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David Clemmer创立的初创公司 2018年8月在印第安纳州布卢明顿。 Megadalton旨在商业化电荷检测质谱法 （CDMS）。该建议描述了实现这一目标的关键一步。我们建议建造 独立的CDMS仪器将大大扩展新生的收费业务业务 表征基因治疗产品。基因疗法为一次性治疗提供了机会 最破坏性的疾病。 FDA的第一个基因疗法批准是在2017年。 有2400多个注册基因治疗临床试验，因此预计在 接下来的几年。在基因治疗中，基因组通常通过病毒载体插入细胞。活性剂 （载体及其封装的基因组）大，直径为10-100 nm，难以表征。这 制剂中的功能颗粒数量通常很少，并且显示出明显的地段变化。这是 在没有良好的分析工具的情况下，很难优化生产过程以快速表征产品。大量的 光谱法（MS）是用于表征常规的最强大的分析工具之一 药品。但是，商业质谱仪的上限范围为兆达尔顿 （1 MDA = 1,000,000 Da，其中1 Da是氢原子的质量）。对于基因而言，这种质量极限太低 治疗产品，可以在数百兆瓦尔顿群岛中进行群众。 CDMS是一种单个粒子技术 直接对单个离子测量M/z（质量）比率和电荷。这允许MS 测量值将超出当前1 MDA限制，并进入梅加达尔顿（Megadalton）到吉格达尔顿（Gigadalton）政权。 基于腺体相关病毒（AAV）基因治疗产品的概念证明研究表明，CDM可以 表征粒子异质性。在这种情况下，空颗粒，具有完整基因组的粒子和颗粒 有部分基因组，很容易解决。 Megadalton正在建立收费业务 支持基因治疗产品开发。合同已与少数药品签署 公司对AAV矢量进行CDMS测量。为了满足即时需求，梅加达尔顿 必须扩大测量能力。本提案中描述的拟议的独立工具将允许 这个扩展。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测定法和 将为其他媒介（例如腺病毒）开发测定。独立乐器也将作为 原型将用于开发具有兴趣的专家MS用户的研究级工具 在CDM中。 CDMS仪器的销售是我们商业化计划中的另一个关键目标，因为它将允许 其他科学家探讨了梅加达尔顿的质量测量可以解决的问题 吉格达尔顿政权。新的测量工具，例如CDM，开辟了新的研究领域，并导致 意外发现。