The role of RNA in the response to cellular stress

Lead Research Organisation: University of Cambridge
Department Name: UNLISTED

Abstract

Recently, a new gene delivery system has been developed, to specifically provide diseased cells with a particular protein to correct cell function. This method using messenger RNA molecules as a delivery vehicle. By changing the RNA molecules different proteins can be encoded on these RNA molecules and different human disease can be treated. However, our lack of understanding of these molecules has resulted in safety issue, which need to be resolved before they can be used to treat a large range of human diseases. Our laboratory has been investigating how RNAs are regulated and we have discovered that two particular RNA binding proteins associate with translationally repressed mRNAs. Using methods developed in our laboratory we can now identify RNA repression mechanisms operating in different tissues and thus tailor these RNA molecules for specific delivery to different tissue types, reducing toxic side effects. We will determine the applicability of this approach to identify the repertoire of repressive mechanisms operating within a cell, in order to engineer therapeutic-mRNAs for restricted on-target expression in particular tissues/cell types and disease states. This will facilitate the development of the next generation of mRNA-based therapeutics which will be specifically designed to minimise potential off-target adverse effects.

Technical Summary

Modulation of gene expression via the delivery of nucleotide-based therapeutics has great potential for the treatment of a large range of human diseases. Major challenges still exist in the development of these next generation drugs due to limitations in our knowledge of RNA biology and delivery methodologies. In recent years, most attention with regard to gene-based therapies has focused on DNA and viral systems; however, their use is limited due to low efficacy, genetic transfer risk and poor control over dosage. More recently, the incorporation of modified nucleotides has meant that in vitro transcribed mRNA molecules have been successfully used for the delivery of genetic information without risk of genomic integration. These mRNAs are produced using modified nucleotides that mimic endogenous mRNA molecules and thus avoid activating the innate immune response. The relatively short half-life of RNA compared to DNA also allows precise control over final protein dosage.

In terms of the safety of these synthetic molecules, there are major challenges that need to be addressed before the full potential of mRNA-based therapeutics can be realised. These issues mainly revolve around our current lack of understanding of how these RNA molecules are controlled. Our laboratory has been investigating how mRNAs are regulated and we have discovered that two RNA DEAD-box helicases associate with translationally repressed mRNAs. The association of mRNAs with these DEAD-box proteins has allowed us to identify multiple repressive mechanisms imposed by the major cellular mRNA silencing apparatus - the Ccr4-NOT complex. Until now, identification of mRNAs controlled by the variety of mechanisms that the Ccr4-NOT complex plays a role in would have been extremely labour-intensive, requiring a number of different techniques and would not have given sufficient resolution for mRNAs with low cellular abundance. In contrast, our methodology is a relatively straightforward approach, which allows for simultaneous identification of mRNAs repressed by the Ccr4-NOT1 complex in a given cell type or tissue. These repressive characteristics can be used to build a signature of the regulatory mechanisms operating within a particular cell type. We will determine the applicability of this approach to identify the repertoire of repressive mechanisms operating within a cell, in order to engineer therapeutic mRNAs for restricted on-target expression in particular tissues/cell types and disease states. This will facilitate the development of the next generation of mRNA-based therapeutics which will be specifically designed to minimise potential off-target adverse effects.

Publications

10 25 50

Related Projects

Project Reference Relationship Related To Start End Award Value
MC_UU_00025/1 31/03/2018 30/07/2020 £1,680,000
MC_UU_00025/2 Transfer MC_UU_00025/1 31/03/2018 29/09/2020 £3,488,000
MC_UU_00025/3 Transfer MC_UU_00025/2 31/03/2018 31/03/2024 £2,873,000
MC_UU_00025/4 Transfer MC_UU_00025/3 31/03/2018 31/03/2024 £3,108,000
MC_UU_00025/5 Transfer MC_UU_00025/4 31/03/2018 31/03/2024 £2,200,000
MC_UU_00025/6 Transfer MC_UU_00025/5 31/03/2018 30/05/2019 £76,000
MC_UU_00025/7 Transfer MC_UU_00025/6 31/03/2018 31/03/2024 £2,547,000
MC_UU_00025/8 Transfer MC_UU_00025/7 30/09/2019 31/03/2024 £2,438,000
MC_UU_00025/9 Transfer MC_UU_00025/8 31/08/2019 31/03/2024 £1,721,000
 
