Early Translational II
$1 666 212
Multiple Sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS) with a prevalence of 1 in 700 adults in the United States (US). MS results in permanent and progres-sive neurological disability, and currently, treatment costs for MS in the US are ~$23 billion/year. MS symptoms are caused by inflammation and loss of neuronal axons. Inflammation results in demyelination and transient abnormalities of axonal conduction, which underlie relapses, while axon loss produces irreversible functional impairment, leading to chronic disability. Axon loss has two major causes: (i) acute axonal transection due to inflammation and (ii) chronic axonal degeneration secondary to the initial dysfunction of the myelin sheath (eg., Wallerian degenera-tion). The importance of the latter is highlighted by axon loss seen in genetic diseases affecting oligodendrocytes in mice and humans. Thus, on-going processes caused by long-standing mye-linopathy likely cause progressive functional loss seen in MS. Successful treatments for MS that will halt or prevent disability will require not only immune modulatory drugs, but also therapies capable of promoting myelin repair, or remyelination. Currently, no single drug and/or compound can provide these multiple activities. Here we propose a novel developmental candidate - Schwann cell precursors (SCPs) derived from human embryonic stem cells (hESCs) or induced pluripotent cells (iPSCs). We argue that human ES cell-derived SCP-like cells (hESC-SCPs) may fulfill both fast-acting immune modulatory abilities and long-term myelination capacity, in particular by generating low immunogenic peripheral type myelin. Animal models provided experimental proof that Schwann cells transplanted into host CNS survive, integrate and support regeneration. Published data and our preliminary results strongly suggest that SCPs possess both required activities upon terminal maturation - immune modulation and myelin repair. Furthermore, the oligodendrocyte-based remyelination might be inefficient, because newly formed CNS-type myelin can be easily destroyed by successive waves of autoimmune attacks. In contrast, Schwann cell-produced myelin almost entirely lacks major immunogenic epitopes present on the oligodendrocyte-produced myelin, thus preventing the autoimmune T cell destruction of CNS neurons. Because SCPs represent glial committed progenitors they can’t differentiate into neurons, avoiding potential complications from dyskinesia observed with some therapeutic approached using multipotent neural stem cells. Because Schwann cells are derived from the neural crest, a transient developmental cell population obtaining the fetal material at this stage is virtually impossible. The use of hESCs and/or iPSCs represents the only realistically feasible cell source for SCP-based therapy. Relatively slow progression of MS could provide a realistic window for the derivation of patient-specific iPSCs and SCPs.
Statement of Benefit to California:
Cell therapies proposed for traumatic CNS injuries, ischemia and several neurodegeneration conditions such as Parkinson’s, Alzheimer’s and ALS rely on our ability to manipulate neural stem and progenitor cells. Their therapeutic use depends on our understanding of the genes and pathways that govern proliferation of multipotent stem cells and progenitors as well as their differentiation under the appropriate stimuli. Here we will determine whether or not human embryonic stem cell-derived Schwann precursors are optimally positioned to provide both immune modulatory protection and myelinogenic repairmen to treat multiple sclerosis. If successful, these studies provide the proof of principle/feasibility and in the future personalized cell lines as a novel candidate cell type for treatment of demyelination disorders such as multiple Sclerosis. An effective, straightforward, and understandable way to describe the benefits to the citizens of the State of California that will flow from the stem cell research we propose to conduct is to couch it in the familiar business concept of “Return on Investment”. The novel therapies that will be developed as a result of our research program and the many related programs that will follow will provide direct benefits to the health of California citizens. These financial benefits will derive directly from two sources. The first source will be the sale and licensing of the intellectual property rights that will go to the state and its citizens from stem cell research programs financed by the CIRM. The second source will be several types of tax revenues that will be generated from the increased bio-science and bio-manufacturing businesses that will be attracted to California by the success of the CIRM.
The goal of this Development Candidate Feasibility (DCF) proposal is to assess the potential use of Schwann cell precursors (SCPs) derived from human embryonic stem cells (hESCs) for treating demyelinating disorders such as multiple sclerosis (MS). Myelin forms a sheath around neuronal axons and is critical for efficient conduction of electrical signals in a healthy, functional nervous system. In MS, autoimmune attack and inflammation leads to demyelination and ultimately loss of axons in the brain and spinal cord. The applicant hypothesizes that SCPs might contribute to myelin repair while simultaneously modulating the immune system, thereby combining two potential therapeutic activities in a single treatment. Moreover, the peripheral-type myelin generated as the SCPs differentiate and mature might prove less susceptible to subsequent immune attack than that produced by oligodendrocytes, the myelinating cells of the central nervous system. Three aims have been proposed to explore the feasibility of this approach. First, the applicant will characterize the myelinogenic potential and immunomodulatory properties of hESC-derived SCPs in vitro. Next, hESC-derived SCPs will be transplanted into a model system of hypomyelination and evaluated for their long term myelinogenic properties in vivo. The final aim is to assess the neuroprotective potential and immunomodulatory properties of hESC-derived SCPs in representative models of chronic and relapsing MS. The reviewers acknowledged that in theory, this application proposes a reasonable objective and would address a clear, unmet medical need. They were concerned, however, at the lack of data supporting the applicant╒s ability to maintain a stable, unipotent SCP population with the desired activities. Without evidence for an expandable precursor population with well-defined, reproducible phenotypic characteristics, the basis for the proposed genetic modifications and lengthy differentiation procedure was considered precarious. The extent to which SCPs would prove immunomodulatory was also questioned, given the lack of evidence provided that even bona fide Schwann cells would possess this activity in the proposed setting. While these weaknesses undermined their confidence in the premise, reviewers agreed that hESC and/or included pluripotent cells represent the best and perhaps only realistic source for obtaining sufficient SCPs for therapeutic consideration. Reviewers raised significant concerns about the feasibility of the research plan. Notably, the approach to explore immunomodulatory effects of SCP on mouse cells was considered flawed. Reviewers questioned the applicability of xenogenic immune responses and suggested that human immune cells would provide a more relevant model. Furthermore, the use of murine cells would limit the rigor with which the rationale could be tested. Reviewers also discussed a number of concerns relating to translatability, noting that the proposed differentiation procedure relies on reagents and genetic manipulation that would prove challenging for clinical consideration. They also found the preliminary data to be weak and suggested that the proposal would benefit from a greater emphasis on cell production, characterization, and in vivo demonstration of myelination prior to undertaking work with the MS disease model. In the end, they were not convinced that an appropriate SCP candidate had been derived, or that it would be obtained through the proposed research. Reviewers acknowledged the principal investigator╒s (PI) training but expressed concern over his/her diffuse publication record and apparent lack experience with myelination. They key collaborators were considered excellent, although some reviewers would have appreciated a more detailed description of their respective contributions. In summary, while reviewers appreciated the objective of this DCF application, they expressed concerns about the rationale, cell choice, feasibility, and experience of the PI. Ultimately, reviewers concluded that the status of the underlying research was not sufficiently mature and therefore they did not recommend this application for funding. PROGRAMMATIC REVIEW A GWG member proposed a motion to assess the level of enthusiasm among the panel for considering this application from a programmatic perspective, given the relevance of MS to CIRM╒s mission. Reviewers reiterated their overriding concern that the applicant had not identified the correct cell type nor presented an appropriate plan for doing so. They highlighted the PI╒s limited experience with myelination and clinically challenging differentiation procedures. The project was deemed premature to have any translational impact for MS and the GWG did not support a motion to consider the application further.
- Charles ffrench-Constant