New oligonucleotide analogues for therapeutic applications
Lead Research Organisation:
University of Oxford
Department Name: Oxford Chemistry
Abstract
Therapeutic oligonucleotides (Th-ONs) are rapidly becoming highly important agents for hard to treat diseases. They target mRNA thereby changing protein expression. With four Th-ONs now in the clinic; Eteplirsen, Nusinersen, Mipomersen and Patisiran, the market is worth billions of dollars. Moreover, with ~150 Th-ONs currently in clinical trials for cancer and other diseases the field is set for rapid commercial growth. Chemical modifications are essential to make ThONs bind tightly to their RNA targets, to resist enzymatic degradation in vivo and improve uptake into cells. Further improvements in these areas are urgently needed to improve efficacy, reduce toxicity and lower costs. In a BBSRC-funded project we have designed an entirely new class of ThONs (LNA-triazole and LNA-amide) to address these problems and we now plan to evaluate them in biological assays. When this data has been obtained we will file additional patents and set up a new company to exploit the technology.
People |
ORCID iD |
| Tom Brown (Principal Investigator) |
Publications
Baker Y
(2020)
Searching for the ideal triazole: Investigating the 1,5-triazole as a charge neutral DNA backbone mimic
in Tetrahedron
Epple S
(2020)
Consecutive 5'- and 3'-amide linkages stabilise antisense oligonucleotides and elicit an efficient RNase H response.
in Chemical communications (Cambridge, England)
De Fazio AF
(2021)
Chemically modified nucleic acids and DNA intercalators as tools for nanoparticle assembly.
in Chemical Society reviews
Epple S
(2021)
A New 1,5-Disubstituted Triazole DNA Backbone Mimic with Enhanced Polymerase Compatibility.
in Journal of the American Chemical Society
Jin C
(2022)
Engineering Enzyme-Cleavable Oligonucleotides by Automated Solid-Phase Incorporation of Cathepsin B Sensitive Dipeptide Linkers
in Angewandte Chemie
Dysko A
(2022)
Covalently attached intercalators restore duplex stability and splice-switching activity to triazole-modified oligonucleotides.
in RSC chemical biology
Jin C
(2022)
Engineering Enzyme-Cleavable Oligonucleotides by Automated Solid-Phase Incorporation of Cathepsin B Sensitive Dipeptide Linkers.
in Angewandte Chemie (International ed. in English)
Baker YR
(2022)
An LNA-amide modification that enhances the cell uptake and activity of phosphorothioate exon-skipping oligonucleotides.
in Nature communications
McGorman B
(2022)
Enzymatic Synthesis of Chemical Nuclease Triplex-Forming Oligonucleotides with Gene-Silencing Applications.
in Nucleic acids research
| Description | We have developed oligonucleotide analogues with artificial backbones that can hybridise to complementary RNA sequences and are stable in cell culture. They have potential for use in therapeutic applications. |
| Exploitation Route | First we have to carry out more work in cell culture. If the findings are still positive biologists can evaluate the oligonucleotide analogues in animal models and eventually if this is promising they could be considered as analogues to treat human diseases. We are endeavoring to disseminate our results by publication and at conferences so that the wider biological and biomedical community are aware of them. This is in addition to our own existing collaborations. |
| Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |
| Description | Award from the CRUK Oxford Centre Development Fund |
| Amount | £12,500 (GBP) |
| Funding ID | CRUKDF 0920 - YB TB |
| Organisation | Cancer Research UK |
| Department | Cancer Research UK (CRUK) Oxford Centre |
| Sector | Private |
| Country | United Kingdom |
| Start | 07/2020 |
| Title | A new platform technology for antisense therpaeutics |
| Description | We have developed novel chemical methods to constructs heavily modified oligonucleotides that show promising biological properties. The technology is versatile, and we have shown that it can be applied to any sequence of nucleobases Initial data suggests that the technology can improve the cellular uptake of antisense oligonucleotides and reduce their toxicity The technology has the potential to be automated, increasing its potenial appeal to industrial partners and also improving the future adoption of the technology. |
| Type Of Material | Technology assay or reagent |
| Year Produced | 2021 |
| Provided To Others? | No |
| Impact | This technology has not yet been published or made available to other but will be once the relevant IP is protected |
| Description | Exon skipping collaboration |
| Organisation | University of Oxford |
| Department | Department of Physiology, Anatomy and Genetics |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Antisense assays for the project have been carried out the the Wood laboratory. Ysobel Baker (PDRA) has been performing cell culture and exon-skipping assays with guidance from the Wood Group |
| Collaborator Contribution | The Wood group provided consumables, cell lines, and laboratory space for the project, along with critical input into experimental design. |
| Impact | tbc |
| Start Year | 2019 |