Targeting the unique barcode of MLL/AF4

Patients harbouring MLL/AF4 remain a high-risk subgroup, with a need for improved therapies. Fusion genes have a unique sequence in their breakpoint; therefore, we designed an siRNA targeting the fusion site within MLL/AF4. We aim to improve activity with encapsulation into a standard Onpattro formulation (LNP-chol) or a sphingomyelin rich (LNP-SM) particle, similar to the membranes seen in exosomes and viruses and comparing. The aim of this study is to develop a LNP delivery system to optimise siRNA delivery and explore this MLL/AF4 positive cell lines. SEM cells were treated with siMA6 or siMM (control) siRNA encapsulated in LNP-chol or LNP-SM. Cells were given 2ug/ml of siMA6 of LNP-chol or LNP-SM. Sequentially dosed cells with LNP-chol showed a 25-65% KD of MLL/AF4, but LNP-SM could produce 40-60% over 9 days. Furthermore, LNP-SM increased the number of apoptotic cells to 50% compared to only 30% with LNP-chol. Enhanced effects of LNP-SM were seen to lesser extent on impaired cell proliferation, cell cycle arrest and self-renewal.

We demonstrate that siRNA delivery in LNP-SM enhances activity of siMA6. These positive results could lead to improved therapies for these patients.

Publication History

Article published online:
17 May 2022