Safety of a Mesenchymal-Like Adherent Stromal Cell (PLX-PAD) in a Human Model of Pulmonary Arterial Hypertension (PAH)

• Published in: The Journal of heart and lung transplantation Vol. 32; no. 4; pp. S65 - S66
• Main Authors: Chambers, D.C, Hunt, W, Naidoo, R, Wall, D, Choudhary, J, Enever, D.L, Samson, L, Yerkovich, S.T, Rapchuk, I.L, Smith, I.J, Hopkins, P.M.A, Kermeen, F.D
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01-04-2013
• Subjects: Surgery
• ISSN: 1053-2498; 1557-3117
• DOI: 10.1016/j.healun.2013.01.977

Purpose A gap remains between the evidence for safety provided by PAH animal models and that needed to commence early phase human studies, particularly for cell therapies where embolisation after intravenous delivery may further embarrass a compromised pulmonary vascular bed. To bridge this gap we developed a human ex-vivo perfused (EVLP) PAH model to assess the acute haemodynamic effects of a promising PAH-targeted cell therapy. Methods and Materials Organs were studied at normothermia on a cellular EVLP circuit (haematocrit 10-15%; flow 40% of donor cardiac output). PAH (target pulmonary vascular resistance (PVR) 800 dyne.sec.cm-5 ) was induced using a thromboxane analogue (U-46619), prior to the infusion of ≈10*106 /kg(donor) placenta-derived mesenchymal-like adherent stromal cells (PLX-PAD, Pluristem, Haifa) over 15 minutes, directly into the pulmonary artery. The predefined safety endpoint was a PVR increase > 20%. Results PAH was rapidly and stably induced (n=4, table). The PVR remained stable during and after PLX-PAD infusion ( figure ). Histopathology revealed occasional intravascular cells, but no clumping, embolization or thrombosis. Conclusions Human models of lung disease can be feasibly developed using EVLP, with the future potential to utilise explanted organs. With this approach we have demonstrated the acute haemodynamic safety of a supratherapeutic dose of PLX-PAD in PAH. Age Sex Weight (kg) Donation process PO2 at retrieval Reason declined for transplant U-46619 dose (μg) MSC dose (*106 /kg) 60 F 127 DCD 469 Worsening oedema despite EVLP 260 9.45 40 M 90 DBD 304 Bilateral consolidation 660 10 63 M 75 DBD 400 Age, smoking history, emphysema at retrieval 280 10.67 40 F 50 DBD 250 (PEEP 10) Gas exchange, smoking history 74 10.5