The surgical tools currently available to transplant cells to the human brain are crude and underdeveloped. In current clinical trials, a syringe and needle device has been used to inject living cells into the brain. Because cells do not spread through the brain tissue after implantation, multiple brain penetrations (more than ten separate needle insertions in some patients) have been required to distribute cells in the diseased brain region. Every separate brain penetration carries a significant risk of bleeding and brain injury. Furthermore, this approach does not result in effective distribution of cells. Thus, our lack of appropriate surgical tools and techniques for clinical cell transplantation represents a significant roadblock to the treatment of brain diseases with stem cell based therapies. A more ideal device would be one that can distribute cells to large brain areas through a single initial brain penetration.
In rodents, cell transplantation has successfully treated a great number of different brain disorders such as Parkinson’s disease, epilepsy, traumatic brain injury, multiple sclerosis, and stroke. However, the human brain is about 500 times larger than the mouse brain. While the syringe and needle transplantation technique works well in mice and rats, using this approach may not succeed in the much larger human brain, and this may result in failure of clinical trials for technical reasons.
We believe that the poor design of current surgical tools used for cell delivery is from inadequate interactions between basic stem cell scientists, medical device engineers, and neurosurgeons. Using a multidisciplinary approach, we will first use standard engineering principles to design, fabricate, refine, and validate an innovative cell delivery device that can transplant cells to a large region of the human brain through a single brain penetration. We will then test this new prototype in a large animal brain to ensure that the device is safe and effective. Furthermore, we will create a document containing engineering drawings, manufacturing instructions, surgical details, and preclinical data to ensure that this device is readily available for inclusion in future clinical trials.
By improving the safety and efficacy of cell delivery to the brain, the development of a superior device for cell transplantation may be a crucial step on the road to stem cell therapies for a wide range of brain diseases. In addition, devices and surgical techniques developed here may also be advantageous for use in other diseased organs.
The citizens of California have invested generously into stem cell research for the treatment of human diseases. While significant progress has been made in our ability to produce appropriate cell types in clinically relevant numbers for transplantation to the brain, these efforts to cure disease may fail because of our inability to effectively deliver the cells. Our proposed development of a superior device for cell transplantation may thus be a crucial step on the road to stem cell therapies for a wide range of brain disorders, such as Parkinson’s disease, stroke, brain tumors, epilepsy, multiple sclerosis, and traumatic brain injury. Furthermore, devices and surgical techniques developed in our work may also be advantageous for use in other diseased organs. Thus, with successful completion of our proposal, the broad community of stem cell researchers and physician-scientists will gain access to superior surgical tools with which to better leverage our investment into stem cell therapy.
This application is focused on the development of a novel device to deliver cells to the brain. The applicant notes that in preclinical models, in which cell therapies have had some success, large numbers of cells are delivered to small brains, achieving widespread distribution. The much larger human brain requires many brain penetrations to achieve similar distribution. The applicant identifies the lack of devices capable of delivering large numbers of cells in a single, non-traumatic penetration as a roadblock to the translation of cell therapies for neurological diseases. There are three Specific Aims: (1) to design, optimize and validate a novel delivery device for dissemination of human embryonic stem cell (hESC)-derived neural precursor cells (NPCs) to a large target volume via a single cranial penetration; (2) to demonstrate safety and efficacy of the device in a relevant preclinical model; and (3) to compile preclinical data and lay the groundwork for inclusion of the device in future Investigational New Drug (IND) applications to the FDA.
The reviewers agreed that this innovative proposal addresses a significant translational bottleneck. They noted that while the development of a cell delivery device may seem a bit mundane, there is a real, practical need for this technology. Multiple injection tracts are typically required to deliver cells to the human brain which significantly increases the risk of adverse events during the implantation procedure. Reviewers agreed that a device that achieves large-scale cell delivery from a single needle tract could have a major impact in the field of regenerative medicine. They suggested that this bottleneck may even represent the rate-limiting step in the translation of neural cell therapies.
Reviewers described the research plan as well conceived, straightforward and feasible. They appreciated the carefully planned timeline and well-articulated milestones. Reviewers praised the strong preliminary data, which suggest that the applicant has made significant progress toward designing the device and defining a series of bioengineering specifications for further development. Potential pitfalls and alternative approaches are considered and discussed. Reviewers generally found the choice of preclinical model to be a strength, but noted that its immune competence will affect cell survival. The reviewers’ major concern with the proposal was that the applicant does not propose to examine behavior outcomes in the preclinical model following transplant. They noted that behavioral analysis is essential to evaluate the safety of the device and the potential for adverse events. They also would have appreciated a greater emphasis on neuropathological analyses of the grafts and effects of the device on brain tissue.
The reviewers praised the Principal Investigator (PI) and the strong, interdisciplinary research team. They described the PI as a true clinician/scientist with an outstanding record of training and publication. Reviewers appreciated the team’s extensive expertise in neurosurgery, neural transplantation, stem cell biology, bioengineering and medical device delivery. Despite the large assembled team, reviewers did suggest that the proposal could benefit from the presence of a veterinary neurologist to assist with behavioral analyses in the animal model and a neuropathologist to assess any traumatic changes.
Overall, reviewers were enthusiastic about this proposal to develop a novel cell delivery device for the brain. They suggested some additional experiments in the preclinical model, but generally found the proposal to be innovative, feasible and highly significant. Reviewers agreed that, if successful, this proposal could have a major impact on the field of regenerative medicine.
- A motion was made to move this application into Tier 1, Recommended for Funding. No specific programmatic reason was identified. The motion carried.