Targeting the genetic drivers of disease with nucleotide-based therapeutics
What are nucleotide-based therapeutics?
以核苷酸为基础的治疗提供了巨大的潜力，可以以以前不可能的方式特异性调节细胞通路. 这些疗法包括所有基于核酸的方法，这些方法在细胞内起作用，影响基因表达——疾病的遗传蓝图——最终改变蛋白质表达，并可能改变疾病的进程.1
核苷酸是构成核酸的基本结构单位，如DNA(脱氧核糖核酸)和RNA(核糖核酸)。. 有时, nucleotide-based therapeutics are called nucleic acid therapies or therapeutic nucleic acids, 出于这个原因.
What are the advantages of nucleic acid therapies?
A major advantage of nucleic acid-based therapies is they can modulate expression of disease-causing genes, which can have potential therapeutic benefit. By targeting the underlying genetic drivers of disease, 核酸疗法提供了实现持久治疗的潜力，同时支持精准医学方法.1
What are the different types of nucleotide-based therapeutics?
Antisense oligonucleotides (ASOs)
Antisense oligonucleotides (ASOs) are short, 合成, chemically modified chains of nucleotides that have the potential to target any gene product of interest.2, 3 ASOs是单链RNA分子，由于其作用，为治疗干预提供了新的机会 内部 the cell to influence protein production.4, 5 一旦进入, ASOs bind with high specificity to target mRNA or pre-mRNA, 诱导其降解——有效地使其沉默——以防止其转化为有害的蛋白质产物. They are a promising approach for the treatment of genetic drivers of disease.
We are currently working to further our precision medicine approaches in non-alcoholic steatohepatitis (NASH), a leading cause of chronic liver disease. NASH occurs when fat builds up in the liver, leading to inflammation and cell damage. This complex disease has numerous drivers, including strong genetic factors, 哪些已经在 国际肝病杂志.6 Recent research using omics technologies, 比如大规模基因组学, has enabled identification of new disease-causing gene variants:
PNPLA3
A single nucleotide substitution in the PNPLA3 gene results in a mutation that impairs the breakdown of fat in liver cells which raises the risk of NASH.
Through collaboration with the biotechnology company Ionis制药 and the University of 哥德堡, we are developing an ASO that can target liver cells to ‘silence’ PNPLA3 with the aim of restoring fat break down in the liver. 澳门葡京赌博游戏的临床前研究显示，针对PNPLA3的ASO治疗可以减少肝细胞中的脂肪堆积.7
小干扰RNA (siRNA)
类似于aso, 小干扰RNA (siRNA)是在细胞内调节基因表达以防止疾病相关蛋白产生的核酸. However, siRNA are double-stranded RNA molecules whereas ASOs are single-stranded.10-12
通过内部开发技术和与沉默疗法等生物技术公司的外部合作的平衡方法, we are identifying and progressing liver-based targets, as well as developing new delivery approaches for targeting other tissues such as the heart, 肺和肾. Targeted siRNA delivery to these other tissues represents a new opportunity to treat cardiovascular, 肾, metabolic and respiratory diseases.
信使RNA (mRNA)
信使RNA (mRNA) is the cell’s blueprint for building proteins. 它是一种单链RNA分子，编码DNA的遗传信息，将其翻译成功能性蛋白质分子.
mRNA is a compelling therapeutic modality because of its ability to drive high-efficiency, 存在剂量依赖的相关性, protein expression which represents a unique approach for regulating aberrant or absent protein function. Combined with state-of-the-art drug delivery systems, such as 脂质纳米颗粒(LNPs), they offer opportunities for the delivery of a wide range of next generation medicines to patients.12
Latest updates in nucleotide-based therapeutics
Ensuring specific and targeted therapeutic delivery
脂质纳米颗粒(LNPs)) 基于核苷酸的治疗药物的细胞内递送是否有希望和创新的载体用于细胞内蛋白质治疗药物的生产. They have a successful track record of delivering nucleic acids and are an advanced approach for mRNA delivery.14,15 例如, we have shown that LNPs can deliver mRNA into cells to initiate cellular protein production after intravenous, subcutaneous and pulmonary administration. 现在, we are focusing our research on enhancing the efficacy and safety profile of this drug delivery system.
