scholarly journals Pan-lysyl oxidase inhibitor PXS-5505 ameliorates multiple-organ fibrosis by inhibiting collagen crosslinks in rodent models of systemic sclerosis

2021 ◽  
Author(s):  
Yimin Yao ◽  
Alison Findlay ◽  
Jessica Stolp ◽  
Benjamin Rayner ◽  
Kjetil Ask ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Lysyl Oxidase ◽  
Multiple Organ ◽  
Oxidase Inhibitor ◽  
Lung Model ◽  
Rodent Models ◽  
Collagen Crosslinks ◽  
Fibrotic Liver ◽  
Lysyl Oxidases ◽  
Organ Fibrosis

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.

scholarly journals Evaluation of a Pan-Lysyl Oxidase Inhibitor, Pxs-5505, in Myelofibrosis: A Phase I, Randomized, Placebo Controlled Double Blind Study in Healthy Adults

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 16-16
Author(s):  
Joan How ◽  
Yiwen Liu ◽  
Jennifer Lombardi Story ◽  
Donna S. Neuberg ◽  
Katya Ravid ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Research Funding ◽  
Lysyl Oxidase ◽  
Oxidase Inhibitor ◽  
Double Blind Study ◽  
Bone Marrow Fibrosis ◽  
Double Blind ◽  
Lysyl Oxidases ◽  
Separate Cohort ◽  
Marrow Fibrosis

BACKGROUND: Myeloproliferative neoplasms (MPNs) are clonal stem cell neoplasms characterized by terminal expansion of the myeloid cell lineage and include essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). MF carries the worst prognosis and is characterized by reactive bone marrow fibrosis. Currently bone marrow transplant is the only known therapy that can reverse fibrosis and alter the disease course. Lysyl oxidases (LOX, LOXL1-4) are copper amine oxidase enzymes that facilitate the cross-linking of collagen and elastin through deamination and oxidization of lysine residues, yielding highly reactive aldehydes. This is essential for fibrotic tissue formation. An earlier study identified an important role for LOX in the development of MF in mice (Eliades et al, J. Biol. Chem. 2011; PMID: 21665949). Furthermore, small molecule pan-LOX inhibitors reduced spleen size and bone marrow fibrosis in mouse models of MF (Leiva et al, Int J. Hemat. 2019; PMID: 31637674). This provides clinical rationale for the use of pan-lysyl oxidase inhibition in MF. A Phase 1 study was conducted to establish the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of PXS-5505, a pan-lysyl oxidase inhibitor. Plasma levels of LOX and LOXL2 were investigated in a separate cohort of MPN patients, with the ultimate goal to develop PXS-5505-based therapy in MF patients. METHODS: PXS-5505 was dosed orally in a Phase I, randomized, placebo-controlled, single ascending (Part A) and multiple ascending dose (Part B) double-blind study in healthy male volunteers. Plasma LOX and LOXL2 levels were also measured in a separate cohort of MPN patients using ELISA-based Single Molecule Array technology (Simoa; Quanterix). RESULTS: Forty subjects were enrolled in Part A and 16 were enrolled in Part B. In Part A, there were 5 cohorts consisting of 8 subjects (6 active, 2 placebo) with doses of 10, 50, 100, 200 or 300 mg administered once. In Part B, there were 2 cohorts of 8 subjects each (6 active, 2 placebo) at doses of 100 or 200 mg daily for 14 days. There were no significant treatment-related adverse events. Mean age in Part A was 32.0 years (SD 11.14) and 32.1 years (SD 12.14) in Part B. Cmax and AUC increased linearly across the dose range of 10 to 300 mg for single dose administration. In multiple dosing at 200 mg daily, Cmax was 916 ng/mL and AUC0-24 was 7421 hr*ng/mL on Day 14, with median Tmax of 1 hour and t1/2 of 7 hours. When measured in plasma, LOX was dose-dependently inhibited and achieved very strong inhibition (median 80%) with a 200 mg dose around Tmax. The 300 mg dosing did not significantly increase inhibition. Multiple daily doses of 100-200 mg resulted in 60-70% and 50-60% inhibition of plasma LOX at 12 and 24 hours. Average LOX plasma levels were 3.61 ng/mL (range: 3.20-13.42 ng/mL; SD: 2.92 ng/mL). We measured plasma LOX and LOXL2 levels in a separate MPN cohort of 9 ET, 8 PV, and 13 MF patients (mean age 61.4, range:24-84, 65% males). LOXL2 levels were higher in MF (mean 415 pg/mL) compared to ET (mean 209 pg/mL) and PV (mean 322 pg/ml), although this was not significant. However, LOXL2 levels in all MPN patients (mean 333 pg/mL) were significantly higher than LOXL2 levels in normal controls (mean 152 pg/mL, p<0.01). There were no significant differences in LOX levels in the two groups. DISCUSSION: PXS-5505 demonstrated an excellent safety profile and was well tolerated in healthy human subjects. PK/PD properties are consistent with preclinical data and support once or twice daily >100 mg dosing over 14 days. PXS-5505 achieves long-lasting, strong inhibition of lysyl oxidases. Plasma LOXL2 levels are higher in MF patients compared to healthy controls, and we found no significant disease associations of LOX or LOXL2 among MPN subtypes in our small cohort. LOXL2 is likely a more sensitive MF biomarker as it is present at low concentrations in the blood, while LOX is constantly produced from major organs making detection due to disease more difficult. Based on previous mouse studies, it is possible that LOX levels would be higher in MF patients when compared to age-matched controls, which we will investigate further. We will open a Phase IB/II study of PXS-5505 in MF patients resistant to ruxolitinib. Disclosures Neuberg: Madrigak Pharmaceuticals: Current equity holder in publicly-traded company; Celgene: Research Funding; Pharmacyclics: Research Funding. Ravid:Pharmaxis: Research Funding. Jarolimek:Pharmaxis Ltd: Current Employment. Charlton:Pharmaxis Ltd: Current Employment. Hobbs:Novartis: Honoraria; Constellation: Honoraria, Research Funding; Jazz: Honoraria; Celgene/BMS: Honoraria; Merck: Research Funding; Incyte: Research Funding; Bayer: Research Funding.

