Preclinical Studies of Induced Pluripotent Stem Cell-Derived Astrocyte Transplantation in ALS

Principal Investigator: MARAGAKIS, NICHOLAS J
Institution Receiving Award: JOHNS HOPKINS UNIVERSITY
Program: ALSRP
Proposal Number: AL093061
Award Number: W81XWH-10-1-0520
Funding Mechanism: Therapeutic Development Award
Partnering Awards:
Award Amount: $1,854,934.00


Amyotrophic lateral sclerosis (ALS) is the most common form of adult motor neuron disease in which there is progressive degeneration of both motor neurons in the brain and spinal cord. The majority of ALS cases are apparently sporadic (SALS) but some occur in families -- classified as familial ALS (FALS). In 1993 FALS cases were found to be associated with mutations in superoxide dismutase (SOD1). It now appears that SOD1 mutations account for about 10% of all familial cases of ALS. Since then, several SOD1 mouse models of ALS have been developed. While these animal models recapitulate the relative selective loss of motor neurons resulting in limb paralysis and death, they may only represent a small proportion of relevant ALS pathobiology -- familial ALS. Because modeling ALS has been largely limited to the use of the SOD1 animal models, a significant proportion of ALS biology (particularly relevant to sporadic ALS) has gone largely unstudied. Recently, an exciting technique called induced pluripotent stem cell (iPSC) methodology has allowed for the generation of pluripotent stem cells from skin. This methodology holds great promise in medicine. Most basically, the ability to produce stem cells from skin cells obviates the need for obtaining human embryonic stem cells and at least easing this ethical dilemma. The technique is also powerful because we can obtain tissue not only from a few ALS patients, but the hundreds that are seen in our clinic each year. This allows us to create cell lines of patients with a variety of ALS presentations and allows us to ask questions regarding differences in the disease. We may also be able to use these iPSCs for transplantation into ALS patients. We will focus on making cells called iPSC-glial restricted precursors. These cells can develop into astrocytes -- key players in ALS disease and neuroprotection.

Previous ALS stem cell transplantation studies have focused mostly on motor neuron replacement. However, replacement of astrocytes, derived from human induced pluripotent stem cell-derived glial restricted precursors (iPSC-GRPs), may represent a more feasible approach towards host motor neuron protection.

We envision that what we learn from this proposal will allow us to understand whether the source of the iPSC-GRPs is important. For example, we don't know whether iPSC-GRPs from ALS patients will be normal (and thus neuroprotective) or whether these iPSC-GRPs harbor ALS-specific abnormalities that may lack benefit or potentially exacerbate disease. In that case, ALS patients may benefit more from the transplantation of iPSC-GRPs from normal subjects.

We hope that what we learn will allow us to develop a clinical trial where we can transplant iPSC-GRPs into the spinal cords of ALS patients. In order to attempt this, we must first make certain that these cells are able to improve the course of the disease in ALS rats. Studying these rats will also help us to understand some of the risks that may be involved in the procedure and to assess whether the cell transplantation strategy is safe. Risks that we must consider include weakness from the injection of the cells and uncontrolled growth of the cells once they are transplanted. Other concerns would be that cells taken from ALS patients may not survive well following transplantation. We have designed this study to recapitulate how we would transplant the cells into ALS patients and to carefully address the issues of safety.

This proposal will be of benefit in two critical ways. First, we will be able to study the clinical applicability of transplanting these iPSC-GRPs into ALS animals and eventually ALS patients. Second, the iPSCs derived from subjects with familial ALS, sporadic ALS, and control subjects can be used for future analysis and an increased understanding of what causes ALS.