寡核苷酸轭合物 enable targeting to specific cells and tissues. 没有结合, 细胞中寡核苷酸的摄取是有限的，并且仍然是扩大这种治疗方式范围的障碍. 使用链接器, we can perform novel conjugation chemistry to attach different drug modalities – small molecules, 肽, 抗体, etc – to direct the oligonucleotide to the tissue of interest.15,16 以肝脏为靶点, the state-of-the-art targeting ligand is the N-acetylgalactosamine (GalNAc), which binds a receptor that is highly expressed on hepatocytes in the liver. GalNac偶联导致肝脏中特异性mrna的强靶向性和随后的下调或失活.16,17 To realise the full potential of oligonucleotide therapeutics, 澳门葡京赌博游戏正在探索通过利用特定的细胞表面受体来促进靶细胞的吸收，从而将配体靶向到其他细胞类型. If we can achieve effective targeted delivery of oligonucleotides to specific cells and tissue, we can expand the druggable target space, be able to treat diseases in a better way and ultimately make an impact on patients’ lives.
Quantitative analysis of ASO subcellular distribution
To develop effective ASOs and other nucleotide-based therapeutics, we need to be able to visualise their distribution 内部 of cells. One good way to do this is by transmission electron micropscope, where a beam of electrons is transmitted through a specimen to form an image. Using nanoscale secondary ion mass spectrometry (nanoSIMs), we can accurately measure drug uptake to better capture pharmokinetic information at the subcellular level.
Working together to advance nucleotide-based therapeutics
Accelerating nucleotide-based therapeutic development through collaborations
Ionis制药
For nearly a decade, we have partnered with Ionis制药 to discover and develop nucleotide-based therapeutics across numerous disease areas, 包括心血管, 肾, 代谢与肿瘤学. This strategic collaboration aims to ultimately get RNA-targeted treatments to the patients who need them most.
RNA治疗研究所
澳门葡京赌博游戏正在与 RNA治疗研究所, an academic department at UMass Chan Medical School to optimise antisense oligonucleotides (ASOs). The RNA治疗研究所 faculty are recognised as scientific trailblazers, and we are collaborating with Jonathan Watts, 他是RNA治疗研究所的教授，在寡核苷酸和药物开发方面拥有丰富的经验.
沉默疗法
与…合作 沉默疗法, we are advancing our siRNA drug discovery efforts to address unmet medical needs in cardiovascular, 肾, metabolic (CVRM) and respiratory diseases.
VaxEquity
警卫室生物
Mutations in RNA genes may dysregulate biological pathways that contribute to numerous diseases, including heart failure with preserved ejection fraction (HFpEF). 与 警卫室生物, leveraging its AI-powered Code-Breaker™ Platform, designed to identify novel small RNA mutations, we are closing the gap between RNA modality, AI, and disease biology with the shared goal of developing RNA-based treatments in heart failure.
Join us: Working together to advance nucleotide-based therapeutics
澳门葡京赌博游戏欢迎, talented scientists to join us on what promises to be one of the most exciting, stimulating and rewarding journeys in 21st century medicine. We are uniquely positioned to develop cutting-edge nucleotide-based therapeutics, 澳门葡京赌博游戏已经在开发针对特定细胞和组织的差异化管道，以实现基于核苷酸的治疗的全部潜力. By giving our people the resources and support to push the boundaries of science, we are going beyond the ordinary to help improve billions of lives worldwide.
澳门葡京赌博游戏招募具有相关专业知识的科学家加入澳门葡京赌博游戏在哥德堡新建的最先进的研究设施, 瑞典, 剑桥, UK, 和盖, US. 澳门葡京赌博游戏为澳门葡京赌博游戏的进步感到自豪, prepared for the challenges that lie ahead, 并且确信, 在未来的5到10年, aso和基于rna的疗法将有助于改善当今一些最严重和限制生命的疾病患者的前景.