scholarly journals Targeting CD38-dependent NAD+ metabolism to mitigate multiple organ fibrosis

iScience ◽  
2021 ◽  
Vol 24 (1) ◽  
pp. 101902
Author(s):  
Bo Shi ◽  
Wenxia Wang ◽  
Benjamin Korman ◽  
Li Kai ◽  
Qianqian Wang ◽  
...  
Keyword(s):  
Multiple Organ ◽  
Nad Metabolism ◽  
Organ Fibrosis

The lysyl oxidase inhibitor (β-aminopropionitrile) reduces leptin profibrotic effects and ameliorates cardiovascular remodeling in diet-induced obesity in rats

2016 ◽  
Vol 92 ◽  
pp. 96-104 ◽  
Author(s):  
Ernesto Martínez-Martínez ◽  
Cristina Rodríguez ◽  
María Galán ◽  
María Miana ◽  
Raquel Jurado-López ◽  
...  
Keyword(s):  
Lysyl Oxidase ◽  
Oxidase Inhibitor ◽  
Cardiovascular Remodeling ◽  
Diet Induced Obesity

The selective guanylate cyclase inhibitor ODQ reduces multiple organ injury in rodent models of Gram-positive and Gram-negative shock

2001 ◽  
Vol 29 (8) ◽  
pp. 1599-1608 ◽  
Author(s):  
Kai Zacharowski ◽  
Reinhard Berkels ◽  
Antje Olbrich ◽  
Prabal K. Chatterjee ◽  
Salvatore Cuzzocrea ◽  
...  
Keyword(s):  
Guanylate Cyclase ◽  
Multiple Organ ◽  
Organ Injury ◽  
Rodent Models ◽  
Gram Positive ◽  
Gram Negative ◽  
Multiple Organ Injury ◽  
Negative Shock

