RAPOD: Rapid Assembly of Programmable Oligonucleotide Delivery systems for increased gene therapeutic load

RAPOD aims to expand the drug delivery capabilities of Sixfold's Programmable Oligonucleotide Delivery System (PODS) for delivery of short-interfering RNA (siRNA) gene silencing cargo to specific cancer cells by increasing therapeutic loading capacity. By taking advantage of the interdisciplinary and complementary expertise of the partner/subcontractor --Sixfold and SEDA-- the project allows for rapid scientific and commercial progress directed at early R&D collaboration and licensing with identified pharmaceutical companies.

Compared to small molecule and antibody-based drugs, siRNAs can act on virtually unrestricted choice of --otherwise "undruggable"-- therapeutic targets, with high specificity and potency; while their easy manufacturing allows for rapid lead optimization **\[1\]**. As such, siRNAs have the potential to provide effective treatment options for diverse diseases including cancer.

The first regulatory approvals of Alnylam's siRNA therapies for liver disorders in 2018-19 **\[2-3\]** have validated the clinical and commercial opportunity for such therapies. However, the major limiting factor for their further success remains the lack of effective systems for systemic delivery of siRNAs to specific diseased cells **\[4\]**. Current approaches, primarily GalNAc-conjugates, lipid nanoparticles and viral vectors, are sub-optimal given their limited cell targeting specificity, cargo loading capacity, high toxicity, and complex/expensive manufacturing that limit the type of addressable disease indications.

PODS can address this drug delivery challenge given their modular design based on a central RNA nanoscaffold, which can be functionalised with therapeutics and targeting molecules that recognise biomarkers on cancer -but not healthy- cells. Although first-generation PODS demonstrated promising _in vitro_ and _in vivo_ results, with highly competitive safety and favourable cost profiles, the efficacy remains to be optimised.

RAPOD will aim to address three main objectives: 1) **increase the therapeutic loading capacity** of our PODS technology using three radically different technological approaches 2) in an **environmentally sustainable way** with a focus on reducing API, waste and reagent consumption and 3) devising a **strategic R&D strategy** to accelerate PODS preclinical transition to IND-enabling stage by maximising resources available. This will also enhance PODS versatility and speed of development, i.e. ability to readily adapt to delivery of multiple, different cargo types, creating an intelligent delivery system that goes beyond the limitations of current standards.

As such, PODS represent an attractive opportunity to capture a significant portion of the thriving gene therapy delivery market and could accelerate other Advanced Therapy Medicinal Products (ATMP), through improved safety, efficacy and reduced cost of goods, especially compared to viral technologies.

SEDA's unique expertise in delivering numerous products to approval, commercialisation and subsequent product maintenance allows for strategic development of PODS R&D strategy to pharmaceutical industry standards and requirements for rapid commercialization and clinical advancement via licensing.

Sixfold's broad IP portfolio and licensing strategy engage the entire biopharmaceutical supply chain, providing diverse benefits to the wider UK life sciences sector. \[1\]Lam\_J.K.W\_et\_al.\__Mol\_Ther\_Nucleic\_Acids_\_2015\_4(9):e252\. \[2\]Alnylam\_Press\_release\_10\_August\_2018\. \[3\]Alnylam\_Press\_release\_20\_November\_2019\.

\[4\]Payne\_D\__Nature_\_574\_S1\_2019\.