GenScript and Gladstone-UCSF Institute of Genomic Immunology Collaborate on Groundbreaking Non-Viral Cell Therapy Study

The study, published in Nature Biotechnology, describes methods using ssDNA donor templates to reduce cellular toxicity and achieve 40% knock-in editing efficiency with minimal cellular toxicity across numerous primary cell types

PISCATAWAY, N.J., Sept. 22, 2022 /PRNewswire/ -- GenScript USA Inc., the world's leading life-science research tools and services provider, is collaborating with researchers at the Gladstone-UCSF Institute of Genomic Immunology to advance the development of new, non-viral cell therapies that modify genomic sequences in the pursuit of more effective cell therapy products while limiting the cellular toxicity that is typically associated with previously available methods.

A new study, published in Nature Biotechnology, details methods for achieving highly efficient non-viral knock-in using GenScript's GenExact™ single-strand DNA (ssDNA) modified with Cas9-target sequences (CTS). This method achieved up to ˜90% knock-in efficiency in primary immune cell types.

One powerful application of CRISPR/Cas genome editing technology involves the precise insertion (or, knock-in) of DNA sequences via the HDR pathway. Traditionally, researchers have relied on viral vectors to deliver DNA insertion templates used for gene therapy into cells. However, difficulties manufacturing large amounts of clinical-grade viral vectors have delayed getting cell therapies to patients. Additionally, viral vectors can insert genes at any location within the genome, leading to safety concerns.

Previous research by the group at Gladstone and UCSF has shown that synthetic DNA templates can be delivered without the use of viral vectors, but high levels of double-stranded DNA can be toxic to cells, resulting in low efficiency. Efficiency can be improved using a modified version of the DNA templates that can bind to the Cas9 enzyme. However, additional work was required to improve the yield of successfully engineered cells and to make the process compatible with the manufacturing of future cell therapies. Those goals motivated the team's current study.

In this study, the team tested modified GenExact ssDNA designed with Cas9-targeted sequences to determine if the gene-editing efficiency could be improved with lower toxicity. First, synthetic sgRNA was complexed with Cas9 protein to form a RNP complex. Then the RNP and ssDNA template were delivered into the cell via electroporation, enabling efficient gene editing.

The team discovered that this combination of GenExact ssDNA with Cas9-targeted sequence offers up to 40% knock-in editing efficiency with minimal cellular toxicity. This approach can accelerate the development and manufacture of novel, high-yield non-viral gene therapies — and at lower cost.

"We are very proud to have collaborated on this groundbreaking scale-up work by the talented team at Gladstone and UCSF. GenScript is excited for the opportunities that this high-yield cell-line engineering process will provide to our customers," said Ray Chen, Ph.D, president of GenScript Life Science Group.

"We were very happy to partner with Genscript on critical experiments demonstrating high efficiency and yield of CAR knock-in cells at clinical scale. The long ssDNA produced by Genscript exceeded our expectations and helped us clearly demonstrate the potential for future therapeutic applications using these methods.", said first author Brian Shy, MD, PhD, a former clinical fellow in the lab of Alex Marson, MD, PhD, director of the Gladstone-UCSF Institute of Genomic Immunology.

GenScript Biotech Corporation (Stock Code: 1548.HK) is a global biotechnology group. Based on its leading gene synthesis technology, GenScript has developed four major platforms including the global cell therapy platform, the biologics contract development and manufacturing organization (CDMO) platform, the contract research organization (CRO) platform, and the industrial synthesis product platform.

GenScript was founded in New Jersey, USA in 2002 and listed on the Hong Kong Stock Exchange in 2015. GenScript's business operation spans over 100 countries and regions worldwide, with legal entities located in the USA, mainland China, Hong Kong, Japan, Singapore, the Netherlands, and Ireland. GenScript has provided premium, convenient, and reliable products and services for over 100,000 customers.

GenScript owns a number of intellectual property rights and technical secrets, including more than 100 patents and over 270 patent applications. As of Q3 2022, GenScript's products and services have been cited by 57,000 peer-reviewed journal articles worldwide. For more information visit genscript.com.

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Company Codes: HongKong:1548