Babies born preterm have fragile blood vessels that put them at risk of brain bleeds early in life. Bleeds in the cerebellum are especially common, affecting around 20 percent of the youngest preterm infants. Unfortunately, the consequences can be severe. For some, bleeding in the brain can be fatal. For others, the bleeding damages the newborn’s burgeoning brain during a crucial window of development and leads to long-term neurological conditions. Currently, doctors lack treatments to offer because it’s still not known what a drug should target.
Mark Petersen, a neonatologist and neuroscientist at the University of California, San Francisco, and his colleagues recently discovered that the protein fibrinogen crosses the blood-brain barrier during a bleed and impairs normal growth of the cerebellum (1). Though fibrinogen is usually helpful as a blood clotting protein elsewhere in the body, once inside the brain, it prevents neurons from being created during brain development.
Motivated by his passion to help babies and their families during such a critical time, Petersen aims to turn his team's findings into a treatment to target misplaced fibrinogen in the brain and allow for normal brain development in premature infants with brain bleeds. “These interventions could change the course of their life,” he said.
Mark Petersen (left) with staff research associate Caroline Brandt (right) aims to develop a therapeutic for neonatal brain bleeds by targeting misplaced fibrinogen in the brain.
Credit: Gladstone Institutes
What are the consequences of a neonatal brain bleed?
We know that after these brain bleeds, the baby’s brain has a lot of inflammation, and the normal developmental processes are blocked. This early brain growth sets the neural connections with all the parts of the brain that will be there for the rest of their life. When this development is disrupted, it can lead to conditions such as cerebral palsy, autism, or problems with attention and performing well in school. Those are some of the things that are set early on, so if we can intervene and correct those pathways, we can get the infant on that developmental path to help them reach their full potential. We think that the earlier the intervention, the more we can promote these normal developmental processes. It’s so different from an adult brain which has very limited capacity to repair itself.
Why did you study the effects of fibrinogen in the neonatal brain?
For several years, we followed a cohort of 59 preterm infants who got serial magnetic resonance imaging scans over time so that we could see the development and growth of their brains. We found that the babies that had these bleeds had smaller cerebellums. We know that the proliferation of progenitor cells drives the normal growth of the cerebellum. We hypothesized that something in the blood might be blocking that growth process — but we didn’t know the specifics of the protein and its mechanism. Based on our previous work and others’ work in adult neurologic diseases, we thought that maybe this coagulation protein, fibrinogen, could play a role. But we had never looked at this in a preemie population or animal models of newborn brain injury.
Fibrinogen glows red in the cerebellum of a neonatal mouse with an inflammatory brain injury.
Credit: Gladstone Institutes
What did you find in your mouse models of newborn brain injury?
We found that if we injected blood proteins into the brains of mice, or if the mice had leaky blood vessels, we saw a decrease in cerebellum growth in the mice as they developed, similar to human babies. In these same animal models of cerebellar injury, genetically modified mice that did not have fibrinogen in their blood were protected. These mice had improved cerebellar growth, less inflammation in the cerebellum, and increases in markers of Sonic hedgehog signaling, a developmental pathway necessary for brain development. Because they still had all of the other proteins in their blood, we were able to show it was really the lack of fibrinogen in the blood that was the main reason for this effect.
How does fibrinogen cause damage and stop the growth of the cerebellum?
Outside the brain, fibrinogen is a clotting protein. In the brain, it doesn't just have a clotting function anymore, it also has other effects during an injury. It induces inflammation from brain immune cells called microglia, and it also binds to cell receptors and alters stem cell differentiation. And in this case, we also found that it will inhibit some of the developmental pathways and block cell proliferation.
Fibrinogen tends to bind to other classes of cell receptors that we know are expressed on these cells and we know can impact Sonic hedgehog signaling. So that's some of the work that we're doing now to find the exact mechanism for how it's inhibiting Sonic hedgehog. We have an R01 grant from the National Institute of Neurological Disorders and Stroke (NINDS) to look at those very things and now tease out the therapeutics to test in preclinical models. We want to move quickly in that realm, to be able to get it towards a therapy and test in the larger animal models.
What kind of therapies would be developed based on this study?
Based on our findings in the fibrinogen-lacking genetically modified mice that were protected from brain bleeds, we could imagine a strategy using anticoagulants or other things to deplete fibrinogen. In the case of preterm infants, since one of the major risks is bleeding in the brain, that strategy wouldn't be the right one. So, what we could do instead is target the different aspects of these receptor interactions or these downstream pathways to limit fibrinogen’s deleterious effects while preserving the blood coagulation function.
We see in our models that there's an increase in inflammation and a direct effect on the progenitor cells. Both of them could be impacting the cerebellum. Our colleague Katerina Akassoglou and her team at the Gladstone Institutes developed antibodies that will target the specific site on fibrinogen that binds to a receptor on innate immune cells to block the inflammatory effects of fibrinogen (2). We’re doing more work to find whether we can have a similar strategy to target the effect on progenitor cells by first finding exactly how fibrinogen blocks Sonic hedgehog signaling in these cells. An antibody-based approach would be very intriguing because this would have the advantage of being a more stable and longer lasting treatment in a preterm infant. That also raises the possibility that pregnant mothers could receive the antibody or a vaccine that will induce the antibodies in a high-risk pregnancy, or if we thought that a baby was going to be born early, to impact these pathways before the baby is born.
What did you find to be most exciting about this work?
The most exciting part is that we've identified an actual protein in blood that has therapies that are already in clinical development or moving towards clinical trials. That means the path to translate these therapeutics into clinical trials for infants is much shorter. When there is bleeding in the brain, all of our therapies are really just supportive, such that we continue to support the development and the nutrition and the breathing of the baby, but we don't have anything specific to target what the blood is doing in the brain. This is the first specific therapy that has real therapeutic potential with real agents that is being developed.
These interventions could change the course of their life.
– Mark Petersen, University of California, San Francisco
It's a pathway that's very attractive since what we’re targeting is a specific protein that's in the wrong spot. There will be less chance of affecting normal developmental pathways compared to therapies that target a pathway that’s activated in brain cells that oftentimes has other important developmental processes.
What motivates you to do this research?
This path isn't an easy one for anyone as a physician scientist. It takes a lot of time and effort and sacrifice. We're better at taking care of the babies, but after several decades, we still don't have a real treatment for brain bleeds. The basic science is what drives new discoveries, so I always wanted to have a part in that, but it is also that connection to the bedside and families to find a real treatment that keeps us all motivated to continue to do the work.
This interview has been condensed and edited for clarity.
References
- Weaver, O. et al. Fibrinogen inhibits sonic hedgehog signaling and impairs neonatal cerebellar development after blood–brain barrier disruption. Proc Natl Acad Sci USA 121, e2323050121 (2024).
- Kantor, A.B., Akassoglou, K., & Stavenhagen, J.B. Fibrin-Targeting Immunotherapy for Dementia. J Prev Alzheimers Dis 10, 647–660 (2023).
