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

SUMMIT旨在开发和验证Sixfold的寡核苷酸递送系统Mergo？，用于将（同时开发的）短干扰RNA （siRNA）基因沉默货物递送到特定组织类型（未公开）。SUMMIT结合了多学科合作伙伴，在交付成功项目方面具有高度互补的专业知识和经验，并在早期研发合作方面取得了快速的科学和商业进展。与小分子和基于抗体的药物相比，sirna可以作用于几乎不受限制的治疗靶点，具有高特异性和效力；而他们的易于制造有利于快速优化\[1\]。因此，sirna具有有效治疗多种疾病的潜力。Alnylam的siRNA治疗肝脏疾病在2018-19年获得初步监管批准\[1-2\]验证了此类治疗的临床和商业机会。然而，进一步成功的主要限制因素仍然是缺乏将sirna系统递送到特定病变细胞的有效平台\[4\]。目前的方法，主要是galnac偶联物、脂质纳米颗粒和病毒载体，由于其有限的细胞靶向特异性、载货能力、高毒性和复杂/昂贵的制造，限制了可治疗的疾病适应症，因此不是最佳的。通过围绕中心RNA纳米支架的模块化设计来解决这一挑战。这可以与治疗和靶向分子功能化，仅识别感兴趣的特定细胞的生物标志物。这使得该平台仅针对患病细胞，从而大大减少了治疗在其他细胞和组织中的毒副作用。尽管之前的Mergo？数据显示了有希望的体外和体内结果，极具竞争力的安全性和有利的成本概况，需要进一步验证特定组织类型的作用机制。SUMMIT将开发一种针对特定肝外组织的内部siRNA，并利用Mergo？利用核酸化学改善组织靶向递送。这将产生一个内部资产，加速候选开发，并作为Mergo？递送不同的货物（mrna， CRISPR疗法）和针对其他适应症。因此，Mergo？这是一个极具吸引力的机会，可以占据蓬勃发展的基因治疗和递送市场的很大一部分，并可以通过提高安全性、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（ATMPs）的发展。Pharmidex和MDC在先进的临床前筛选和成像方面的独特专业知识使临床前数据包的生成能够通过许可快速商业化和临床进展。Sixfold广泛的知识产权组合和许可策略涉及整个生物制药供应链，为更广泛的英国生命科学领域提供多样化的利益。\[1\] 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\。

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\.