ESPEYB16 14. Year in Science and Medicine 2019 (1) (18 abstracts)
14.4. A reprogramming human T cell function and specificity with non-viral genome targeting
Roth TL , Puig-Saus C , Yu R , Shifrut E , Carnevale J , Li PJ , Hiatt , Saco J , Krystofinski P , Li H , Tobin V , Nguyen DN , Lee MR , Putnam AL , Ferris AL , Chen JW , Schickel JN , Pellerin L , Carmody D , Alkorta-Aranburu G , Del Gaudio D , Matsumoto H , Morell M , Mao Y , Cho M , Quadros RM , Gurumurthy CB , Smith B , Haugwitz M , Hughes SH , Weissman JS , Schumann K , Esensten JH , May AP , Ashworth A , Kupfer GM , Greeley SAW , Bacchetta R , Meffre E , Roncarolo MG , Romberg N , Herold KC , Ribas A , Leonetti MD & Marson A
To read the full abstract: Nature. 2018 Jul;559(7714):405–409
This article decries a CRISPR-Cas9 genome-targeting system that does not require viral vectors, allowing rapid and efficient insertion of large DNA sequences at specific sites in the genomes of primary human T cells, while preserving cell viability and function.
The common approach to genetically reprogram T cells for therapeutic purposes is through recombinant viral vectors. However, this fails to target transgenes to specific genomic sites. New methods of genome editing such as CRISPR-Cas9 enable more specific insertion of large transgenes into target cells.
The authors used a CRISPR–Cas9 genome-targeting approach that does not require viral vectors to rapidly and efficiently insert large DNA sequences at selected sites in the genomes of human T cells. They applied this strategy to correct a pathogenic IL2RA mutation in cells from patients with monogenic autoimmune disease, and demonstrate improved signalling function. They replaced the endogenous T cell receptor (TCR) locus with a new TCR that redirected T cells to a cancer antigen. The engineered TCR T cells specifically recognized tumor antigens, and provided anti-tumor cell responses in vitro and in vivo.
The technique may open up new possibilities for treating cancer, infections such as H.I.V., and also autoimmune diseases. There is no therapeutic immunotherapy product based on the new technique. Yet, it has been announced that the researchers also corrected – in the lab – the T-cells of three children with a rare mutation that causes autoimmune diseases. The plan now is to return these corrected cells to the children, expect them to function normally and suppress the defective immune cells, and thereby cure these children.
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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