SUMMIT: SiRNAs Utilising Mergo? delivery for post-Myocardial Infarction Treatment

Summit的目标是开发和验证Six的寡核苷酸传递系统Mergo？，用于将(同时开发的)短干扰RNA(SiRNA)基因沉默货物传递到特定的组织类型(未披露)。Summit结合了在交付成功项目方面具有高度互补性的专业知识和经验的多学科合作伙伴，以及朝向早期研发合作的快速科学和商业进展。与小分子和基于抗体的药物相比，siRNAs可以对治疗目标的几乎不受限制的选择起作用--否则是“不可用药的”，具有高度的特异性和有效性；而它们的容易制造促进了快速的铅优化[1]。因此，siRNAs具有有效治疗多种疾病的潜力。Alnylam的siRNA疗法在2018-19年首次获得监管部门的批准，用于治疗肝病[1-2]，证实了此类疗法的临床和商业机会。然而，进一步成功的主要限制因素仍然是缺乏系统地将siRNA输送到特定疾病细胞的有效平台[4]。目前的方法，主要是GalNAc结合物、脂质纳米粒和病毒载体，由于其有限的细胞靶向特异性、货物装载能力、高毒性和复杂/昂贵的制造限制了可寻址的疾病适应症，因此是次优的。通过基于中心RNA纳米支架的模块化设计解决了这一挑战。这可以通过治疗和靶向分子来实现，这些分子只识别特定感兴趣细胞上的生物标记物。这使得该平台只针对患病的细胞，从而显著减少了该疗法在其他细胞和组织中的毒副作用。尽管之前的Mergo？数据显示了良好的体外和体内结果，极具竞争力的安全性和有利的成本概况，需要对特定组织类型的作用机制进行进一步验证。SUMMIT将开发针对特定肝外组织的内部siRNA，并利用Mergo？利用核酸化学通过组织靶向来改善递送。这将产生内部资产(S)，加快候选开发，并作为Mergo应用程序的演示？以提供不同的货物(mRNAs、CRISPR疗法)并针对其他适应症。因此，莫戈？代表着在蓬勃发展的基因治疗和交付市场中占据相当大份额的诱人机会，并可能通过提高安全性、有效性和降低商品成本，特别是与病毒技术相比，加速其他先进治疗药物产品(ATMP)的开发。Pharmidex和MDC在先进的临床前筛查和成像方面的独特专业知识使临床前数据包能够通过许可生成快速商业化和临床进步的数据包。Sixx的广泛知识产权组合和许可战略涉及整个生物制药供应链，为更广泛的英国生命科学sector.\[1\]Lam\_J.K.W\_et\_al.\__Mol\_Ther\_Nucleic\_Acids_\_2015\_4(9)：e252\.提供各种好处\[2\]Alnylam\_Press\_release\_10\_August\_2018\.\[3\]Payne\_D\__Nature_\_574\_S1\_2019\.

SUMMIT aims to develop and validate Sixfold's oligonucleotide delivery system, Mergo?, for delivery of (simultaneously developed) short-interfering RNA (siRNA) gene silencing cargo to a specific tissue type (undisclosed). SUMMIT combines multidisciplinary partners with highly complementary expertise and experience in delivering successful projects, with rapid scientific and commercial progress towards early-stage R&D collaboration.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 facilitates rapid lead optimization\[1\]. Therefore, siRNAs have the potential to effectively treat numerous diseases. Initial regulatory approvals of Alnylam's siRNA therapies for liver disorders in 2018-19 \[1-2\] validated clinical and commercial opportunity for such therapies. However, the major limiting factor for further success remains the lack of effective platforms 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 addressable disease indications.Mergo? addresses this challenge through its modular design based around a central RNA nanoscaffold. This can be functionalised with therapeutics and targeting molecules that recognise biomarkers on specific cells of interest only. This allows the platform to target only diseased cells, thus significantly reducing toxic side-effects from the therapy in other cells and tissues. Although previous Mergo? data demonstrated promising _in vitro_ and _in vivo_ results, highly competitive safety and favourable cost profiles, further validation of mechanism-of-action is required for specific tissue types.SUMMIT will develop an in-house siRNA targeted towards a specific extrahepatic tissue, and exploit the versatility of Mergo? using nucleic acid chemistry to improve delivery via tissue targeting. This will generate an in-house asset(s), speed candidate development, and act as a demonstrator for application of Mergo? to deliver diverse cargo (mRNAs, CRISPR therapeutics) and to target other indications. Consequently, Mergo? represents an attractive opportunity to capture a significant portion of the thriving gene therapy and delivery markets and could accelerate other Advanced Therapy Medicinal Products (ATMPs), through improved safety, efficacy and reduced cost of goods, especially compared to viral technologies.Pharmidex and MDC's unique expertise in advanced preclinical screening and imaging enables generation of preclinical data-pack for rapid commercialization and clinical advancement via licensing.Sixfold's broad IP portfolio and licensing strategy engages 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\.\[3\]Payne\_D\__Nature_\_574\_S1\_2019\.