Brain damage affects 1 in 700 California newborns, yet there are very few ways of treating newborn brain damage. Prematurity, stroke and vascular accidents are the main culprits. These forms of brain damage can have long-lasting effects, including loss of intellectual and motor function. We have shown that a rarely-studied steroid called allopregnanolone (ALLO), which is made in the normal newborn brain, helps the brain recover from injury. We aim to develop the use of ALLO to treat newborn brain damage. We have already shown that ALLO slows brain degeneration and prolongs life in mice that have genetic brain diseases that also affect children. We propose to develop ALLO treatment by testing its effects in mice with brain injury. ALLO should stimulate the damaged brain to produce more stem cells and integrate these cells into the damaged tissue, facilitating healing. We will also use mice to test whether ALLO can increase the survival and growth of human neural stem cells that are being used in clinical trials. We will check our results using the same tests used for human assessments, so that our results can be rapidly brought to clinical trials. We have also been developing ALLO for the treatment of other brain diseases (lysosomal storage diseases), so its clinical use for neonatal brain injury should progress rapidly to IND. Development of ALLO as a way to stimulate regeneration following newborn brain injury may prevent the life-long consequences of cerebral palsy.
Statement of Benefit to California:
Cerebral palsy affects approximately 1 in 700 children in California. Overall lifetime costs of cerebral palsy exceed $1 million per individual, costing Californians approximately $53 billion in total costs. The most frequent cause of this lifelong disability is preterm birth, closely followed by hypoxic-ischemic encephalopathy in term infants. We propose harnessing the protective and regenerative capacity of allopregnanolone (ALLO), a steroid endogenously made by the normal brain, to prevent the long-term sequelae of neonatal brain damage by stimulating the proliferation and functional differentiation of neural and glial cells. In this Early Translational work, we will use rodent models that mimic the damage associated with preterm birth and cerebral palsy to: (1) establish biological markers of recovery that parallel those seen in human infants, and (2) determine optimal regimens for ALLO stimulation of neurological repair. Development of ALLO as a stem cell stimulant to prevent cerebral palsy and improve neurological function of compromised infants should result in an improved quality of life for Californian children and families. In addition, it will reduce medical costs, limit the financial burden of care-taking, and increase Californian families' household earning potential.