Early Translational III
Hypoxic ischemic (HI) brain injury occurs when the brain does not receive enough oxygen during the birthing process. Based on our proof on concept study showing that transplantation of neural stem cells into a model of HI brain injury improves sensorimotor skills, we propose to generate human neural stem cell banks that will qualify for the FDA mandated quality controls and complex testing processes. We will perform studies that will confirm the long-term safety and efficacy of the transplanted cells in HI brain injury model. In the United States, neonatal HI injury is sustained by 1-8 per 1,000 births. In severe cases, the mortality rate is 25-50% with most deaths occurring in the first week of life. The large majority of survivors develop serious complications, such as cerebral palsy. These statistics, costs for care and rehabilitation and lack of therapy indicate that HI brain injury is a current significant unmet medical need in California and US - one that is not represented in CIRM’s current Translation Portfolio. Our proposal involves milestone-driven deliverables to develop a neural stem cell product that may improve the quality of life for these children who demonstrate a deep inner strength when tackling their daily challenges.
Statement of Benefit to California:
Based on our proof on concept study in which we demonstrated that the transplantation of neural stem cells into a model of hypoxic ischemic (HI) brain injury improves sensorimotor skills, we propose milestone-driven deliverables that will allow us to develop a neural stem cell product for the treatment of children with HI brain injury in California, US and the world. In the United States, neonatal HI brain injury is sustained by 1-8 per 1,000 births. In severe cases, the mortality rate is 25-50% with most deaths occurring in the first week of life. The long-term complications depend on the severity of the lesion, with the large majority of survivors developing serious complications, such as cerebral palsy. These statistics, costs for care and rehabilitation and lack of therapy indicate that HI brain injury is a current significant unmet medical need in California and US - one that is not represented in the CIRM’s current Translation Portfolio. We believe that we have a cellular product that may improve the quality of life for children with HI injury who demonstrate a deep inner strength when tackling their daily challenges. Furthermore, the technology used to create the stem cell banks will have been developed in California and provide a significant beneficial impact on the economy in terms of employment and commercialization of the cellular product.
This is a development candidate proposal to develop a therapy for the treatment of neonatal hypoxic-ischemic brain injury (HI) in infants. The objective is to create qualified research cell banks of human embryonic stem cell-derived human neural stem cells (hNSCs) and to evaluate these cells in a rodent model of HI, exploring possible mechanisms of action in terms of altering the innate immune response to injury. The applicant proposes four key Aims: 1) optimize cell production and the assays required evaluate cell identity, purity and immunogenicity; 2) quantify and define sensorimotor and cognitive improvements resulting from cell transplantation; 3) characterize the therapeutic dose with Good Manufacturing Practice (GMP)-grade cells; and 4) evaluate long-term efficacy and safety of the candidate cell line. Objective and Milestone - The proposed Milestones lack clarity in articulating success criteria for the project. - The applicant did not provide clear GO/NO GO types of criteria on specific outcomes. - It is unclear how the data will be handled and evaluated. - Some reviewers argued that milestone 4 is particularly weak, as it proposes a long-term safety study, but only efficacy outcomes are measured. Reviewers emphasized that the proposal would have benefited from some estimates of potential toxicity and the use of immunosuppression or immune-compromised rodents. Rationale and Significance - The development of a useful treatment for HI would be highly significant. - Reviewers expressed major concerns that a treatment based on the localized injection of cells was inappropriate for a condition involving global or widespread injury. - The proposal did not employ an appropriate model of white matter injury that is clinically relevant. - The scientific rationale for applying neuronal stem cell therapies to neonatal HI brain injury appears reasonable; however, the proposal does not distinguish between patient populations that are appropriate and inappropriate for such therapies. - Reviewers noted that the preliminary data provided some support for the approach. Research Project Feasibility and Design - Reviewers criticized the animal model as not appropriate for the proposed condition, since it creates a neonatal stroke rather than mirroring neonatal HI. - Reviewers found much of the preliminary data to be largely illegible and uninterpretable. - No clear rationale was provided for the development of additional cell lines, a major focus of proposed activity. - Several of the proposed experiments were not well motivated or described. Qualification of the PI - Reviewers generally agreed that the PI is experienced in the development of stem cell-based therapeutics for ischemic brain injury, although some raised concerns about significant gaps in the PI’s career as evident in the biosketch. - Some reviewers argued that the PI appears to be overcommitted to too many projects. Collaborations, Assets, Resources and Environment - Reviewers had strong concerns about the proposed level of staffing, lack of key personnel and absence of an established research team. - No collaborations were listed or proposed. - Reviewers expressed serious reservations about the ability and suitability of the applicant institution to host the proposed research. - Although the application stated that the researcher would have access to stem cell and other research facilities at a nearby institution, no letter confirming such access was included. Responsiveness to the RFA - No relevant concerns were highlighted by reviewers under this review criterion.