Early Translational II
Lifetime costs for individuals currently living with spinal cord injury (SCI) in California can be estimated at $138 to $304 billion in 2007 dollars. These figures do not take into account indirect costs such as loss of wages; unemployment statistics indicate that only 20% of tetraplegics and 30% of paraplegics are employed five years post-injury, and the National Spinal Cord Injury Statistical Center (NSCISC) has projected the indirect costs of SCI to average an additional $62,270 per individual per year in 2007 dollars. Critically, a therapeutic target that can restore as little as 1-2 segmental levels of spinal cord function, converting a high tetraplegic to a low tetraplegic, or tetraplegic to a paraplegic, has the potential to not only significantly improve individual quality-of-life and independence, but also reduce the shared costs of health care and loss of productive employment, saving $707,616 to $2,037,046 in individual lifetime costs for care. Pharmacological treatment of SCI has primarily relied on the use of steroids, such as methylprednisolone, and other anti-inflammatory agents. This approach has produced limited improvements and increased risk of infection in penetrating injuries. There are no other FDA approved treatments for SCI, however, stem cell-based therapeutics have the potential to contribute to the repair of SCI pathophysiology. Multipotent human neural stem cells (hNSC) can be derived from adult/fetal central nervous system (CNS) tissue as well as pluripotent cells, e.g. hESC or hiPSC. FACS selection for CD133 highly enriches for neural populations. We have shown that fetal hNSC presorted for CD133+/CD34- at the time of isolation, survive, engraft, migrate, differentiate, and promote recovery after contusion SCI in multiple models. Further, proof of concept experiments testing human fetal CD133+/CD34- hNSC are at an advanced stage, including multiple FDA-authorized Phase I trials. These data support the potential of sorted fetal hNSC for SCI and other CNS indications. The development of a cell-based therapy for SCI that can be individualized based on the generation of patient-specific hiPSC lines address significant limiting factors for clinical immunosuppression in this population, and will contribute to addressing the large unmet medical need for patients with this debilitating injury. Accordingly, the disease candidate feasibility studies proposed seek to establish proof of concept, method of action, and safety studies for patient-specific CD133+/CD34- hiPS-NSCs as therapeutic candidates for SCI and other CNS disorders and diseases. Ultimately, these studies may also permit the development of strategies to screen/select cell therapeutics for safety and disease modifying potential, maximizing the translation of stem cell-based neurotherapeutics. Outcome of the proposed studies will help not only those Californians with SCI, but will more globally pave the way for the use of stem cells in a variety of diseases.
Statement of Benefit to California:
Spinal cord injury (SCI) causes a devastating condition resulting in partial to complete loss of motor and/or sensory function below the spinal level of the injury. The average age at the time of SCI in 2009 was 34 in the USA, resulting in a lifetime of paralysis that is associated with a host of medical complications. According to a 2009 survey by the CDC and Christopher and Dana Reeve Foundation there are 1.3 million SCI individuals living in the USA, which translates to 147,027 SCI individuals living in California; 52.4% (77,042) of these are tetraplegic and 41.5% (61,016) paraplegic. Critically, the economic impact of SCI is disproportionate to the incidence of SCI. The average estimated lifetime cost for individuals sustaining an SCI resulting incomplete motor function at any level at the age of 25 is $681,843 in 2007 dollars. For individuals sustaining an SCI resulting in paraplegia this figure rises to $1,022,138, and for individuals sustaining an SCI resulting in tetraplegia this figure further increases to range between $1,729,754 and $3,059,184, depending on the vertebral level affected. Translated to California alone, the lifetime costs for SCI individuals currently living with SCI can thus be estimated at $138 to $304 billion in 2007 dollars. These figures do not take into account indirect costs such as loss of wages; unemployment statistics indicate that only 20% of tetraplegics and 30% of paraplegics are employed five years post-injury, and the National Spinal Cord Injury Statistical Center (NSCISC) has projected the indirect costs of SCI to average an additional $62,270 per individual per year in 2007 dollars. Critically, a therapeutic target that can restore as little as 1-2 segmental levels of spinal cord function, converting a high tetraplegic to a low tetraplegic, or tetraplegic to a paraplegic, has the potential to not only significantly improve individual quality-of-life and independence, but to also reduce the shared costs of health care and loss of productive employment, saving $707,616 to $2,037,046 in individual lifetime costs for care. The results of the feasibility studies proposed will establish proof of concept and method of action studies supporting the initiation of the development of patient specific therapeutic candidate methodology, with the goal of leading to the regulatory approval for clinical trials in SCI. Beyond motor function, the broader range of potential benefit includes improved sensory, motor, bowel/bladder, and or autonomic, function. Furthermore, therapeutic strategies designed to restore function by restoring connectivity in the sub-acute to chronic stages post-traumatic SCI could eventually provide more far reaching benefits to non-traumatic spinal cord etiologies. The outcome of the proposed studies will help not only those Californians with SCI, but will more globally pave the way for the use of stem cells in a variety of diseases.
