Neonatal Brain Ischemia: Neuroimaging as a Basis for Rational Stem Cell Therapy

Funding Type: 
Disease Team Planning
Grant Number: 
ICOC Funds Committed: 
Public Abstract: 

This grant proposes to use stem cells to treat neonatal hypoxic-ischemic brain injury (HII), a common and serious problem with well-established long-term complications including mental retardation, cerebral palsy and epilepsy. HII is due to a lack of oxygenated blood going to brain tissue around the time that a newborn is delivered and can result in irreversible brain injury. We will use magnetic resonance imaging (MRI) which has greatly advanced our ability to ‘look inside’ the brain and better detect brain injury. One of the major problems found when investigators tried to treat adult stroke was that it was very difficult to have good animal models that reflected what was happening in humans. The same problem occurs in newborns. If we can successfully treat newborns with stem cells this may result in a lifelong benefit of improved neurological and developmental outcome. We will try to determine how advanced imaging can be used to develop parallel models of HII severity in rat pups and human neonates. We believe that such models can be used in a unique approach to assess the optimal methods to monitor stem cell implantation using long-term imaging and behavioral outcomes. In the animal studies, we will implant iron-labeled stem cells and use imaging to monitor migration, proliferation, and location in a newborn rat pup model that mimics neonatal HII. By varying the duration of how long these rat pups are exposed to hypoxia, we can create a model of injury severity (3 levels—mild/moderate/severe). We have developed methods to quantify the severity of injury using different types of analysis of the MRI scans. We will implant stem cells into pups with mild/mod/severe injury to determine which group shows the best response. We hope that the optimal method of stem cell implantation will improve neurological recovery at 6 months without adversely affecting these animals and we will use behavioral testing of the animals and imaging to assess how they recovered. In the human newborn studies, we will develop and apply a similar imaging model of injury severity using imaging data from 4 institutions ({REDACTED}, {REDACTED}, {REDACTED} and {REDACTED}). We will use this information to develop/refine these methods to do further studies that will use initial imaging data together with 18-month follow-up data from the same newborns. We hope that imaging data in humans can help us decide which human newborns might be good candidates for stem cell therapy and that the rat pup studies will give us the optimal methods of how to implant stem cells and monitor their effect. Additional research in higher-order animals and in further validating the clinical model will subsequently form the basis for clinical trials of using stem cells in neonates with HII. We believe that the detailed approach outlined in this proposal provides a cautious road map towards determining whether and how stem cells can be safely and optimally offered for use in selected newborns with HII.

Statement of Benefit to California: 

This proposal will benefit children born in California who suffer acute hypoxic brain injury at birth and who develop long term neurological and developmental disorders such as mental retardation, cerebral palsy or epilepsy. Treatment with stem cells should reduce the burden of illness of this very common disorder that occurs in full term newborn infants. It will also benefit the families and caretakers of affected children as it will be easier to provide care for such children as they will have less severe neurological deficits. The long-term outcome of severe perinatal brain injury is a life-time of disability and if this can be reduced, it will also reduce the costs of chronic care, hospitalizations, rehabilitation and care in long-term nursing facilities of affected children. Finally, by developing the imaging methods to help improve candidate selection for treatment, for monitoring stem cell implantation, and for following the effects of treatment on outcome, this will provide a way to use these imaging methods for other acute diseases that affect the nervous system that are even more common and devastating such as traumatic brain injury.