New mRNA Therapy Restores Blood Vessel Growth in Premature Infant Lungs

A major breakthrough from a UCLA-led research team is offering new hope for treating bronchopulmonary dysplasia (BPD), a serious lung disease that affects babies born extremely early. The researchers have identified a molecular switch that determines whether tiny blood vessels in a premature infant’s lungs can repair and regrow after injury. Even more importantly, they have demonstrated a way to flip that switch back on.

The study, published in Cell Stem Cell, focuses on why the lungs of many premature infants fail to recover after lifesaving medical interventions like oxygen therapy and mechanical ventilation. These treatments are essential for survival, but they can unintentionally damage the developing lungs during a critical growth period.

Understanding Bronchopulmonary Dysplasia and Why It Matters

Bronchopulmonary dysplasia is one of the most common and challenging complications of extreme prematurity. Babies born very early often have lungs that are not fully developed, especially when it comes to forming tiny air sacs (alveoli) and the dense network of blood vessels needed for oxygen exchange.

BPD develops due to a combination of factors, including premature birth, inflammation or infection, and prolonged exposure to high oxygen levels and breathing support. Over time, these stressors disrupt normal lung development. Children who survive BPD often face long-term breathing problems, frequent hospitalizations, and an increased risk of chronic lung disease later in life.

At present, there are no treatments that repair the underlying vascular damage in BPD. Medical care mainly focuses on managing symptoms rather than restoring normal lung growth. This is why the findings from this new study are so significant.

The Key Discovery: A Problematic Protein Switch

The UCLA research team discovered that the failure of lung repair in BPD comes down to an imbalance in a single protein called NTRK2. This protein has been extensively studied in the nervous system but had not previously been explored in detail in the pulmonary blood vessels.

In healthy lungs, endothelial cells — the cells that line blood vessels — produce a full-length, functional version of NTRK2 that supports blood vessel growth and repair. However, in lungs affected by BPD, these same cells begin producing a shortened, nonfunctional isoform of NTRK2.

An isoform is essentially a different version of the same protein. In this case, the truncated NTRK2 isoform interferes with the lung’s ability to rebuild the delicate vascular network needed for healthy breathing. When this dysfunctional form dominates, the lung’s natural repair program stalls.

How Researchers Identified the Mechanism

To uncover this process, the team used single-nucleus multiomic sequencing, a powerful technique that allows scientists to see how genes are expressed and regulated within individual cells. They analyzed donated lung tissue from human infants with and without BPD, comparing the cellular and molecular differences between the two groups.

This analysis revealed a distinct population of dysfunctional endothelial cells in BPD lungs that overproduce the truncated NTRK2 isoform. The researchers also mapped the regulatory pathways responsible for shifting production away from the healthy, full-length protein toward the shortened version that blocks regeneration.

This detailed molecular insight provided a clear explanation for why lung repair fails in many premature infants.

Using mRNA to Restore Healthy Lung Repair

Once the researchers identified the problem, they turned to a solution inspired by recent advances in messenger RNA (mRNA) technology. Messenger RNA acts as temporary instructions that tell cells how to produce specific proteins.

The team designed mRNA that encodes the healthy, full-length NTRK2 protein. To ensure the therapy reached the right cells, the mRNA was packaged inside lipid nanoparticles engineered to selectively target lung endothelial cells. This targeted delivery helped minimize unwanted effects on other lung cell types.

In mouse models of BPD, newborn mice were exposed to high oxygen levels, a standard method for mimicking the disease. When treated with the full-length NTRK2 mRNA, the results were striking. The therapy restored blood vessel growth, supported the formation of healthy lung air sacs, and reversed structural damage caused by oxygen injury.

Testing the Therapy in Human Blood Vessel Organoids

To further validate their findings, the researchers tested the approach in human blood vessel organoids. These are small, three-dimensional tissues grown from human induced pluripotent stem cells, which can develop into nearly any cell type. The organoids replicate key features of human vascular biology.

Under high-oxygen conditions, these organoids typically show poor blood vessel growth, similar to what happens in BPD. However, when treated with the full-length NTRK2 mRNA, the organoids formed more new blood vessels and developed a healthier, more organized vascular system.

This result strengthened the case that the therapy could be relevant not only in animal models but also in human lung tissue.

Why Isoform Balance Is So Important

One of the most important insights from this study is that BPD is not just caused by injury, but by the lung’s inability to repair itself afterward. The disease progresses when the balance between healthy and dysfunctional gene isoforms is disrupted.

By pinpointing this isoform imbalance as a root cause of vascular failure, the study opens the door to targeted, disease-modifying treatments rather than symptom management alone. Restoring the healthy version of NTRK2 effectively reactivates the lung’s natural repair system.

Broader Implications Beyond Premature Lungs

While this research focuses on BPD, the implications extend much further. Blood vessel injury plays a role in many diseases, from chronic lung conditions to heart disease and organ damage following inflammation or oxygen deprivation.

The success of this isoform-specific mRNA therapy suggests that similar strategies could be used to promote vascular repair in other organs. It also highlights how precise molecular targeting can make regenerative therapies safer and more effective.

What Comes Next for This Research

The research team plans to conduct additional preclinical studies to assess long-term safety and optimize dosing. These steps are critical before any therapy can move toward clinical testing in human infants.

They also aim to explore whether gene-isoform rebalancing could be applied to other diseases where blood vessel regeneration is impaired. While clinical use is still in the future, this study represents a significant step toward repair-based treatments for conditions once thought to be irreversible.

Why This Study Is a Big Deal

This work changes how scientists think about bronchopulmonary dysplasia. Instead of viewing it solely as a complication of prematurity, the study shows that BPD involves a shutdown of the lung’s natural repair machinery. By restoring the correct protein signals, it may be possible to help premature lungs rebuild themselves.

For families affected by BPD, and for clinicians who currently have limited treatment options, this research offers a glimpse of a future where therapy goes beyond survival and focuses on true lung regeneration.

Research paper:
https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(25)00440-0