New chemistry to enhance splice-switching oligonucleotides

剪接开关寡核苷酸(SSO)最近已成为治疗危及生命的疾病的强大精准药物。与作用于蛋白质的传统药物不同，SSO与mRNA加工结合并重新定向，改变与疾病相关的蛋白质的生产。SSO可以根据患者的基因组为个别患者设计，并且可以在比其他类别的药物更短的时间内开发出来。这一点在2018年得到证明，当时FDA批准了治疗巴顿病的SSO药物Milasen。Milasen是有史以来第一个针对单个患者设计的个性化药物，并在10个月内开发出来，开创了开创性的先例，可能会彻底改变遗传病的治疗方式。该项目的目的是开发一类新的SSO类似物，旨在克服现有的限制，减少所需的剂量，并降低毒副作用的可能性。核酸化学方面的创新对于SSO在临床上的成功是不可或缺的。化学修饰保护SSO在体内不被快速消化，并增强它们与RNA的相互作用。尽管如此，由于与疗效、交付和毒性相关的挑战，SSO尚未充分发挥其潜力。我们将开发新的合成路线来制备SSO类似物，进行生物物理研究以调查新化合物与目标RNA的相互作用情况，并使用临床相关疾病模型在基于细胞的检测中评估它们的生物活性。

Splice-switching oligonucleotides (SSOs) have recently emerged as powerful precision medicines for life-threatening diseases. Unlike conventional drugs which act on proteins, SSOs bind to and re-direct mRNA processing, altering the production of disease-associated proteins. SSOs can be designed for individual patients based on their genome and can be developed in a much shorter time frame than other classes of drugs. This was proven in 2018 when the FDA approved the SSO drug Milasen for Batten disease. Milasen was the first ever personalised medicine designed for a single patient and was developed in ten months, setting a ground-breaking precedence that could revolutionise how genetic diseases are treated. The aim of this project is to develop a new class of SSO analogues designed to overcome existing limitations, reduce the required dose, and decrease the likelihood of toxic side effects. Innovation in nucleic acid chemistry has been integral to the success of SSOs in the clinic. Chemical modifications protect the SSOs from rapid digestion in vivo as well as enhance their interaction with RNA. Despite this, SSOs have yet to reach their full potential due to challenges associated with efficacy, delivery, and toxicity. We will develop new synthetic routes to prepare the SSO analogues, perform biophysical studies to investigate how well the new compounds interact with target RNA, and evaluate their biological activity in cell-based assays using clinically relevant disease models.