The goal of this Development Candidate Feasibility Award proposal is to develop human neural stem cell (hNSC) lines derived from induced pluripotent stem cells (iPSCs) for transplantation to treat spinal cord injury (SCI). The proposal addresses three aims: 1) to develop research cell banks of iPSC-derived hNSCs enriched for a specific cell population (CD133+/CD34-) by FACS sorting; 2) to evaluate cell fate and myelination potential as well as functional recovery following transplantation of these hiPSC-NSC; 3) to examine their safety by evaluating in vivo tumorigenicity following transplantation. The principal investigator (PI) previously provided some evidence that fetal human neural stem cells sorted for CD133+/CD34- survive, differentiate, and promote recovery after SCI in multiple animal models. The proposed research is focused on demonstrating and developing a significant potential for patient-specific treatment of multiple central nervous system (CNS) diseases using sorted hiPSC-NSCs. The reviewers agreed that the objective of this proposal was reasonable and that a final product effective for treatment of SCI patients would have a significant impact on an important unmet medical need. However, there were several significant concerns about the approach that lowered reviewer enthusiasm for this proposal. First, the use of NSCs derived from iPSCs generated from patients with SCI would require several months for derivation, differentiation, and safety checks prior to implantation. Consequently, transplantation would take place in a chronic SCI environment where extensive glial scarring and neurodegeneration have already occurred. Such a scenario is inconsistent with the proposed experimental plan in which cells are transplanted nine days after injury, a relatively acute post-injury period. The reviewers agreed that for the study to provide relevant information, it would need to employ chronic SCI models; this would require a major redesign of the proposal. A second major concern focused on the fate and action of the transplanted cells. Based on preliminary data with sorted hNSC from other sources than hiPSC, the applicant proposed that these cells have the ability to differentiate and integrate as oligodendrocytes and neurons into the damaged spinal cord, but reviewers found that substantial evidence for this (e.g rigorous quantitative stereological data) was lacking. Such data were deemed essential, since the therapeutic basis of the overall approach depends on functional cellular replacement rather than trophic support or neuroprotection. Reviewer enthusiasm was further dampened by a number of concerns about the feasibility of the research plan. First, the use of a proposed marker for identification of myelination was felt to be insufficient, since this marker is expressed in oligodendrocytes even in the absence of neurons, i.e. when no myelination can have occurred. Second, antibodies proposed for characterization of the oligodendroctye lineage lacked specificity. Additionally, the applicant intends to genetically manipulate hiPSC-NSC to enable proposed mechanism of action studies, but there was no information to indicate that the applicant had adequate experience or expertise with zinc finger nuclease technology. The reviewers described the investigators as outstanding scientists and well suited to carry out portions of the proposed research plan. The research team was praised for their extensive experience in the area of SCI and their appropriate publication record in specialist journals. The PI’s institutional support and environment was judged to be of excellent quality. Reviewers expressed concern about the lack of sufficient expertise in iPSC biology and derivation and suggested that the development of an appropriate collaboration would significantly strengthen the project. In summary, this is a proposal to develop an iPSC-based treatment for spinal cord injury. Strengths of the proposal included its focus on an important unmet medical need and the experience of the applicant in the SCI field. Weaknesses include a number of significant problems with the rationale and experimental design, greatly diminishing the feasibility of the proposed approach.