Oligonucleotides with Modified Backbones as a Strategy to Improve the Delivery of Biomolecules

具有修饰主链的寡核苷酸作为改善生物分子递送的策略

• 批准号: RGPIN-2021-03883
• 负责人: Bujold, Katherine
• 金额: $ 1.75万
• 依托单位: McMaster University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=742769
• 关键词: Oligonucleotides; Modified; Backbones; Strategy; Improve

Nucleic acid therapeutics and biologics (drugs derived from living organisms) hold transformative potential for the treatment of genetic diseases, where their unmatched selectivity is expected to result in effective therapies for previously unattainable disease targets. However, their translation to the clinic is slowed down by their high molecular weight and hydrophilicity, which prevent them from easily crossing cell membranes to access intracellular targets. As a result, effective and biocompatible delivery strategies are highly sought after to accelerate the development of these drug categories. DNA, as a material, is uniquely placed to address these challenges due to its biocompatibility, automated synthesis, precise base-pairing alphabet, and complete addressability. These properties have given rise to the synthesis of 3D architectures with unmatched precision that show great promise for drug delivery since they can enter cells as opposed to most oligonucleotides. This suggests their 3D organization plays a big role in dictating their biological properties. However, further work is required to ensure nucleic acid nanostructures can access intracellular compartments reliably and unleash their therapeutic potential. Replacing the phosphodiester backbone of DNA is a promising strategy that has the potential to redefine how nucleic acids interact with cells and are internalized. Yet, it has been comparatively unexplored due to synthetic requirements. Consequently, further development of accessible backbone modifications and their incorporation into 3D DNA architectures offers an unparalleled opportunity to simultaneously address a fundamental gap in knowledge in understanding oligonucleotide backbone modifications and to harness their unleveraged potential for the rational delivery of biologics and nucleic acid therapeutics. Towards this, I propose to establish a group that will explore this topic through three specific aims: 1. Backbone modifications to improve the delivery of DNA nanostructures for gene editing 2. Development of self-assembling nucleic acid polyampholytes as a versatile drug delivery platform 3. Protein spherical nucleic acids with matched oligonucleotide shells for the effective delivery of enzyme therapeutics This new knowledge will be transformative in dictating the rational design of oligonucleotide-based drug delivery vehicles and will provide a road map for incorporating backbone modifications into nucleic acid-based nanostructures. Moreover, this research area holds tremendous potential for the successful development of nucleic acid therapeutics and biologics, which require effective and biocompatible delivery strategies to reach their full clinical potential. Further developments in this area will be of tremendous value in the health sector, where the development of effective therapies for cancer and genetic diseases that are highly prevalent in Canada is the limiting step towards improving patient recovery.

核酸疗法和生物制品(来自活体的药物)对遗传病的治疗具有变革性的潜力，它们无与伦比的选择性预计将导致对以前无法实现的疾病目标的有效治疗。然而，由于它们的高分子量和亲水性，它们转移到临床上的速度很慢，这阻碍了它们很容易穿过细胞膜访问细胞内靶点。因此，有效和生物相容的给药策略备受追捧，以加速这些药物类别的发展。DNA作为一种材料，由于其生物兼容性、自动合成、精确的碱基配对字母表和完全的可寻址能力，在应对这些挑战方面处于独特的地位。这些性质导致了以无与伦比的精度合成3D结构，这些结构显示出巨大的药物输送前景，因为它们可以进入细胞，而不是大多数寡核苷酸。这表明它们的3D组织在决定它们的生物学特性方面发挥了重要作用。然而，还需要进一步的工作来确保核酸纳米结构能够可靠地进入细胞内的隔间，并释放它们的治疗潜力。取代DNA的磷酸二酯骨架是一个很有希望的策略，它有可能重新定义核酸与细胞相互作用和内化的方式。然而，由于合成要求，它相对来说还没有被探索过。因此，进一步开发可获得的骨架修饰并将其整合到3D DNA结构中，提供了一个无与伦比的机会，可以同时解决了解寡核苷酸骨架修饰方面的基本知识差距，并利用它们未被利用的潜力，合理地提供生物药物和核酸治疗药物。为此，我建议成立一个小组，通过三个具体目标来探讨这一主题：1.骨架修饰，以改进用于基因编辑的DNA纳米结构的传递；2.开发自组装核酸聚两性聚合物作为多功能药物输送平台；3.具有匹配的寡核苷酸壳层的蛋白质球形核酸，用于有效地输送酶疗法。这一新知识将对指导基于寡核苷酸的药物输送载体的合理设计起到革命性的作用，并将为将骨架修饰纳入基于核酸的纳米结构提供路线图。此外，这一研究领域对核酸疗法和生物制品的成功开发具有巨大的潜力，这需要有效的和生物相容的递送策略来充分发挥其临床潜力。这一领域的进一步发展将对卫生部门具有巨大的价值，在卫生部门，开发在加拿大非常普遍的癌症和遗传病的有效治疗方法是改善患者康复的限制步骤。