Spina bifida is a devastating and costly birth defect that causes lifelong paralysis and is one of the most common birth defects worldwide. Spina bifida affects physical, educational, social, and psychological development, and most children require many operations throughout life. A recent randomized controlled trial showed for the first time that spina bifida can be improved by surgically repairing the defect before birth. However, improvements in the distal neurological consequences (such as paralysis and bladder incontinence) were less strong. This project aims to address these problems by developing a stem cell product from the fetus's own tissue and applying these cells during surgery before birth in order to take advantage of the unique immunology of the developing fetus. In this project we will complete the development of this stem cell product and establish its preliminary safety and efficacy in appropriate animal models. Successful use of stem cell therapy for spina bifida could potentially cure this devastating disease and would introduce the concept of using a fetus's own tissue to treat existing or later disease.
Statement of Benefit to California:
Spina bifida is one of the most disabling and costly birth defects compatible with life. California’s 5-year statewide rate for spina bifida was 6.8 per 10,000 live births between 1999 and 2003—significantly higher than the Healthy People 2010 target of 3 per 10,000 births. Average total lifetime cost to California is approximately $532,000 per child. For many children, the cost may be several millions of dollars, and these figures do not account for indirect medical costs, pain and suffering, and lost time of unpaid caregivers. There is no cure for spina bifida, and interventions that mitigate the negative consequences of the disease (lower body paralysis, bowel and bladder incontinence) are urgently needed. Hope was recently provided by a clinical trial which demonstrated, for the very first time, that the paralysis associated with spina bifida might be improved by repairing the defect before birth. The great promise of fetal therapy for spina bifida is that by intervening as early as possible—in the womb—the potential exists to correct the problem in time to prevent permanent damage. This proposal presents an innovative stem cell-based prenatal therapy that may further improve and possibly cure the neurologic deficits of spina bifida. A cure for spina bifida would relieve families and society of the tremendous cost burden of the disease and would be life-changing for future children afflicted with spina bifida.
This development candidate (DC) proposal will test autologous placental-derived stem cells (p-SC) in a delivery vehicle, as a candidate therapy for the prenatal treatment of spina bifida. The principal investigator (PI) plans to refine methods to characterize p-SC and use these assays to profile the cells through isolation, expansion and formulation. Next, he/she plans to identify a surgical delivery vehicle and develop a reproducible, scalable process to produce therapeutically relevant quantities of p-SC in a clinically relevant time frame. When this has been accomplished, the PI proposes to demonstrate disease-modifying activity in relevant preclinical models of spina bifida as well as perform preliminary safety testing.
Objective and Milestones
- Reviewers found the milestones poorly focused and often lacking in quantitative success criteria. Further, they noted that plans to achieve the milestones were poorly described in the application.
- The TPP is scientifically and clinically reasonable
Rationale and Significance
- The proposed DC, if successfully developed, could have a major impact upon patients. Spina bifida is a major disabling condition for which even prenatal surgery has had only limited success.
- The proposal builds upon pioneering clinical work performed by the PI.
Research Project Feasibility and Design
- The panel agreed that the plan lacked so many critical details as to be fatally flawed. For example, the cell biology as presented in the application was weak; the method of cell isolation, relevant starting cell numbers, cell expansion characteristics and differentiation procedure, if applicable, are all lacking from the application. This hindered the ability to assess feasibility of the proposed program.
- Reviewers questioned the rationale for using term placenta as a source for many studies, as it may differ substantially from the therapeutically relevant pre-term placenta, the source for the actual DC. Further, the donor origin of placental material should be determined.
-The applicants have not provided any data to substantiate that the small pre-term placental sample obtained at the developmentally appropriate stage for clinical use could provide adequate cells in the targeted time window for transplantation.
- Several concerns regarding the relevant preclinical model were raised. This proposed preclinical model is immunologically competent to reject the transplanted human cells at the specified developmental stage and the applicant did not properly address this concern. In addition, given the variability of recovery following repair, the proposed animal numbers might be inadequate to detect subtle functional improvements and demonstrate in vivo disease modifying activity. Further, it is not clear that the proper controls have been selected.
- While the immunostaining in the preliminary data are encouraging, reviewers did not find them convincing evidence that the desired cell population could be derived from placenta. They noted a lack of data demonstrating generation of functional neurons, glia and Schwann cells from this cell source.
- The timeline to achieve many of the milestones is unrealistic.
Qualification of the PI (Co-PI and Partner PI, if applicable) and Research Team
- The PI is an accomplished surgeon with laudable expertise in spinal bifida repair and relevant preclinical models, but does not possess a track record in cell therapy.
- The application would benefit from more experienced cell therapy and cell biology leadership. The co-investigator providing cell therapy expertise as yet has no independent track record, and input from an accomplished former mentor will be limited to a consultant role.
- A formal communication plan was not evident from the application and should be developed to ensure integration of the diverse expertise of the team members.
Collaborations, Assets, Resources and Environment
- Collaborators are excellent investigators, but the cell biology expertise is not evident in the application. Some, but not all of the proposed collaborations are already established.
- Reviewers were not clear regarding some of the consultants’ roles and questioned whether some of these individuals would be able to commit the necessary time to the project.
- The host institution is strongly committed to translational research.
Responsiveness to the RFA
- The proposal is responsive to the RFA.