INDUCE: Development of siRNA-Mergo® therapeutics for lung indications.

INDUCE旨在开发和验证Sixfold的RNA治疗递送系统Mergo？，用于将（同时开发的）短干扰RNA（siRNA）基因沉默货物递送至特定组织类型（未公开）。INDUCE汇集了多学科、高专业知识的合作伙伴，并有成功完成项目的记录，从而实现了快速的科学进步和商业进步。与小分子和抗体相比，siRNA可以作用于几乎不受限制的选择，否则“不可药物化”的治疗靶点，具有高效力和特异性，具有治疗一系列疾病适应症的潜力。2018-2019年Alnylam的siRNA治疗肝病的开创性监管批准[2]证实了此类疗法的临床和商业机会。然而，目前的交付方法仍然不够理想由于围绕细胞特异性靶向、货物装载能力、高毒性和复杂/昂贵的制造的限制，因此需要新的制剂来增加可寻址的疾病适应症[3]。Mergo（r），Sixfold的专有递送系统，通过其基于中央RNA纳米支架的模块化设计解决了这些挑战，该支架可以用治疗剂/靶向分子进行功能化，以识别感兴趣的特定细胞上的生物标志物，显着减少治疗剂在其他细胞和组织中的毒副作用。在通过体外/体内试验结果证明了有前景的技术成熟度之后，需要对特定组织类型的作用机制进行额外的验证。INDUCE将开发一种针对特定肝外组织的内部治疗药物，并利用Mergo（r）的多功能性，通过特定组织靶向改善给药。反过来，INDUCE将产生内部资产，同时加快候选开发，并作为临床前示范应用Mergo（r）针对其他临床适应症。Mergo（r）通过提高安全性、有效性和降低商品成本（特别是与病毒技术相比），在蓬勃发展的siRNA治疗和相关递送市场中具有巨大的价值捕获潜力。Pharmidex在先进的临床前药物开发方面的独特专业知识将能够生成临床前数据包，通过生成许可协议实现快速商业化和临床进展。Sixfold全面的知识产权组合和许可策略涉及更广泛的生物制药供应链，为更广泛的英国生命科学行业带来多种利益。[1] Lam J.K.W等人Mol\_Ther\_Nucleic\_Acids_\_2015\_4（9）：e252\. [2]Debacker A.J等人摩尔\_治疗_ 2020\_28（8）：1759-1771.\ [3\]Payne\_D\__Nature_\_574\_S1\_2019\.

INDUCE aims to develop and validate Sixfold's RNA therapeutics delivery system, Mergo?, for delivery of (simultaneously developed) short-interfering RNA (siRNA) gene silencing cargo to a specific tissue type (undisclosed). INDUCE brings together multidisciplinary, high-expertise partners with a track record of successful project completion, allowing for both fast scientific progress and commercial advancement.In comparison to small molecules and antibodies, siRNAs can act on a virtually unrestricted choice of otherwise 'undruggable' therapeutic targets, with high potency and specificity, with the potential to treat a range of disease indications \[1\]. Pioneering regulatory approvals of Alnylam's siRNA therapeutics for liver disorders in 2018-2019 \[2\] substantiated clinical and commercial opportunities for such therapies. However, current delivery approaches remain suboptimal (e.g. GalNAc-conjugates, lipid nanoparticles, viral vectors) due to limitations surrounding cell-specific targeting, cargo-loading capacity, high toxicity and complex/expensive manufacturing, highlighting the need for novel formulations to increase addressable disease indications \[3\].Mergo(r), Sixfold's proprietary delivery system, addresses these challenges through its modular design based around a central RNA nanoscaffold, which can be functionalized with therapeutics/targeting molecules to recognise biomarkers on specific cells of interest, significantly reducing toxic side-effects from the therapeutic in other cells and tissues. Following demonstration of promising technological maturity through _in vitro/in vivo_ results, additional validation of mechanism-of-action for specific tissue types is needed.INDUCE will develop an in-house therapeutic targeted towards a specific extrahepatic tissue, and exploit the versatility of Mergo(r) to improve delivery via specific tissue-targeting. In turn, INDUCE will generate in-house asset(s) whilst speeding candidate development, and act as a preclinical demonstrator for the application of Mergo(r) to target other clinical indications. Mergo(r) holds significant value-capturing potential in the thriving siRNA therapeutics and associated delivery markets, through improved safety, efficacy, and reduced cost-of-goods (particularly compared to viral technologies).Pharmidex's unique expertise in advanced preclinical drug development will enable the generation of a preclinical data-pack for rapid commercialization and clinical advancements via generation of licensing deals. Sixfold's comprehensive IP portfolio and licensing strategy engages the broader biopharmaceutical supply chain, generating diverse benefits to the wider UK life sciences sector.\[1\]Lam\_J.K.W\_et\_al.\__Mol\_Ther\_Nucleic\_Acids_\_2015\_4(9):e252\. \[2\]Debacker\_A.J\_et\_al.\__Mol\_Ther._\_2020\_28(8):1759-1771.\[3\]Payne\_D\__Nature_\_574\_S1\_2019\.