AB0141 Lysyl oxidase is correlated with fibrosis in systemic sclerosis

2013 ◽  
Vol 72 (Suppl 3) ◽  
pp. A828.3-A828
Author(s):  
D. Rimar ◽  
I. Rosner ◽  
G. Slobodin ◽  
M. Rozenbaum ◽  
T. haj ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Lysyl Oxidase

scholarly journals Collagen Biosynthesis, Processing, and Maturation in Lung Ageing

2021 ◽  
Vol 8 ◽  
Author(s):  
Ceylan Onursal ◽  
Elisabeth Dick ◽  
Ilias Angelidis ◽  
Herbert B. Schiller ◽  
Claudia A. Staab-Weijnitz
Keyword(s):  
Lung Disease ◽  
Cell Function ◽  
Lysyl Oxidase ◽  
Advanced Glycation Endproducts ◽  
Mouse Lung ◽  
Chronic Obstructive ◽  
Collagen Biosynthesis ◽  
Collagen Crosslinks ◽  
Collagen Crosslinking ◽  
Chronic Lung Diseases

In addition to providing a macromolecular scaffold, the extracellular matrix (ECM) is a critical regulator of cell function by virtue of specific physical, biochemical, and mechanical properties. Collagen is the main ECM component and hence plays an essential role in the pathogenesis and progression of chronic lung disease. It is well-established that many chronic lung diseases, e.g., chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) primarily manifest in the elderly, suggesting increased susceptibility of the aged lung or accumulated alterations in lung structure over time that favour disease. Here, we review the main steps of collagen biosynthesis, processing, and turnover and summarise what is currently known about alterations upon lung ageing, including changes in collagen composition, modification, and crosslinking. Recent proteomic data on mouse lung ageing indicates that, while the ER-resident machinery of collagen biosynthesis, modification and triple helix formation appears largely unchanged, there are specific changes in levels of type IV and type VI as well as the two fibril-associated collagens with interrupted triple helices (FACIT), namely type XIV and type XVI collagens. In addition, levels of the extracellular collagen crosslinking enzyme lysyl oxidase are decreased, indicating less enzymatically mediated collagen crosslinking upon ageing. The latter contrasts with the ageing-associated increase in collagen crosslinking by advanced glycation endproducts (AGEs), a result of spontaneous reactions of protein amino groups with reactive carbonyls, e.g., from monosaccharides or reactive dicarbonyls like methylglyoxal. Given the slow turnover of extracellular collagen such modifications accumulate even more in ageing tissues. In summary, the collective evidence points mainly toward age-induced alterations in collagen composition and drastic changes in the molecular nature of collagen crosslinks. Future work addressing the consequences of these changes may provide important clues for prevention of lung disease and for lung bioengineering and ultimately pave the way to novel targeted approaches in lung regenerative medicine.

scholarly journals Perturbations to lysyl oxidase expression broadly influence the transcriptome of lung fibroblasts

2017 ◽  
Vol 49 (8) ◽  
pp. 416-429 ◽  
Author(s):  
Ivana Mižíková ◽  
Francesco Palumbo ◽  
Tamás Tábi ◽  
Susanne Herold ◽  
István Vadász ◽  
...  
Keyword(s):  
Steady State ◽  
Lysyl Oxidase ◽  
Lung Fibroblasts ◽  
Mouse Lung ◽  
Cell Phenotype ◽  
Mrna Levels ◽  
Lysyl Oxidases ◽  
Primary Mouse ◽  
The Impact

