Intranasal epidermal growth factor treatment rescues neonatal brain injury

Abstract

There are no clinically relevant treatments available that improve function in the growing population of very preterm infants (<32 weeks gestation) with neonatal brain injury. Diffuse white matter injury (DWMI) is a common finding in these children and results in chronic neurodevelopmental impairments1,2. As shown recently, failure in oligodendrocyte progenitor cell maturation contributes to DWMI3. In a previous study, we demonstrated that epidermal growth factor receptor (EGFR) plays an important role in oligodendrocyte development4. Here, we examine whether enhanced epidermal growth factor receptor (EGFR) signaling stimulates the endogenous response of EGFR-expressing progenitor cells during a critical period after brain injury, and promotes cellular and behavioral recovery in the developing brain. Using an established model of very preterm brain injury, we demonstrate that selective overexpression of human (h)EGFR in oligodendrocyte lineage cells or the administration of intranasal heparin binding EGF immediately after injury decreases oligodendroglia death, enhances generation of new oligodendrocytes from progenitor cells (OPCs) and promotes functional recovery. Furthermore, these interventions diminish ultrastructural abnormalities and alleviate behavioral deficits on white matter-specific paradigms. Inhibition of EGFR signaling with a molecularly targeted agent used for cancer therapy demonstrates that EGFR activation is an important contributor to oligodendrocyte regeneration and functional recovery after DWMI. Thus, our study provides direct evidence that targeting EGFR in OPCs at a specific time after injury is clinically feasible and applicable for the treatment of premature children with white matter injury.

WITHDRAWN: Intranasal GM-CSF enhances efficacy of local ACNU delivery rendezvousing with TMZ plus irradiation in glioblastoma

“…Studies have shown that the nasal route could be used to successfully deliver drugs to the central nervous system (CNS) [22]. Joseph Scafidi et al [21] provided direct evidence that intranasal treatment is a plausible route to introduce sufficient HB-EGF into the brain and WM of critically ill VPT infants. This approach allows the GM-CSF cytokine to target the brain more directly, leading to less impact on other parts of body.…”

Oligodendrocyte Development and Plasticity

“…Epidermal growth factor (Egf ) has a profound effect on the production of OPCs in vivo, greatly increasing numbers of OPCs when Egf is delivered into the intact adult CNS and significantly improving the repair of demyelinating damage caused by gliotoxin injection or perinatal ischemia (Cantarella et al 2008;Scafidi et al 2014). In this context, Egf is likely to act by steering SVZ stem cells away from their default fate (generation of olfactory interneurons) toward production of glial cells, including OPCs Cantarella et al 2008;Gonzalez-Perez and Alvarez-Buylla 2011).…”

Radiation-induced brain injury: low-hanging fruit for neuroregeneration

“…We speculate that such risks may be lower with cellular therapies than with strategies aiming to "reactivate" endogenous progenitors via growth factor infusion, as has been considered for other CNS diseases. 76,98 In fact, NSCs themselves exhibit innate antitumor properties. 84 Given the migratory capacity of OPCs throughout previously irradiated brain, and the tropism of many progenitor cell types for tumors, 1,17,43,87 OPCs or NSCs engineered to additionally produce antitumor and/or proregenerative molecules may enable broad delivery of protective and regenerative cells throughout irradiated portions of the CNS.…”