Moffett et al. developed targeted mRNA nanocarriers that can easily and robustly reprogram specific cell types to replace or complement the existing gene therapy toolbox (viral vectors and electroporation). To demonstrate the generalizability of this method, the team disrupted endogenous TCR expression in CAR T cells, reprogrammed effector T cells into a central memory-like state, and accelerated the in vitro expansion of hematopoietic stem cells.
Therapies based on immune cells have been applied for diseases ranging from cancer to diabetes. However, the viral and electroporation methods used to create cytoreagents are complex and expensive. Consequently, we develop targeted mRNA nanocarriers that are simply mixed with cells to reprogram them via transient expression. Here, we describe three examples to establish that the approach is simple and generalizable. First, we demonstrate that nanocarriers delivering mRNA encoding a genome-editing agent can efficiently knock-out selected genes in anti-cancer T-cells. Second, we imprint a long-lived phenotype exhibiting improved antitumor activities into T-cells by transfecting them with mRNAs that encode a key transcription factor of memory formation. Third, we show how mRNA nanocarriers can program hematopoietic stem cells with improved self-renewal properties. The simplicity of the approach contrasts with the complex protocols currently used to program therapeutic cells, so our methods will likely facilitate manufacturing of cytoreagents.Current widely used viral and electroporation methods for creating therapeutic cell-based products are complex and expensive. Here, the authors develop targeted mRNA nanocarriers that can transiently program gene expression by simply mixing them with cells, to improve their therapeutic potential.
Author Info: (1) Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. (2) Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
Author Info: (1) Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. (2) Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. (3) Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. (4) Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. (5) Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. (6) Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. (7) Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. (8) Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA, 98109, USA. (9) Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. mstephan@fredhutch.org. Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA, 98109, USA. mstephan@fredhutch.org. Department of Bioengineering and Molecular Engineering & Sciences Institute, University of Washington, Seattle, WA, 98105, USA. mstephan@fredhutch.org.
