The findings of an interdisciplinary team of medical professionals and researchers reveal a breakthrough discovery regarding the role of a blood protein called fibrin in impeding a crucial biological process essential for brain development in early life. This discovery sheds light on the root cause behind developmental delays resulting from brain bleeds in preterm infants, offering new avenues for therapeutic interventions to mitigate long-term health risks.
Dr. Mark Petersen has witnessed the devastating impact of brain bleeds in premature infants firsthand. This common condition affects up to 20% of babies born before 28 weeks of gestation, increasing the likelihood of developmental delays and autism.
“As a neonatologist and neuroscientist, it’s frustrating that we lack effective treatments to counteract the harmful effects of bleeding in the developing brain, despite the well-known long-lasting consequences,” explains Petersen, who is the director of the Neuro-Intensive Care Nursery at UC San Francisco (UCSF) and an associate professor of pediatrics at UCSF. “Until now, the understanding of why brain bleeding is closely linked to the neurological issues these babies often face has been limited.”
In a study published in Proceedings of the National Academy of Sciences (PNAS), Petersen and a team from Gladstone and UCSF elucidate this complex medical condition, showcasing that fibrin, a blood protein, obstructs a crucial cell-signaling pathway crucial for neuron development, especially in the cerebellum.
When extremely premature babies are born, the delicate blood vessels in their brains can rupture, leading to bleeding; the earlier the baby, the higher the risk. Though the exact cause remains unclear, the adverse neurological impacts of brain bleeding are well-documented, says Petersen, who heads a research laboratory at the UCSF Newborn Brain Research Institute.
In the recent study, researchers demonstrated in mouse models that fibrin, typically involved in blood clotting, hinders the cell-signaling pathway pivotal for neuron creation in the cerebellum. This was corroborated using brain scans from nearly 60 preterm babies. Petersen notes that no other blood protein exhibited the same inhibitory effect on this pathway, pinpointing fibrin as a promising therapeutic target for infants affected by brain bleeds.
Target for Treatment
The study’s implications extend beyond neonatal care, as the signaling pathway under scrutiny (known as the “sonic hedgehog” pathway, or SHH) plays vital roles in human development and is associated with various diseases.
Collaborating with Senior Investigator Dr. Katerina Akassoglou’s lab at Gladstone, Petersen delves into understanding how blood leakage into the brain triggers neurological diseases by interfering with the brain’s immune system, leading to harmful effects on cognition and motor functions.
“The detrimental effects of blood in the developing brain suggest new insights into neurodevelopmental disorders linked to preterm births,” says Akassoglou, also the director of the Gladstone-UCSF Center for Neurovascular Brain Immunology. “Neutralizing fibrin’s toxic effects in the brain presents a promising therapeutic avenue for neurological diseases and potentially for treating the youngest patients.”
Akassoglou’s team previously developed a drug, a therapeutic monoclonal antibody, that specifically targets fibrin’s harmful properties while preserving its clotting function. This fibrin-targeting immunotherapy has shown protective effects in conditions like multiple sclerosis and Alzheimer’s disease in mice and is currently in Phase 1 clinical trials by Therini Bio.
“We are optimistic about our ability to identify the cause of enduring neurological issues in preterm babies due to brain bleeding and the potential treatment target we have discovered,” Petersen remarks. “Our study lays the foundation for exploring our therapeutic approach in developmental brain injury and other conditions involving neurovascular disruption or abnormal SHH signaling.”
Shaping Early Life
Over the past three years, Petersen has led the study, beginning with observations of smaller cerebellums in premature babies over time. Working with MRI experts and neurologists at UCSF, the team connected the reduced cerebellum size to brain bleeding rather than other possible causes.
“During this critical developmental phase, the cerebellum undergoes rapid changes and is highly vulnerable to injury,” states Petersen. “Any factor impeding the SHH pathway could significantly impact the brain, prompting us to investigate fibrin’s role.”
In conjunction with MRI analyses led by Dr. Dawn Gano, a pediatric neurologist at UCSF, the team conducted experiments in animal models to comprehend how fibrin influences the SHH pathway and neuron growth.
Dr. Lennart Mucke, director of the Gladstone Institute of Neurological Disease, praises the research for addressing a fundamental biomedical query and its potential to prevent lasting neurological issues stemming from early infancy.
“The team’s discovery promises to potentially alter the life trajectory of young patients with brain bleeds,” Mucke affirms. “The current focus is on expediting the translation of this research to clinical practice.”
