Novel Remyelination Approaches Using Human Schwann Cell Precursors
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.
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.