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Vivo-Morpholinos as switching molecules for virally-delivered targets in mice

The authors of this new paper use an engineered viral vector (AAV) to express a secreted antibody. They make a version where the antibody is out-of-frame and a Morpholino is used to skip an exon, bring the antibody in-frame and switch on its functional expression; the target is a payload of the AAV and the switching molecule is the Morpholino. This use of Morpholinos as switching molecules in engineered systems has great therapeutic potential. In the same paper, they controlled the expression of their AAV cargo with a Vivo-Morpholino after delivery into a mouse. This is a potential of Morpholino oligos that has not yet been talked about much, but I've been excited about for many years; I recall a similar switching technique used with an engineered plasmid long ago, and this traces its roots to the pluc705 splice-actuated reporter plasmid and similar constructs from Ryszard Kole's group in the '90s.

Cripe TP, Hutzen B, Currier MA, Chen CY, Glaspell AM, Sullivan GC, Hurley JM, Deighen MR, Venkataramany AS, Mo X, Stanek JR, Miller AR, Wijeratne S, Magrini V, Mardis ER, Mendell JR, Chandler DS, Wang PY. Leveraging gene therapy to achieve long-term continuous or controllable expression of biotherapeutics. Sci Adv. 2022 Jul 15;8(28):eabm1890. doi: 10.1126/sciadv.abm1890. Epub 2022 Jul 13.

T cells redirected to cancer cells either via a chimeric antigen receptor (CAR-T) or a bispecific molecule have been breakthrough technologies; however, CAR-T cells require individualized manufacturing and bispecifics generally require continuous infusions. We created an off-the-shelf, single-dose solution for achieving prolonged systemic serum levels of protein immunotherapeutics via adeno-associated virus (AAV) gene transfer. We demonstrate proof of principle in a CD19+ lymphoma xenograft model using a single intravenous dose of AAV expressing a secreted version of blinatumomab, which could serve as a universal alternative for CD19 CAR-T cell therapy. In addition, we created an inducible version using an exon skipping strategy and achieved repeated, on-demand expression up to at least 36 weeks after AAV injection. Our system could be considered for short-term and/or repeated expression of other transgenes of interest for noncancer applications.

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