Background: A Disintegrin And Metalloprotease (ADAM)33 is an asthma susceptibility and airway remodelling gene expressed in mesenchymal cells. Soluble ADAM33 is increased in asthmatic airways and induces airway remodelling. Adam33-null mice were protected from developing allergic asthma. Here, we test different anti-ADAM33 oligonucleotides (aA33Oligos) that specifically silence ADAM33 mRNA, as a potential novel disease-modifying asthma therapy.

Aim: To test the efficiency of aA33Oligos in ex-vivo mouse and human lung tissue explant (LTE) culture models for future in-vivo work.

Methods: Mouse and human lungs (n=3) were collected after informed consent and dissected into ~8mm³ LTE pieces. These were cultured in the presence of 4 murine (0.11, 0.33, 1 or 3 nmol/ml) or 7 human (0.5, 1, 2 or 4 nmol/ml) aA33Oligos or non-targeting control for 3 and 7 days. ADAM33, remodelling and inflammatory gene expression were determined.

Results: In murine LTE cultures, there was up to 80% and 70% suppression of Adam33 (p<0.0001) at 3 nmol/ml of murine aA33Oligos at 3 and 7 days, respectively. In hLTEs cultured for 3 days, 6 out of 7 human aA33Oligos suppressed ADAM33 by up to 75%, without affecting the remodelling genes ACTA2 or COL1A1, or the inflammatory gene IL-6.

Conclusion: Murine and human aA33Oligos successfully silence ADAM33 expression by up to 70% in complex lung tissues ex vivo, without significant off-target effects. This will help us to select the most efficacious aA33Oligos for testing in preclinical mouse models of allergic asthma.