Human stem cell-derived motor neurons as an experimental model for ALS

Funding Type: 
SEED Grant
Grant Number: 
ICOC Funds Committed: 
Disease Focus: 
Parkinson's Disease
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
Cell Line Generation: 
Embryonic Stem Cell
Public Abstract: 
Effective treatments for motor neuron diseases, such as Amyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy (SMA), Kennedy's Disease and Hereditary Spastic Paraplegias (HSP), have yet to be developed. Currently the only FDA-approved drug for treating motor neuron diseases is riluzole. However, riluzole has only moderate success in prolonging patient survival. One possible reason for the lack of effective treatments for motor neuron diseases is that drugs for such diseases were previously developed for humans based on animal models which may not accurately reflect motor neuron diseases in humans. Therefore, establishing a human system to study motor neuron diseases is a crucial step in developing successful therapeutic treatments. Human Embryonic Stem (hES) cells constantly self-renew and have the potential to grow into any type of cell in the human body. Since little hES research has been conducted, it is not clear whether these cells can be used in scientific models to understand cell death in motor neuron diseases. Therefore, in this study we propose to steer hES cells into becoming motor neurons so that we may gain a better understanding of the aforementioned motor neuron diseases. Because of their self-renewing properties and their ability to be fostered in a scientific environment, our studies of hES cells could provide a useful source of knowledge to develop therapies for patients with motor neuron diseases or spinal cord injuries. Aim 1: We will take motor neurons from hES cell lines and study their molecular and cellular properties. These studies will allow us to identify how motor neurons express specific genes and proteins. In addition, we will be able to evaulate how effective hES cell-derived motor neurons are in developing treatments for motor neuron diseases. We will also improve the mothod used by the scientific community to induce motor neurons from hES cells. The goal is to develop a reliable method to use hES cells for deriving motor neurons useful for basic research and clinical applications. Aim 2: We will evaluate toxicity in hES cell-derived motor neurons to test whether human cell cultures can be used as experimental models to investigate motor neuron diseases. We will first analyze how well functional ionotropic glutamate receptors (the basic building blocks of motor neurons in the brain) in these hES-derived motor neurons are expressed using both a pharmacological approach and by recording the electrical activities of motor neurons (electrophysiology). We will then investigate cell death in motor neurons using specific toxins that will target glutamate receptors and transporters. We will also determine the effect of drugs in protecting these cells from toxin-induced death.
Statement of Benefit to California: 
The goal of our proposed research is to use hES cells to develop a reliable method for deriving motor neurons. Since hES cells can self-renew and be maintained in vitro the motor neurons derived from hES cells could provide useful knowledge that could be applied to treatments for patients with motor neuron diseases or spinal cord injuries. This proposed research will benefit the State of California and its citizens in several ways. The most obvious way in which this research will benefit Californians is through the reduction of pain and suffering undergone by Californian patients suffering from motor neuron diseases or spinal cord injuries. Caretakers and relatives of those with motor neuron-related medical problems will also experience the benefits. As the state with the largest population in the nation, California spends a enormous amount of money on healthcare for its residents. In the future, finding a cure for neurodegenerative diseases like ALS will significantly reduce state healthcare costs by lessoning the amount of time patients are treated for such diseases. In addition, conducting research in the stem cell field will create job opportunities and attract highly skilled personnel to California. Other states will not be able to attract these workers because of federal restrictions on stem cell research funding. The technologies, drugs, and patents which will result from our studies will allow Californians to be the first people in the country to benefit from stem cell research with respect to its ability to positively affect healthcare, the economy and technological advances.
Progress Report: 
  • Parkinson’s disease (PD) is the most frequent neurodegenerative movement disorder caused by damage of dopamine-producing nerve cells (DA neuron) in patient brain. The main symptoms of PD are age-dependent tremors (shakiness). There is no cure for PD despite administration of levodopa can help to control symptoms.

  • Most of PD cases are sporadic in the general population. However, about 10-15% of PD cases show familial history. Genetic studies of familial cases resulted in identification of PD-linked gene changes, namely mutations, in six different genes, including α-synuclein, LRRK2, uchL1, parkin, PINK1, and DJ-1. Nevertheless, it is not known how abnormality in these genes cause PD. Our long-term research goal is to understand PD pathogenesis at cellular and molecular levels via studying functions of these PD-linked genes and dysfunction of their disease-associated genetic variants.

  • A proper experimental model plays critical roles in defining pathogenic mechanisms of diseases and for developing therapy. A number of cellular and animal models have been developed for PD research. Nevertheless, a model closely resembling generation processes of human DA nerve cells is not available because human neurons are unable to continuously propagate in culture. Nevertheless, human embryonic stem cells (hESCs) provide an opportunity to fulfill the task. hESCs can grow and be programmed to generate DA nerve cells. In this study, we propose to create a PD model using hESCs.

  • During the funding period, we have generated a number of human ES cell lines overexpressing α-synuclein and two disease-associated α-synuclein mutants. These cells are being used to determine the cellular and molecular effects of the disease genes on human ES cells and the PD affected dopaminergic neurons made from these cells. We have found that normal and disease α-synucleins have little effect on hESC growth and differentiation. We will continue to investigate roles of this protein in modulating PD affected dopaminergic neurons. Completion of this study will allow us to study the pathological mechanism of PD and to design strategies to treat the disease.

© 2013 California Institute for Regenerative Medicine