Early Translational I
Many injuries to the brain and spinal cord do not heal. Spinal cord injury can leave a patient confined to a wheelchair for life. After suffering a stroke a patient is often left unable to move parts of their body or have impaired brain function such as losing the ability to speak. With both stroke and spinal cord injury the window for spontaneous healing is typically about three months. After that time has passed, conventional therapeutic interventions do not significantly help. Multiple sclerosis is another type of injury to the brain and spinal cord. The immune system in these patients attacks the insulation (called myelin) that surrounds nerve fibers. The body attempts to repair this damage but cannot keep up with the progression of the disease. The nerves of the injured brain and spinal cord do not regenerate for several reasons. In stroke and spinal cord injury a scar forms (the glial scar), physically preventing the regrowth of nerve fibers. In multiple sclerosis the progressive loss of the myelin insulation causes the nerves to malfunction and die. One possible way to overcome both of these problems is to add a type of cell with potential to destroy or prevent the formation of the scar, encourage the growth of new nerve fibers, and re-establish the myelin insulation. A scientist in Japan has attempted to create a cell able to do some of these potentials from an a from bone marrow adult stem cell. Treatment of these cells with a collection of reagents and growth factors caused them to resemble in certain ways the cells that form part of the myelin insulation. This has inspired several researchers to test these cells in animal models of nerve injury. The cells, now called SB618 cells, were very effective in restoring nerve function. Exactly how SB618 cells restore nerve function is not understood. This project will optimize the production of SB618 cells so that additional experiments can be performed. Effects on models of stroke, spinal cord injury and multiple sclerosis will be examined. Tests to help determine the mechanism of action will be performed in the laboratory. If this three year project is successful, it will trigger the production of clinical grade SB618 cells and the safety studies required by the FDA for the filing of an Investigational New Drug application (an IND). SB618 cells will be ready for human clinical a little more than a year later.
Statement of Benefit to California:
This proposed research is for the translation of experimental observations made in academia to the point where a product will be ready for pre-clinical and clinical development. If all goes well, the product will be ready to initiate human clinical trials four years from the beginning of the project and be ready for commercialization six years after that. During the 10 years between project initiation and commercialization, the company will need to add skills and manpower. This will bring high paying jobs to California, adding to the tax base for the benefit of all Californians. This will be part of the movement, already underway, making California the leading center for stem cell research and development in the world. If the project is commercially successful, there is an agreement with CIRM that revenue would be shared with the State of California. The amount to be shared is up to three times the amount of CIRM grant money awarded. If the therapy achieves blockbuster status the amount paid to California could be many millions of dollars more than that. There is also an agreement with CIRM that a therapy resulting from CIRM funds will be made available to uninsured Californians through the California Discount Prescription Drug Program. Finally, and most importantly, this project aims to provide relief from stroke, spinal cord injury and multiple sclerosis. These devastating conditions have huge impacts on the quality of life and the productivity of people everywhere. Californians do not benefit disproportionately from this except in taking pride in the fact that the voters had the wisdom to put this in motion.
In this development candidate grant proposal, the goal is to develop a specialized mesenchymal stem cell line that could be used clinically to treat nervous system damage due to injury or disease. Initially, the applicants propose to optimize and improve procedures for generating a human bone marrow-derived line with many of the properties of Schwann cells. Once these cells have been reproducibly obtained, their efficacy for restoring nerve function will be evaluated in three preclinical models of disease, including spinal cord injury (SCI), stroke, and multiple sclerosis (MS). For the final aim, the applicants propose a series of in vitro analyses to elucidate the mechanisms of action that underlie the regenerative capacity of these cells. Reviewers agreed that the proposed research represents an appropriate target for early translation and addresses an important medical need. The key innovation was thought to be the mesenchymal stem cell (MSC) line which has been exposed to Schwann cell-generating factors, a regimen that might improve their ability to restore nerve function to damaged tissues. Mesenchymal cell therapies have already shown promise in the treatment of disorders of the nervous system, and further advances such as those represented by the proposed technology could have a profound impact on the field. The significance of this project was therefore considered to be high. In spite of this potential impact, reviewers pointed to a number of flaws in scientific rationale and experimental design that severely affected the feasibility of the proposal. First, the overall strategy was predicated on the notion that this particular MSC line can promote myelination, a hypothesis that was not convincingly supported by the preliminary data. Second, reviewers commented on the applicant’s failure to adequately address aspects of immune modulation throughout the grant. The possibility that immunosuppressive effects of the cells might contribute to their efficacy in vivo, which has been reported elsewhere, was not considered. Furthermore, experimental allergic encephalitis (EAE), the preclinical model of MS proposed in this application, can be favorably influenced by a number of immunological manipulations. Since none of these manipulations have shown to be very effective in human MS, the use of the EAE model in these experiments was questioned. Finally, some reviewers were concerned that the measures taken to insure that transplanted cells would escape host immune rejection were inadequate, especially in the case of the stroke model. In addition to these fundamental concerns, the reviewers were mixed about the technical merits of the proposal. In general, the in vitro mechanism-of-action studies were praised for being straightforward and well laid out. One reviewer especially approved of the stroke model and acknowledged the expertise of the collaborating investigator. In contrast, experiments to assess the myelination potential of the MSCs were criticized as inadequate, with most reviewers advocating for the evaluation of an increased number of phenotypic markers. Similarly, a much more detailed histological analysis was desired in order to adequately assess the activity of the MSC line in vivo. Finally, while most of their concerns were technical, the reviewers were also somewhat uncertain of the qualifications of the investigative team. Although well-published in other areas, there is little track record to support the principal investigator’s capacity to direct a project of this complexity, despite the inclusion of a qualified collaborator. The environment appeared adequate for the conduct of the studies. Finally, several reviewers expressed concern that the budget was poorly justified, significantly inflated, and proposed a level of staff that is out of scale with the needs of the project. In summary, the reviewers felt that the proposed research addresses an important topic and provides an interesting and relevant candidate for translational consideration. However, their enthusiasm was significantly diminished by uncertainties in both the experimental design as well as the qualifications of the research team.