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Application of RNA nanotechnology for delivery of mRNA therapeutics

Periodic Reporting for period 1 - mRNA NanoDeli (Application of RNA nanotechnology for delivery of mRNA therapeutics)

Reporting period: 2020-02-10 to 2021-04-09

RNA therapeutics have huge potential to effectively treat a diverse range of diseases (including some that are otherwise “undruggable”) with high specificity and potency. However, the major limiting factor for their further success remains the lack of effective systems for systemic delivery of RNA therapeutics to specific diseased cells. Sixfold Bioscience is addressing this challenge through their modular RNA delivery system, MergoⓇ, which can be functionalised with therapeutics and targeting molecules that recognise biomarkers on specific cells of interest and not others. First-generation siRNA-MergoⓇ demonstrated promising in vitro and in vivo results, with highly competitive safety and favourable cost profiles. This project aimed to package mRNA and bioconjugate it with MergoⓇ, in order to diversify the therapeutic cargo possible to be delivered by MergoⓇ to cells.

The overall objectives of this project were:
Recruitment, integration and training of an Innovation Associate with the necessary expertise to complete the project to a high standard, and add knowledge value to our SME.
Generation of multiple MergoⓇ versions for further in-house in vitro and in vivo characterisation.
Development of bioconjugation and packaging methods for mRNA delivery.
Protection of IP generated during the grant through patent applications.

Conclusions of the action:
The Innovation Associate was recruited and completed his training (to the extent which was possible, given travel restrictions from the covid19 pandemic). Additional internal training was provided, covering Project Management and Prioritisation, Leadership, Grant Writing and Health and Safety.
All project objectives were fulfilled, however these were performed on shorter RNA strands and served as the groundwork for additional follow-on studies.
Additional work to synthesise, optimise and conjugate endosomal escape peptides (important to increase drug availability in the cell’s cytoplasm) was also completed.
IP has been filed to protect the bioconjugation strategies and peptides established and validated in this project.
Key scientific outputs:

Structure prediction software was used to check secondary structure of RNA and the assembly of RNA nanostructures.
Non-covalent conjugation of RNA by means of hybridization reaction was established.
Methods of covalent conjugation of two different RNAs by three orthogonal chemistries was optimized.
Synthesis of different endosomal escape peptides and covalent conjugation to RNA was successfully demonstrated. The RNA-peptide conjugates did not hinder the assembly of nanostructures.

Exploitation and dissemination:

Broad dissemination has occurred at a variety of conferences and partnership events. Several thorough FTO analyses have been performed and a patent application filed relating to work performed in this project. Customer feedback has been received from various companies (ranging from large pharma to SMEs). This project has set up the groundwork for additional grants, with a Knowledge Transfer Partnership and Pathfinder grant being obtained for work to follow-up on this project.
Progress beyond state-of-art:

Generation of RNA-RNA conjugations with potential for release under different physiological conditions
Use of peptide-based endosomal escape molecules in conjunction with RNA structures. This is not a field that has been well-explored to-date.

Potential impacts:

Development of preclinical knowledge with regards to our delivery platform, enabling increased expertise and scientific/commercial progress for our SME.
Socio-economic: Outputs from the project have to date generated 2 highly-skilled jobs. Further development will result in economic upturn and facilitate creation of additional highly-skilled jobs at Sixfold and in the broader supply-chain. Downstream impacts of the grant may accelerate Sixfold’s progression to clinical development, capture a portion of the thriving RNA therapy market, and accelerate existing Advanced Therapy Medicinal Products (ATMPs) through improved safety, efficacy and reduced cost of goods.
Wider societal: Long-term, MergoⓇ could enable siRNA and other ATMPs to be used for larger number of disorders given their versatility of targeting siRNAs to specific cells with high efficacy and safety. At the same time, MergoⓇ could make ATMP therapies more affordable, given that they are c.1/100th of viral cost, improving the quality-of-life for larger number of patients. MergoⓇ also has potential to reduce the regulatory burden associated with viral technologies. By working towards the improvement and development of the MergoⓇ platform, this project is contributing to these wider, eventual impacts.
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