Mid-Scale RNA Synthesis, Purification and Quality Control System

中规模 RNA 合成、纯化和质量控制系统

• 批准号: 8826399
• 负责人: ANASTASIA KHVOROVA
• 金额: $ 56.31万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-24 至 2016-03-23
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8826399
• 关键词: Amyotrophic Lateral Sclerosis; Animal Model; Area; Development; Disease; Equipment; Foundations; Funding; Grant; Hereditary Sensory Neuropathy; High Pressure Liquid Chromatography; Huntington Disease; Inflammatory Bowel Diseases; Massachusetts; Modality; Nobel Prize; Oligonucleotides; Pharmaceutical Preparations; Pre-Eclampsia; Quality Control; RNA; RNA Interference; RNA chemical synthesis; Research; Research Design; Research Personnel; Research Support; Staging; System; Therapeutic; Translational Research; United States National Institutes of Health; Universities; autonomic neuropathy; base; clinical efficacy; functional genomics; in vivo; instrumentation; medical schools; novel; pre-clinical; preclinical study; professor; programs; research and development

 DESCRIPTION (provided by applicant): Oligonucleotide- based therapeutics and in vivo functional genomics is a cutting-edge area of research and development. The discovery of RNAi by University of Massachusetts Medical School Professor Craig Mello received the Nobel Prize in 2006. RNAi and Antisense-based drugs have proven clinical efficacy and are believed to become a novel major class of therapeutic modalities. At the University of Massachusetts Medical School (UMMS), there are multiple groups whose research has reached the stage at which functional analysis of novel and advanced oligonucleotides in animal models and preclinical development is necessary. These types of studies require access to mid-scale, uniquely chemically modified oligonucleotides that have limited commercial availability and are outside the reach of academic investigators. A Shared Instrumentation Grant will allow us to purchase the equipment to support mid scale synthesis, purification and quality control of chemically modified RNA that will enable ongoing and planned animal models and preclinical studies for research supported by 11 NIH grants and multiple grants from private foundations. Specifically, we are requesting funds to purchase a GE AKTA Pilot 10 RNA synthesizer, 218 Prep HPLC and 6530 QTOF LC- MS. The acquisition of this state-of-the-art RNA synthesis capability will propel our research and translational programs and enable the development of novel RNA-based therapies, specifically for treatment of Preeclampsia, ALS (amyotrophic lateral sclerosis), HSAN (hereditary sensory and autonomic neuropathy), Huntington, IBD (inflammatory bowel disease) and other diseases.

 描述（由申请人提供）： 基于寡核苷酸的疗法和体内功能基因组学是研究和开发的前沿领域。马萨诸塞大学医学院克雷格·梅洛教授因发现RNAi而获得2006年诺贝尔奖。RNAi和反义药物已被证明具有临床疗效，并被认为将成为一类新型的主要治疗方式。马萨诸塞大学医学院 (UMMS) 的多个研究小组的研究已达到需要在动物模型和临床前开发中对新型和先进寡核苷酸进行功能分析的阶段。这些类型的研究需要获得中等规模、经过独特化学修饰的寡核苷酸，这些寡核苷酸的商业可用性有限，超出了学术研究人员的能力范围。共享仪器补助金将使我们能够购买设备来支持化学修饰 RNA 的中型合成、纯化和质量控制，这将使正在进行和计划中的动物模型和临床前研究能够得到 11 项 NIH 补助金和来自私人基金会的多项补助金的支持。具体来说，我们正在申请资金购买 GE AKTA Pilot 10 RNA 合成仪、218 Prep HPLC 和 6530 QTOF LC-MS。获得这种最先进的 RNA 合成能力将推动我们的研究和转化计划，并促进基于 RNA 的新型疗法的开发，特别是用于治疗先兆子痫、ALS（肌萎缩侧索硬化症）、HSAN（遗传性感觉和自主神经病）、亨廷顿、IBD（炎症性肠病）和其他疾病。

项目成果

Heavily and fully modified RNAs guide efficient SpyCas9-mediated genome editing.

• DOI: 10.1038/s41467-018-05073-z
• 发表时间: 2018-07-06
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Mir A;Alterman JF;Hassler MR;Debacker AJ;Hudgens E;Echeverria D;Brodsky MH;Khvorova A;Watts JK;Sontheimer EJ
• 通讯作者: Sontheimer EJ

Asymmetric trichotomous partitioning overcomes dataset limitations in building machine learning models for predicting siRNA efficacy.

在构建机器学习模型中，不对称的三分法分区克服了数据集限制，以预测siRNA功效。

• DOI: 10.1016/j.omtn.2023.06.010
• 发表时间: 2023-09-12
• 期刊: MOLECULAR THERAPY NUCLEIC ACIDS
• 作者: Monopoli, Kathryn R.;Korkin, Dmitry;Khvorova, Anastasia
• 通讯作者: Khvorova, Anastasia

Intratracheally administered LNA gapmer antisense oligonucleotides induce robust gene silencing in mouse lung fibroblasts.

• DOI: 10.1093/nar/gkac630
• 发表时间: 2022-08-26
• 期刊: NUCLEIC ACIDS RESEARCH
• 影响因子: 14.9
• 作者: Shin, Minwook;Chan, Io Long;Cao, Yuming;Gruntman, Alisha M.;Lee, Jonathan;Sousa, Jacquelyn;Rodriguez, Tomas C.;Echeverria, Dimas;Devi, Gitali;Debacker, Alexandre J.;Moazami, Michael P.;Krishnamurthy, Pranathi Meda;Rembetsy-Brown, Julia M.;Kelly, Karen;Yukselen, Onur;Donnard, Elisa;Parsons, Teagan J.;Khvorova, Anastasia;Sontheimer, Erik J.;Maehr, Rene;Garber, Manuel;Watts, Jonathan K.
• 通讯作者: Watts, Jonathan K.

Engineered ionizable lipid siRNA conjugates enhance endosomal escape but induce toxicity in vivo.

• DOI: 10.1016/j.jconrel.2022.07.041
• 发表时间: 2022-09
• 期刊: JOURNAL OF CONTROLLED RELEASE
• 影响因子: 10.8
• 作者: Biscans, Annabelle;Ly, Socheata;McHugh, Nicholas;Cooper, David A.;Khvorova, Anastasia
• 通讯作者: Khvorova, Anastasia

Data on enrichment of chitosan nanoparticles for intranasal delivery of oligonucleotides to the brain.

用于将寡核苷酸鼻内递送至大脑的壳聚糖纳米粒子富集的数据。

• DOI: 10.1016/j.dib.2019.105093
• 发表时间: 2020
• 期刊: Data in brief
• 影响因子: 1.2
• 作者: Sava,Vasyl;Fihurka,Oksana;Khvorova,Anastasia;Sanchez-Ramos,Juan
• 通讯作者: Sanchez-Ramos,Juan