Early Translational III
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.
The goal of this Development Candidate (DC) proposal is to use a neurosteroid compound for stimulating endogenous neurogenesis and maturation of oligodendrocyte precursor cells (OPC) for the treatment of hypoxic ischemic encephalopathy (HIE). Aim 1 seeks to understand the enhancement of endogenous neural and glial stem cell repair mechanisms in pre-clinical models of HIE. Aim 2 will examine whether the neurosteroid enhances engraftment of human neural stem cells in a relevant rodent model. Finally, Aim 3 will develop the preclinical tools for IND application. Objective and Milestones -Reviewers generally agreed that the milestones are not quantifiable and lack appropriate indicators for the specified success criteria. For example, increased neurogenesis is not a criterion for success as a milestone. -Reviewers concluded that the Target Product Profile lacked novelty, since neurosteroids have been studied previously in numerous preclinical models of neurological injury and have failed to show desirable outcomes. -Reviewers had serious concerns about the treatment window and considered it to be less than ideal, as previous studies and trials using similar timing for treatment with neurosteroids have all failed. Rationale and Significance - Neonatal hypoxic-ischemic injury is a major medical problem with enormous societal and economic impacts. - The majority of reviewers questioned the scientific rationale for developing a neurosteroid to enhance stem cell-mediated repair of ischemic damage, since previous trials using similar drugs and mechanisms of action have been unsuccessful. However, some reviewers felt the approach had value. - Reviewers agreed that, since success in this project would largely depend on a good safety profile, the toxicology studies should have been complete and submitted with this proposal. Research Project Feasibility and Design - Reviewers were unclear about the relevance of evaluating neurosteroid-enhanced human neural stem cell grafts in the designated preclinical model. - Reviewers strongly disagreed with the applicant’s assertion that evaluation of human stem cells on their own or in combination with neurosteroids in a more relevant model was beyond the scope and time-frame of the proposed project. - Other aspects of the research plan appear straightforward and well designed. Qualification of the PI - The PI has a substantial track record including much expertise in neurosteroid research. - Although more junior, the co-PI has produced a significant body of work. - The research team is strong and multi-disciplinary, with expertise in neurosteroids, neuronal injury models, neonatology, steroid analysis and clinical candidate development. Collaborations, Assets, Resources and Environment - All of the appropriate collaborations are documented and in place. - IP filings have been completed, and the PI has had preliminary discussions with the FDA. - The resources and environment at the applicants’ institutions are world-class and are known for work in this field. Responsiveness to the RFA - Some reviewers found this proposal only marginally responsive to the RFA, while others did not find it responsive at all. They argued that the proposed investigation is essentially a neuroprotection study presented as a regenerative medicine proposal and that stem cells are not necessary to address the use of this neurosteroid in the treatment of hypoxic ischemic brain injury. - Reviewers generally agreed that this proposal is not unique and is the extension of a small molecule therapy that has been used already in numerous pre-clinical models of neurological injury over the past decade.