Five areas of preclinical development
Since 2008, Proteo has been cooperating with a team of scientists at Stanford University in California lead by Dr. Marlene Rabinovitch for the preclinical development of Elafin in the field PAH and other lung diseases. Since 2011, the National Heart, Lung and Blood Institute supports the Elafin development program for lung diseases at Stanford University with a five-year high volume grant for the study of Elafin’s ability to treat three distinct lung diseases. The grant will fund one preclinical project for each disease, all three of which are notoriously difficult to treat: pulmonary arterial hypertension, ventilator-induced injury of the immature lung in premature babies, and chronic lung transplant rejection.
Recently published results from the NIH funded preclinical projects have provided insights into the positive therapeutic effects of Elafin in animal models of lung transplantation and PAH.
In June 2015, Nickel et al. published results showing that Elafin reverses pulmonary hypertension via caveolin-1-dependent bone morphogenetic protein signaling in an animal model of PAH. The potential of Elafin in the treatment of PAH was confirmed in further investigations using explanted lung tissue from PAH patients.
In July 2015, Jiang et al. published research demonstrating that Elafin and cyclosporine act synergistically to prevent irreversible damage to transplanted lung tissue. Treatment with Elafin maintained the blood circulation in the transplanted tissue and reduced the infiltration of rejection-promoting immune cells. The synergistic effect of Elafin and cyclosporine is thought to be due to a concurrent effect of Elafin on the innate immune system and of cyclosporine on the adaptive immune system, as well as an Elafin-mediated suppression of cyclosporine-induced tissue damage.
Jiang X, Nguyen TT, Tian W, Sung YK, Yuan K, Qian J, Rajadas J, Sallenave JM, Nickel NP, de Jesus Perez V, Rabinovitch M, Nicolls MR. Cyclosporine Does Not Prevent Microvascular Loss in Transplantation but Can Synergize With a Neutrophil Elastase Inhibitor, Elafin, to Maintain Graft Perfusion During Acute Rejection. Am J Transplant. 2015; 15:1768-81.
Nickel NP, Spiekerkoetter E, Gu M, Li CG, Li H, Kaschwich M, Diebold I, Hennigs JK, Kim KY, Miyagawa K, Wang L, Cao A, Sa S, Jiang X, Stockstill RW, Nicolls MR, Zamanian RT, Bland RD, Rabinovitch M. Elafin Reverses Pulmonary Hypertension via Caveolin-1-Dependent Bone Morphogenetic Protein Signaling. Am J Respir Crit Care Med. 2015; 191(11):1273-86
Nickel NP, Wang L, Li CG, Spiekerkoetter E, Rabinovitch M. The elastase inhibitor Elafin restores endothelial cell homeostasis in pulmonary arterial hypertension and attenuates vascular remodeling in the sugen/hypoxia rat model. Am J Respir Crit Care Med. 2013; 187: A1031
Hilgendorff A, Parai K, Ertsey R, Juliana Rey-Parra G, Thébaud B, Tamosiuniene R, Jain N, Navarro EF, Starcher BC, Nicolls MR, Rabinovitch M, Bland RD. Neonatal mice genetically modified to express the elastase inhibitor elafin are protected against the adverse effects of mechanical ventilation on lung growth. Am J Physiol Lung Cell Mol Physiol. 2012 Aug 1;303(3):L215-27
Hilgendorff A, Parai K, Ertsey R, Jain N, Navarro EF, Peterson JL, Tamosiuniene R, Nicolls MR, Starcher BC, Rabinovitch M, Bland RD. Inhibiting lung elastase activity enables lung growth in mechanically ventilated newborn mice. Am J Respir Crit Care Med. 2011; 184: 537-46
Kim YM, Haghighat L, Spiekerkoetter E, Sawada H, Alvira CM, Wang L, Acharya S, Rodriguez-Colon G, Orton A, Zhao M, Rabinovitch M. Neutrophil elastase is produced by pulmonary artery smooth muscle cells and is linked to neointimal lesions. Am J Pathol. 2011; 179: 1560-72
From 2010 to 2015, Proteo cooperated with the Molecular Imaging North Competence Center (MOIN CC) at the Christian-Albrechts-University of Kiel. In this cooperation, the effects of Elafin on vascular changes due to vascular damages were examined in animal models.
Kaschwich M, Lützen U, Zhao Y, Tjiong A, Marx M, Haenisch S, Wiedow O, Preuss S, Culman J, Zuhayra M. Biodistribution and pharmacokinetics of the (99m)Tc labeled human elastase inhibitor, elafin, in rats. Drug Metab Pharmacokinet. 2016 Feb 5. pii: S1347-4367(16)00005-7
Zhao Y, Kaschwich M, Culman J, Marx M, Lützen U, Wiedow O, Henze E, Zuhayra M. In-vivo imaging of Tc-99m labeled Elafin in rats. Eur J Nucl Med Mol Imaging (2012) 39 (Suppl 2): S417-418
Kaschwich M, Zhao Y, Marx M, Culman J, Lützen U, Kötz K, Henze E, Wiedow O, Zuhayra M. Radiomarkierung des menschlichen Elastase- Inhibitors, Elafin, mit Tc-99m und Untersuchung der Biodistribution mittels Hi-SPECT in Ratten. 2012 Nuklearmedizin 51 (2): A110