Polymer particle catalysed miRNA therapeutics for HGSOC precision medicines

High grade serous ovarian cancer (HGSOC) is the most common type of Ovarian Cancer (OC), accounting for up to 80% of OC deaths, with only modest advances in OC clinical management over the past 3 decades, highlighting a requirement for modern therapeutics.[1,2] Treating cancer through the transfer of genetic material is one class of precision, advanced therapeutics, being developed. Indeed, miRNAs, whose deregulation has been associated with tumorigenic effects, now serve as disease diagnostic/prognostic biomarkers and are being explored for advanced gene therapy development.[3] At the moment there are no clinically approved gene therapies for OC.

Due to the nature of RNAs and their pharmacokinetic limitations, they require a drug delivery system (DDS) for efficient cellular internalisation and targeted delivery. Using SMART polymer nanovectors (PEG-pTMC), we have developed a flexible DDS with favourable bioaccumulation in OC tumours, that demonstrate increased efficacy of chemotherapeutic drugs. Developed in line with the EMA GoNanoBioMat FRAMEWORK guidelines this platform is compatible with miRNA gene therapy payloads.[4]

Leveraging publically available databases that aggregate current knowledge on disease associated and therapeutic miRNA expression, our team have developed a new in silico methodology for discovery of novel therpeutic miRNAs for advanced gene therapy development in OC.[4] This informatics tool has been used to strategically select three distinct single miRNAs that have shown in vitro anti-cancer efficacy while also allowing potential for synergy when combined in a "cocktail". Subsequently we have successfully encapsulated these miRNA(s) into PEG-pTMC nanoparticles and demonstrated their increased anti-cancer efficacy in established laboratory assays at Swansea University.

Our over arching aim is to develop an innovative nanoparticle-encapsulated miRNA-based gene therapy for HGSOC, with the goal of transitioning from pre-clinical discoveries to a clinically applicable treatment. We have developed 4 clear aims for the project;

Formulate and optimise PEG-pTMC miRNA cocktails, identified through our in silico assays, for maximised anticancer efficacy in HGSOC.

Feedback wet lab in vitro data for iterative development of the in silico tools and optimised selection of miRNA cocktails.

Validate anti-cancer efficacy, dose range and treatment shedules to inform pharmaceutical formulation and in vivo testing using a small-cohort mouse orthotopic study

Demonstrate clinical translational readiness and PEG-pTMC(miRNA) utility through the collection of anti-cancer metrics from pre-clinical models, including assessments of tumour growth inhibition, survival benefits, and potential off-target effects cross-referenced to pertinent regulatory frameworks.

Applications and benefits; Benchmarking against the current DDS standard for miRNA, solid lipid NPs, which improve cellular penetration but still lead to systemic exposure, we will address both the clinical and product development needs in this gene therapy area. Upon project completion, the therapy will have comprehensive preclinical evidence to support clinical translation, underscoring the therapy's efficacy, safety, and readiness for the next stages of development.

Moreover the informatics and separate DDS platforms (Technology Readiness Level 5/6), will have demonstrable applications to other solid tumour contexts (STCs), positioning our approach as an exemplar for gene therapy development in non-lipid based precision medicine catalogues, filling a significant gap in the current landscape of precision medicine.[5] Under the experienced leadership of Professor Francis, our interdisciplianry team combines advanced skill sets to support therapeutic product development, ensuring intellectual property (IP) protection and future translation profiling, toward DPFS funding in 2025.