Development of a charge detection mass spectrometer for the analysis ofgene therapy and other large pharmaceutical biologics

开发用于分析基因治疗和其他大型药物生物制剂的电荷检测质谱仪

• 批准号: 10010597
• 负责人: Benjamin E Draper
• 金额: $ 79.01万
• 依托单位: MEGADALTON SOLUTIONS, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10010597
• 关键词: Address; Adenoviruses; Amplifiers; Biological; Biological Assay; Biological Response Modifier Therapy; Businesses; Caliber; Calibration; Capsid; Carpet; Cells; Charge; Clinical Trials; Complex; Contracts; Custom; Dependovirus; Detection; Development; Disease; Drug Industry; Encapsulated; Ensure; Fee-for-Service Plans; Fees; Future; Gene Transduction Agent; Genetic; Genome; Goals; Growth; Hepatitis B Virus; Heterogeneity; Hybrids; Hydrogen; Indiana; Individual; Ions; Lead; Light; Mass Spectrum Analysis; Measurement; Measures; Medicine; Methods; Molecular Weight; Monitor; Noise; Patients; Pharmacologic Substance; Preparation; Process; Production; Protocols documentation; Publications; Pyruvate Kinase; Recombinant adeno-associated virus (rAAV); Reproducibility; Research; Resolution; Sales; Sampling; Scientist; Services; Signal Transduction; Source; Structure; System; Techniques; Testing; Therapeutic; Time; Treatment Efficacy; Uncertainty; Universities; Validation; Viral Vector; Virus; adeno-associated viral vector; analytical tool; base; beta-Galactosidase; commercialization; cost; design; detector; gene therapy; gene therapy clinical trial; insight; instrument; interest; manufacturing process; mass spectrometer; nano-electrospray; particle; product development; prototype; time use; tool; transduction efficiency; transmission process; two-dimensional; vector; whole genome

Project Summary Megadalton Solutions (Megadalton) is a startup company founded by Martin Jarrold and David Clemmer in August 2018 in Bloomington, Indiana. Megadalton aims to commercialize charge detection mass spectrometry (CDMS). This proposal describes a key step towards realizing this goal. We propose the construction of a standalone CDMS instrument that will greatly expand a nascent fee-for-measurement business dedicated to characterizing gene therapy products. Gene therapy provides the opportunity for a one-time cure to some of the most devastating diseases. The first FDA approval for a gene therapy treatment was in 2017. Currently there are more than 2,400 registered gene therapy clinical trials and so enormous growth is expected in the next few years. In gene therapy, the genome is usually inserted into cells by a virus vector. The active agent (the vector and its encapsulated genome) is large, 10-100 nm in diameter, and difficult to characterize. The number of functional particles in a preparation is often small and shows significant lot-to-lot variability. It is difficult to optimize a production process without good analytical tools to quickly characterize the product. Mass spectrometry (MS) is one of the most powerful analytical tools used to characterize conventional pharmaceuticals. However, commercial mass spectrometers have an upper mass limit of around a megadalton (1 MDa = 1,000,000 Da where 1 Da is the mass of a hydrogen atom). This mass limit is much too low for gene therapy products, where masses can be in the hundreds of megadaltons. CDMS is a single particle technique where the m/z (mass to charge) ratio and charge are measured directly for individual ions. This allows MS measurements to be extended beyond the current 1 MDa limit, and into the megadalton to gigadalton regime. Proof of concept studies for adeno-associated virus (AAV) based gene therapy products show that CDMS can characterize particle heterogeneity. In this case, empty particles, particles with the full genome, and particles with a partial genome, were easily resolved. Megadalton is establishing a fee-for-measurement business to support gene therapy product development. Contracts have been signed with a small number of pharmaceutical companies to perform CDMS measurements on AAV vectors. In order to meet immediate demand, Megadalton must expand measurement capacity. The proposed standalone instrument described in this proposal will allow this expansion. As part of this project, we will develop new assays for AAV based gene therapy products and assays will be developed for other vectors such as adenovirus. The standalone instrument will also serve as a prototype that will be used to develop research-grade instruments for sales to expert MS users with interests in CDMS. Sales of CDMS instruments is another key objective in our commercialization plan as it will allow other scientists to explore problems that can be addressed by mass measurements in the megadalton to gigadalton regime. New measurement tools, such as CDMS, open up new domains of research and lead to unexpected discoveries.

项目摘要 Megadalton Solutions（Megadalton）是一家由Martin Jarrold和大卫·克莱默（David Clemmer）于1999年创立的初创公司。 2018年8月在印第安纳州的布卢明顿。Megadalton旨在将电荷检测质谱商业化 （CDMS）。该提案描述了实现这一目标的关键步骤。我们建议建造一个 独立CDMS工具，将大大扩展一个新兴的收费测量业务，致力于 表征基因治疗产品。基因治疗为某些疾病提供了一次性治愈的机会， 最具破坏性的疾病。FDA首次批准基因治疗是在2017年。目前 有超过2，400个注册的基因治疗临床试验，因此预计 未来几年在基因治疗中，基因组通常通过病毒载体插入细胞中。活性剂 (the载体及其包封的基因组）大，直径为10 - 100 nm，并且难以表征。的 制剂中的功能性颗粒的数量通常很小，并且显示出显著的批次间可变性。是 如果没有良好的分析工具来快速表征产品，就很难优化生产工艺。质量 质谱（MS）是用于表征常规质谱的最强大的分析工具之一。 大药厂然而，商用质谱仪的质量上限约为1兆道尔顿 （1 MDa = 1，000，000 Da，其中1 Da是氢原子的质量）。这个质量限制对基因来说太低了 治疗产品，质量可以达到数百兆道尔顿。CDMS是一种单粒子技术 其中m/z（质荷比）比和电荷直接测量单个离子。这使得MS 测量将扩展到超过目前的1 MDa的限制，并进入兆道尔顿到千兆道尔顿制度。 基于腺相关病毒（AAV）的基因治疗产品的概念验证研究表明，CDMS可以 表征颗粒异质性。在这种情况下，空粒子，具有完整基因组的粒子，以及粒子 与部分基因组，很容易解决。Megadalton正在建立一个收费的测量业务， 支持基因治疗产品开发。已与少数制药公司签订合同， 公司对AAV载体进行CDMS测量。为了满足即时需求，Megadalton 必须扩大测量能力。本提案中所述的拟议独立仪器将允许 这种扩张。作为该项目的一部分，我们将开发基于AAV的基因治疗产品的新检测方法， 将开发用于其它载体如腺病毒的测定法。独立仪器还将作为 原型，将用于开发研究级仪器，销售给有兴趣的MS专家用户 在CDMS CDMS仪器的销售是我们商业化计划的另一个关键目标， 其他科学家探索的问题，可以解决的质量测量在兆道尔顿， 千兆道尔顿体系。新的测量工具，如CDMS，开辟了新的研究领域， 意想不到的发现