Pan-lysyl oxidase inhibitor PXS-5505 ameliorates multiple-organ fibrosis
by inhibiting collagen crosslinks in rodent models of systemic sclerosis
Background/Purpose: Systemic sclerosis (SSc) is characterised by
progressive multiple-organ fibrosis leading to morbidity and mortality.
Lysyl oxidases play a vital role in the cross-linking of collagens and
subsequent build-up of fibrosis in the extracellular matrix. As such,
their inhibition provides a novel treatment paradigm for SSc.
Experimental Approach: Lysyl oxidases are upregulated in preclinical
models of fibrosis in skin, lung, heart, kidney and liver. A novel small
molecule pan-lysyl oxidase inhibitor, PXS-5505, currently in clinical
development for bone fibrosis treatment was evaluated in in vivo rodent
models resembling the fibrotic conditions in SSc. Key Results: Both
lysyl oxidase and lysyl oxidase-like 2 (LOXL2) expression was elevated
in the skin and lung of SSc patients. Once-a-day oral application of
PXS-5505 inhibited lysyl oxidase activity in the skin and LOXL2 activity
in the lung. PXS-5505 exhibited anti-fibrotic effects in the SSc skin
mouse model, reducing dermal thickness and α-smooth muscle actin
compared to the disease controls. Similarly, in the bleomycin-induced
mouse lung model, PXS-5505 reduced tissue fibrosis toward normal levels.
The anti-fibrotic efficacy of PXS-5505 in the bleomycin exposed lungs
was mediated by its ability to normalise collagen/elastin crosslink
formation, a direct consequence of lysyl oxidase inhibition. PXS-5505
also reduced area of fibrosis in rodent models of the
ischaemia-reperfusion heart, the unilateral ureteral obstruction kidney
and the CCl4-induced fibrotic liver. Conclusion/Implication: PXS-5505
consistently demonstrates potent anti-fibrotic efficacy in multiple
models of organ fibrosis relevant to the pathogenesis of SSc, suggesting
that it may be efficacious as a novel approach for treating SSc.