参考文献
1. Kulkarni J.A.维茨曼，D.汤姆森，S。.B. 等. The current landscape of nucleic acid therapeutics. Nat. Nanotechnol. 16, 630–643 (2021). http://doi.org/10.1038/s41565-021-00898-0
2. 里纳尔迪C，伍德MJA. Antisense oligonucleotides: the next frontier for treatment of neurological disorders. Nat Rev Neurol. 2018;14(1):9-21.
3. 班尼特CF. Therapeutic Antisense Oligonucleotides Are Coming of Age. Ann Rev Med. 2019;70:307-321.
4. Khvorova A, Watts JK. The chemical evolution of oligonucleotide therapies of clinical utility. 生物科技Nat》. 2017;35(3):238-248.
5. Crooke ST, Witztum JL, 班尼特CF, Baker BF. RNA-Targeted Therapeutics [published correction appears in 细胞金属底座. 2019年2月5日;29(2):501]. 细胞金属底座. 2018;27(4):714-739.
6. 林德康·D，罗密欧·S. 《澳门葡京网赌游戏》综述:利用基因验证靶点治疗NASH的治疗机会. J乙醇. 2023 May 17:S0168-8278(23)00335-5. doi: 10.1016/j.jhep.2023.05.007
7. Lindén D, Ahnmark A, Pingitore P 等. 用反义寡核苷酸沉默Pnpla3可改善Pnpla3 I148M敲入小鼠的非酒精性脂肪性肝炎和纤维化. 摩尔金属底座. 2019年4月,7 - 61.
8. Abul-Husn NS, Cheng X, Li AH, 等. A Protein-Truncating HSD17B13 Variant and Protection from Chronic Liver Disease. [英]医学. 2018;378(12):1096-1106.
9. Gellert-Kristensen H, Nordestgaard BG, Tybjaerg-Hansen A, Stender S. High Risk of Fatty Liver Disease Amplifies the Alanine Transaminase-Lowering Effect of a HSD17B13 Variant. 肝脏病学. 2020;71(1):56-66.
10. Dana H, Chalbatani GM, Mahmoodzadeh H, 等. Molecular Mechanisms and Biological Functions of siRNA. 生物医学学报. 2017;13(2):48-57.
11. Humphreys SC, Thayer MB, Campbell J, 等. Emerging siRNA Design Principles and Consequences for Biotransformation and Disposition in Drug Development. 医学化学. 2020;63(12):6407-6422.
12. 塞顿RL，罗西JJ，韩SP. 基于rnai的治疗方法的现状和未来方向[发表的更正出现在Nat Rev Drug discovery. 2019 Mar 18;:] [published correction appears in Nat Rev药物发现. 2019年4月24日;:]. Nat Rev药物发现. 2019;18(6):421-446.
13. Yanez阿尔特塔, 玛丽安娜, 托马斯Kjellman, 斯特凡诺Bartesaghi, Simonetta沃林, 吴小秋, 亚历山大J. Kvist, Aleksandra Dabkowska, 等. 2018. 通过功能化脂质纳米颗粒传递mRNA成功重编程细胞蛋白质生产.” Proceedings of the National Academy of Sciences of the United States of America 115 (15): E3351–60.
14. Maugeri M, Nawaz M, Papadimitriou A, 等. Linkage between endosomal escape of LNP-mRNA and loading into EVs for transport to other cells. Nat Commun. 2019;10(1):4333. doi: 10.1038/s41467-019-12275-6
15. Nawez M, Hagvall S, Tanhruksa B, 等. 脂质纳米颗粒在体外和体内传递治疗性VEGFA mRNA，并转化细胞外囊泡以实现其功能扩展. 阿德科学. 2023. http://doi.org/10.1002 /人.202206187
16. 温克勒J. 寡核苷酸轭合物 for therapeutic applications. 其他Deliv. 2013;4(7):791-809.
17. Seth PP, Tanowitz M, 班尼特CF. Selective tissue targeting of 合成 nucleic acid drugs. J临床投资. 2019;129(3):915-925.
Veeva ID: Z4-56660
Date of preparation: August 2023