Targeting cell surface receptors for ASO delivery to bone marrow leukemia cells

Antisense Oligonucleotides (ASOs) have emerged as powerful therapeutic modalities, with the ability to bind cellular RNAs and elicit degradation or alter RNA processing. Oligonucleotides in clinical use typically target diseases of the liver or brain, since delivery of ASOs to these tissues is readily achieved. However, recent progress has expanded the targeting of ASOs to additional cell types using Antibody Oligonucleotide Conjugates (AOCs). Here, we will develop AOCs to optimize delivery of an ASO, developed with prior support from QFASTR, to leukemic cells within bone marrow. This ASO targets a gene that is a selective dependency in a subset of leukemia cells. The ASO elicits potent knockdown of protein levels in cultured cells and anti-tumor activity in mouse xenograft models. We are poised to take the next step, in optimizing delivery of the ASO to the leukemia stem cells in the bone marrow. Success in this project would represent a much-needed therapeutic option for blood cancers and would expand the reach of ASO therapies.