Extreme prematurity is the main cause of child death under age 5. Lung disease remains the leading cause of disease burden in these patients. At no other stage in life is the impact of disability-adjusted life years higher than during the neonatal period. Effective interventions at this stage provide exceptional value. Over the past 10 years, we have focused on umbilical cord cell-based therapies to provide cures for newborns. Optimizing this ideal source of repair cells will also reveal its potential for adult diseases and offers commercialization opportunities. We are now translating innovative cell and gene therapies from the lab into patients to improve outcomes. 

1. Mesenchymal Stromal Cells (MSCs) for lung repair

We were the first to show that MSCs prevent experimental bronchopulmonary dysplasia (BPD) (Am J Respir Crit Care Med 2009, Thorax 2013). Both papers were editorialized. We confirmed these findings in the first neonatal preclinical systematic review and meta-analysis (Stem Cell Transl Med 2017). MSCs, contrary to initial belief, act via a paracrine mechanism rather than by cell replacement: they secrete lung protective factors, modulate lung inflammation and can be enhanced by preconditioning (Am J Respir Cell Mol Biol 2012; AJP Lung 2012; Stem Cells Dev 2012). We developed the INCuBAToR (Stem Cell Transl Med 2021) to accelerate the clinical translation of these innovative therapies. We are now conducting the first phase I trial testing the safety and feasibility of cord-derived MSC in preterm infants (NCT04255147). We used single-cell RNA sequencing to establish the first atlas of normal and impaired lung growth (Nat Commun 2021).

2. Lung angiogenesis for lung regeneration and pulmonary hypertension (PH)

We showed the critical role of the vascular growth factor VEGF for normal alveolar development and lung regeneration after injury (Circulation 2005). These findings suggest angiogenesis, previously seen as a passive bystander during lung growth, as a new therapeutic avenue for lung diseases characterized by arrested lung growth. We confirmed the role of angiocrine factors in lung angiogenesis and their ability to attenuate PH (Circulation 2011, Am J Respir Crit Care Med 2012, Am J Respir Cell Mol Biol 2014). We then identified resident endothelial colony forming cells (ECFCs) in the developing lung and their dysfunction in experimental BPD; cord blood-derived ECFCs promoted lung vascular growth and attenuated PH (Circulation 2014; Nat Protoc 2015).

3. AAV-mediated gene therapy for lethal surfactant protein deficiencies

We showed with our uGuelph collaborators, that a modified AAV vector with enhanced tropism for distal lung epithelial cells efficiently transduces surfactant protein B in deficient mice leading to dramatic improvement in survival, lung structure and function (Nat Commun 2020), suggesting AAV-mediated gene therapy as a clinically viable option for surfactant protein deficiencies. We are currently expanding our AAV platform to other monogenetic lung diseases.

Funded by:
Canadian Institutes of Health Research
Heart & Stroke Foundation of Canada
Stem Cell Network
Children's Hospital of Eastern Ontario Research Institute
The Ottawa Hospital Foundation
Canada Foundation for Innovation