TransNAT: Transforming delivery, safety and efficacy of nucleic acid therapeutics: from intracellular uptake to targeting brain and muscle.

核酸疗法是针对疾病根源的遗传药物，有可能改变医疗保健，并为许多未满足需求的领域提供改变生活的解决方案。神经、神经肌肉和心血管疾病尤其会破坏生命，给全球人口造成非常严重的经济和社会负担。尽管在过去十年中，随着多种药物在美国和欧洲被批准使用，nat已经开始成为现实，但许多挑战仍然存在，特别是对于肝脏以外的疾病，以及那些不易通过当地药物输送解决方案解决的疾病。此外，最近的临床试验结果表明，在开发给药解决方案的同时，应考虑安全性问题。简单地说，NAT递送的挑战是在没有明显安全信号的情况下，以足够的活性浓度，将药物有效地穿过细胞膜，递送到适当的亚细胞区室，即所谓的“有效”递送。因此，我们提出的解决方案是了解高效交付NAT的需求，并利用此知识库开发NAT偶联物-我们的技术解决方案。基于我们的学术和行业科学家联盟的丰富经验，我们将采用两种独立的方法来研究NAT缀合物，其中递送剂直接化学附着在NAT药物上。首先，我们将研究和优化脂质偶联物，其中一系列脂质实体通过一系列具有不同性质的化学连接物直接连接到NAT。在第一种情况下，NAT是针对无治疗相关性的共同基因。我们的第二种高潜力方法将是研究和优化抗体偶联物，其中结合到特定细胞膜配体的抗体（或抗体片段或抗体衍生肽）通过化学连接剂再次化学偶联。在每种情况下，我们都将从已经通过联盟成员的工作出现的缀合物开始，在抗体的情况下，我们将有两种独立的方法来识别和优先考虑抗体靶向的新配体，再次建立在联盟中已有的工作基础上。我们广泛的化学能力将产生用于研究的共轭材料和控制化合物，第一步将是在细胞中进行广泛的体外研究，以开发基于生产细胞摄取机制的知识，使我们能够根据细胞摄取/功效/安全性选择先导化合物进行更详细的研究，并根据新知识，技术诀窍和生成的数据迭代化合物结构和化学。进一步的研究将包括基于人类细胞和干细胞的离体人体模型系统的转化研究，以及基于人类三维器官样系统的转化研究，这些系统提供细胞多样性和更接近模拟人类组织的结构安排。在已建立的和新的啮齿动物模型中进行进一步的转化研究，将允许在单细胞分辨率下详细研究大脑、心脏和肌肉的细胞和组织，从而使细胞/组织的生物分布与有效性和安全性措施相关联。最后，将在亨廷顿氏病和肌肉萎缩症相关的疾病模型中研究少量先导NAT化合物。我们将通过分析和整合整个项目，并实施机器学习方法来利用我们的数据，最大限度地发挥数据的潜力。我们将提供有关生产吸收和具有高治疗潜力的新型脂质/抗体NATs的基础知识、技术诀窍、数据和知识产权，供进一步研究。我们还将通过报告/会议/会议与更广泛的NAT社区接触，并开发培训机会，所有这些都与NATA中心密切合作。

Nucleic acid therapies (NATs) are genetic medicines that address the root cause of disease and have the potential to transform healthcare and provide life changing solutions for numerous areas of unmet need. Neurological, neuromuscular and cardiovascular diseases in particular devastate lives and create a very significant economic and social burden across the entire global population. While NATs have begun to be a reality over the last decade with multiple medicines being approved for use in the US and Europe many challenges remain particularly for diseases outside the liver and for those not easily addressed by local drug delivery solutions. Moreover, recent clinical trial results indicate that safety considerations should be addressed in parallel with the development of delivery solutions. The challenge of NAT delivery put simply is to deliver the drug effectively across the cell membrane into the appropriate sub-cellular compartment at a sufficient concentration required for activity in the absence of significant safety signals - so called 'productive' delivery. Our proposed solution is therefore to understand the requirements for productive delivery of NATs and to exploit this knowledge base for the development of NAT conjugates - our technical solution. Building on extensive experience of our consortium of academic and industry scientists, we will take two independent approaches to NAT conjugates, where delivery agents are directly chemically attached to the NAT drug. First, we will study and optimise lipid conjugates, where a range of lipid entities are directly attached to the NAT via a series of chemical linkers with different properties. In the first instance the NAT is one targeting a common gene of no therapeutic relevance. Our second approach of high potential will be to study and optimise antibody conjugates, where an antibody (or antibody fragment or antibody derived peptide) that binds to a specific cell membrane ligand is conjugated chemically again via chemical linkers. In each case, we will have starting points with conjugates that have already emerged through the work of consortium members, and in the case of antibodies we will have two independent approaches for identifying and prioritising new ligands for antibody targeting, again building on pre-existing work in the consortium. Our extensive chemistry capabilities will generate conjugate materials and control compounds for study and first step of which will be extensive in vitro studies in cells to develop mechanism-based knowledge on productive cell uptake allowing us to select lead compounds for more detailed study based on cell uptake/efficacy/safety properties, and to iterate compound structure and chemistry based on new knowledge, know-how and data generated. Further study will comprise translational studies in ex vivo human model systems based on human cells and stem cells and also based on human three dimensional organ like systems that provide cell diversity and architectural arrangements more closely mimicking human tissues. Further translational studies in established and new rodent models will allow delivery to cells and tissues of brain, heart and muscle to be studied in detail at singe cell resolution permitting cell/tissue biodistribution to be correlated with efficacy and safety measures. Finally, a small number of lead NAT compounds will be studied in disease models related to Huntington's disease and muscular dystrophy. We will maximise the potential of data by analysing and integrating across the programme and implementing machine-learning approaches to exploit our data. We will deliver fundamental knowledge, know-how, data and IP on productive uptake and novel lipid/antibody NATs of high therapeutic potential for further study. We will also engage the broader NAT community via reports/meetings/conferences and develop training opportunities, all of the above working in close collaboration with the NATA Hub.