Published 2023 Aug 14. doi:10.1038/s41467-023-40344-4
6. Bestas, B., Wimberger, S., Degtev, D. et al. A Type II-B Cas9 nuclease with minimized off-targets and reduced chromosomal translocations in vivo. Nat Commun 14, 5474 (2023). http://doi.org/10.1038/s41467-023-41240-7
Veeva ID: Z4-54364
Date of preparation: September 2023