Lysyl oxidases are credited with pathogenic roles in lung diseases, including cancer, fibrosis, pulmonary hypertension, congenital diaphragmatic hernia, and bronchopulmonary dysplasia (BPD). Lysyl oxidases facilitate the covalent intra- and intermolecular cross-linking of collagen and elastin fibers, thereby imparting tensile strength to the extracellular matrix (ECM). Alternative ECM-independent roles have recently been proposed for lysyl oxidases, including regulation of growth factor signaling, chromatin remodeling, and transcriptional regulation, all of which impact cell phenotype. We demonstrate here that three of the five lysyl oxidase family members, Lox, Loxl1, and Loxl2, are highly expressed in primary mouse lung fibroblasts compared with other constituent cell types of the lung. Microarray analyses revealed that small interfering RNA knockdown of Lox, Loxl1, and Loxl2 was associated with apparent changes in the expression of 134, 3,761, and 3,554 genes, respectively, in primary mouse lung fibroblasts. The impact of lysyl oxidase expression on steady-state Mmp3, Mmp9, Eln, Rarres1, Gdf10, Ifnb1, Csf2, and Cxcl9 mRNA levels was validated, which is interesting, since the corresponding gene products are relevant to lung development and BPD, where lysyl oxidases play a functional role. In vivo, the expression of these genes broadly correlated with Lox, Loxl1, and Loxl2 expression in a mouse model of BPD. Furthermore, β-aminopropionitrile (BAPN), a selective lysyl oxidase inhibitor, did not affect the steady-state mRNA levels of lysyl oxidase target genes, in vitro in lung fibroblasts or in vivo in BAPN-treated mice. This study is the first to report that lysyl oxidases broadly influence the cell transcriptome.

scholarly journals Hydrogen Sulfide: A Therapeutic Option in Systemic Sclerosis

2018 ◽  
Vol 19 (12) ◽  
pp. 4121 ◽  
Author(s):  
Amaal Abdulle ◽  
Harry van Goor ◽  
Douwe Mulder
Keyword(s):  
Hydrogen Sulfide ◽  
Systemic Sclerosis ◽  
Animal Studies ◽  
Therapeutic Option ◽  
Multiple Organ ◽  
Current Data ◽  
Organ Systems ◽  
Transsulfuration Pathway ◽  
Exact Etiology ◽  
Vascular Physiology

Systemic sclerosis (SSc) is a lethal disease that is characterized by auto-immunity, vascular injury, and progressive fibrosis of multiple organ systems. Despite the fact that the exact etiology of SSc remains unknown, oxidative stress has been associated with a large range of SSc-related complications. In addition to the well-known detrimental properties of reactive oxygen species (ROS), gasotransmitters (e.g., nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S)) are also thought to play an important role in SSc. Accordingly, the diverse physiologic actions of NO and CO and their role in SSc have been previously studied. Recently, multiple studies have also shown the importance of the third gasotransmitter H2S in both vascular physiology and pathophysiology. Interestingly, homocysteine (which is converted into H2S through the transsulfuration pathway) is often found to be elevated in SSc patients; suggesting defects in the transsulfuration pathway. Hydrogen sulfide, which is known to have several effects, including a strong antioxidant and vasodilator effect, could potentially play a prominent role in the initiation and progression of vasculopathy. A better understanding of the actions of gasotransmitters, like H2S, in the development of SSc-related vasculopathy, could help to create early interventions to attenuate the disease course. This paper will review the role of H2S in vascular (patho-)physiology and potential disturbances in SSc. Moreover, current data from experimental animal studies will be reviewed. Lastly, we will evaluate potential interventional strategies.

Cellular origins of fibroblasts: possible implications for organ fibrosis in systemic sclerosis

2004 ◽  
Vol 16 (6) ◽  
pp. 733-738 ◽  
Author(s):  
Arnold E Postlethwaite ◽  
Hidenobu Shigemitsu ◽  
Siva Kanangat
Keyword(s):  
Systemic Sclerosis ◽  
Organ Fibrosis
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