Use of Human Neural Stem Cells for Neuroprotection Following Hypothermia In Sub-acute Neonatal

Funding Type: 
Disease Team Therapy Planning I
Grant Number: 
DR2-05279
Investigator: 
ICOC Funds Committed: 
$0
Public Abstract: 
Neonatal hypoxic-ischemic injury (HII) (annually ~1700/California & 13,000/US) remains a devastating cause of brain injury resulting in long-term disability (cerebral palsy, mental retardation, epilepsy). Approximately 80% of newborns surviving severe HII are severely impaired and 20% are moderately impaired. It is estimated that the lifetime national costs for persons with mental retardation approaches $51.2 billion and for those affected with cerebral palsy it is $11.5 billion. In many individuals, the etiology is traceable to neonatal HII. The costs of care for a family with these disabilities are prohibitively expensive: it is estimated that the average lifetime additional expenses for an individual with cerebral palsy is ~$921,000. As a result, many newborns with moderate & severe HII have life-long needs for chronic medical and rehabilitative care that in California. is funded by the Dept. of Health Care Services and agencies such as Cal. Children’s Services, Cal. Med. Assistance Program., and the Child Health & Disability Prevention Program. Although hypothermia (HT) has become the standard-of-care treatment for newborns with HII, it must be initiated within hours after birth (making it unfeasible for many newborns), and is only modestly effective in moderate HII & totally ineffective in severe HII. There is a dire need for developing better (& later) treatments that more elegantly target injury processes and pathways that together result in brain damage. Although many agents have been tried, there remain no effective treatments for global or focal ischemic injury in adults or children. Neural stem cells (NSCs) have proven effective in rodent models of HII based on multiple mechanisms leading to several clinical trials in adult stroke. We believe the combination of HT and NSCs may act together because of overlap in their respective reparative mechanisms. This clinical trial will be done at 8 California newborn intensive care units over a 4 year period. We will evaluate term newborns who have suffered HII and undergone therapeutic HT. In half of eligible newborns, NSCs will be implanted by a neurosurgeon into the ventricles of the brain using special endoscopic equipment. These infants will undergo frequent pediatric, neurological and neuropsychological examinations as well as studies using magnetic resonance imaging until study completion at 18 months of life. Our objective is to show that implantation of stem cells into newborns with HII who undergo HT will have better long-term neurological outcomes than newborns who did not receive stem cells. If successful, we can then pursue larger clinical trials nationwide. This hopefully will provide a treatment that could dramatically reduce the morbidity associated with neonatal HII. The potential social and economic benefits to affected children, their families and society would be enormous.
Statement of Benefit to California: 
Neonatal hypoxic-ischemic injury (HII) (annually ~1700/California & 13,000/US) remains a devastating cause of brain injury resulting in long-term disability (cerebral palsy, mental retardation, epilepsy). The majority of newborns surviving severe HII are severely impaired and the costs of care for a family with these disabilities are prohibitively expensive: it is estimated that the average lifetime additional expenses for an individual with cerebral palsy is ~$921,000. As a result, many newborns with moderate & severe HII have life-long needs for chronic medical and rehabilitative care that in California is funded by the Department. of Health Care Services and agencies such as California Children’s Services, California. MEDI-CAL. Assistance Program and the Child Health & Disability Prevention Program. Treatment of newborns with HII consists of using therapeutic hypothermia (HT) which has become the standard-of-care. However, it must be initiated within hours after birth. There is a strong need for developing better treatments that target injury processes and pathways that together result in brain damage. Neural stem cells (NSCs) have proven effective in rodent models of HII based on multiple mechanisms leading to several clinical trials in adult stroke. We believe the combination of HT and NSCs may act together because of overlap in their respective reparative mechanisms. This clinical trial will be done at 8 California newborn intensive care units over a 4 year period. We will evaluate term newborns who have suffered HII and undergone therapeutic HT. In half of eligible newborns, NSCs will be implanted by a neurosurgeon into the ventricles of the brain using special endoscopic equipment. These infants will undergo frequent pediatric, neurological and neuropsychological examinations as well as studies using magnetic resonance imaging until study completion at 18 months of life. Our objective is to show that implantation of stem cells into newborns with HII who undergo HT will have better long-term neurological outcomes than newborns who did not receive stem cells. If successful, we can then pursue larger clinical trials nationwide. This hopefully will provide a treatment that could dramatically reduce the brain injury associated with neonatal HII. The potential social and economic benefits to affected children, their families and society would be enormous. The proposed research will be of great benefit to the citizens of California as it has the potential to substantially reduce the severity of neurological disability in neonates who suffered severe birth asphyxia which would result in improved quality of life, reduced medical and rehabilitation costs and provide the opportunity for affected children to become more independent and benefit from educational and training opportunities and programs offered by our state government.

© 2013 California Institute for Regenerative Medicine