Description CRT translational control allience
Amount £23,000,000 (GBP)
Organisation Cancer Research Technology (CRT) 
Sector Private
Country United Kingdom
Start 05/2018 
End 06/2021
 
Description BMS collaboration using tool compounds to target eIF2B 
Organisation Bristol-Myers Squibb
Country United States 
Sector Private 
PI Contribution We have initiated a collocation with BMS to evaluate targeting eIF2B activity in the tour environment
Collaborator Contribution Providing tool compounds and funding.
Impact Funding from BMS (£218,000)
Start Year 2021
 
Description CTR Collaboration 
Organisation Cancer Research Technology (CRT)
Country United Kingdom 
Sector Private 
PI Contribution Our Lab is actively engaged with CRT within a new alliance to target translational control.
Collaborator Contribution Drug discovery efforts
Impact This has just begun and no outputs so far
Start Year 2017
 
Description Cancer Research Technology mRNA Translation 
Organisation Cancer Research Technology (CRT)
Country United Kingdom 
Sector Private 
PI Contribution This is a drug discovery pipeline around translational control. I am a led PI within this consortium directly contributing to multiple projects.
Collaborator Contribution CRT are conducting the drug discovery activities within this alliance.
Impact I outputs currently that I can comment upon.
Start Year 2017
 
Description Bart's RNA and cancer meeting June 2023 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited speaker. I give a talk about our research and people were very positive and said it had changed the way they were thinking about translational control
Year(s) Of Engagement Activity 2023
 
Description Belfast talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact I give a talk about our research and people were very positive and said it had changed the way they were thinking about translational control
Year(s) Of Engagement Activity 2023
 
Description Feb congress Tours France 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I give a talk about our research and people were very positive and said it had changed the way they were thinking about translational control
Year(s) Of Engagement Activity 2023
URL https://2023.febscongress.org/program
 
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Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited speaker at Univ of Geneva
Year(s) Of Engagement Activity 2022
 
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Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Invited speaker at Sussex University. Gave a talk on translation control and changed the way people think about this level of gene expression control
Year(s) Of Engagement Activity 2019
 
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Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited speaker in Wurzburg Germany. I gave a talk to science in the area and got great feedback and changed the way they think about translational control
Year(s) Of Engagement Activity 2020
 
Description Invited speaker CSHL 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited speaker at CSHL translational control meeting
Year(s) Of Engagement Activity 2022
 
Description Invited speaker Dundee 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Invited speaker at the University of Dundee. Gave a talk on translational control and changed the way they think about this level of gene expression control.
Year(s) Of Engagement Activity 2019
 
Description Invited speaker Galway 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
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Year(s) Of Engagement Activity 2019
 
Description Invited speaker european society of toxicologist 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact To talk to the European Society of toxicologist.
Year(s) Of Engagement Activity 2021
 
Description Organiser for Beatson International Science Meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact I was one of the organisers for this meeting which brought in people from all over the world to talk about their recent results. One of the sessions was focused on translational control which I run and talked in.
Year(s) Of Engagement Activity 2019
 
Description Royal pathology Society invited speaker 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
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Year(s) Of Engagement Activity 2022
 
Description Translation UK 2020 organiser 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
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Year(s) Of Engagement Activity 2019
 
Description Translation UK Keynote address Cambridge July 2023 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I was asked to give the keynote address at the translation UK. I give a talk about our research and people were very positive and said it had changed the way they were thinking about translational control
Year(s) Of Engagement Activity 2023
 
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Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited speaker UCSF
Year(s) Of Engagement Activity 2022