Childhood interstitial lung disease (chILD) is a rare group of genetic lung disorders that affects infants and children, resulting in symptoms such as shortness of breath, rapid breathing, and coughing. Despite numerous identified causal genes for chILD, understanding its pathogenesis has been challenging due to difficulties in accessing primary human cells from affected children and limited methods for maintaining these cells. In a recent study conducted by the Center for Regenerative Medicine (CReM) at Boston University and Boston Medical Center, in collaboration with Washington University School of Medicine, researchers have successfully developed a model to study the most prevalent genetic cause of this debilitating pediatric lung disease. The findings of this study have been published in the Journal of Clinical Investigation.
The researchers utilized induced pluripotent stem cells (iPSCs), which were generated from skin cells obtained from children with chILD who carry mutations in a gene called ABCA3 – the most common genetic cause of the disease. These iPSCs were cultured to differentiate into alveolar epithelial type 2 cells, which are responsible for causing the disease. By comparing the diseased cells from affected children with cells that had been gene-edited to correct the ABCA3 mutation, the researchers were able to identify several measurable differences. The results provided valuable insights into the disease, offering potential opportunities for therapeutic discovery.
Overcoming the challenge of accessing and culturing cells with mutations in the ABCA3 gene from chILD patients has been a significant step forward in the development of therapeutic alternatives. Dr. Yuliang (Leon) Sun, the first author of the study, explains, “In this study, we developed and extensively characterized an in-vitro disease model, overcoming these hurdles.” Dr. Sun recently obtained his dual degree from Boston University, and his dissertation served as the foundation for this research.
According to the researchers, ABCA3 mutant cells exhibited reduced production of surfactants, which are essential for maintaining the shape of the lungs. Additionally, these mutant cells had smaller lamellar bodies, organelles specific to alveolar epithelial type 2 cells, where surfactants are produced. Furthermore, the ABCA3 mutant cells displayed higher levels of inflammation compared to healthy cells. Erin Hennessey, a co-author and Ph.D. student leading the project’s continuation, states, “These findings provide crucial insights into chILD and pave the way for potential cures.”
This study represents a significant advancement in understanding and treating chILD, and it highlights the potential of pluripotent stem cells for disease modeling. The methods used in this research are patented by the CReM at Boston University, which has developed lung cells from iPSCs obtained from skin or blood samples. These iPSCs are stored in the CReM’s national lung disease-specific iPSC repository, an open-source resource available to the global research community in their search for cures for lung diseases, including chILD, which currently lack sufficient treatment options.
Dr. Darrell N. Kotton, senior author of the study and Director of the CReM, expresses hope that the increasing number of available iPSCs from children with chILD in their stem cell repository will aid researchers worldwide in combating this devastating disease. The research conducted by the CReM holds great potential for advancing scientific knowledge and developing effective treatments for chILD and other lung diseases.
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1. Source: Coherent Market Insights, Public sources, Desk research
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