Alexander Marson’s lab at the University of California San Francisco, UCSF, aims to understand gene programs controlling the behavior and properties of immune cells, particularly T cells. His lab leverages genetic engineering strategies to better understand immune cell functions and instruct T cell modification for future cell therapies for a broad range of human disease states.

We have a requirement for long single-stranded DNA that can be used in a clinical manufacturing process, and this is where we benefited from a wonderful collaboration with GenScript

- Alexander Marson at GCE Summit, GenScript

Project’s Critical Challenge

Marson’s team has been developing CRISPR/Cas9 editing tools for non-viral approaches to gene editing, enabling precise and efficient modification of immune cells. They found that co-electroporating the Cas9 ribonucleoprotein complex with DNA payloads into T cells represented an efficient strategy to knock-in gene sequences of interest. For example, by replacing the TCR alpha and beta sequences to re-write T cell specificity.

To improve non-viral gene knock-in efficiency, Marson’s team engineered modifications to the DNA payloads and Cas9 protein, promoting co-localization and delivery or “shuttling” to the nucleus. One essential modification was the adoption of single-stranded DNA payloads, which allowed them to bypass the toxicity associated with high levels of double-stranded DNA. Therefore, Marson’s group adopted the use of single-stranded DNA donor templates to achieve efficient and safe editing of various T cells for therapies. At this stage, the main challenge confronted by the group was achieving the manufacturing of high-quality and reliable single-stranded DNA at sufficient levels for clinical use while meeting GMP standards.

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GenScript Partnership Benefit

To meet manufacturing or “GMP” standards enabling developing T cell therapeutics through non-viral approaches, Marson’s team partnered with GenScript to synthesize long single-stranded DNA (e.g., CAR construct). With GenScript, Marson’s team found a reliable source of GMP-grade long single-stranded DNA, enabling improved knock-in efficiency over that achieved with single-stranded constructs made in-house by his lab.

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