hESC-Derived Motor Neurons For the Treatment of Cervical Spinal Cord Injury

hESC-Derived Motor Neurons For the Treatment of Cervical Spinal Cord Injury

Funding Type: 
Comprehensive Grant
Grant Number: 
RC1-00345
Award Value: 
$2,158,445
Disease Focus: 
Amyotrophic Lateral Sclerosis
Neurological Disorders
Spinal Muscular Atrophy
Spinal Cord Injury
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
Status: 
Closed
Public Abstract: 
Statement of Benefit to California: 
Progress Report: 

Year 1

We have completed the first two AIMs of our proposal on time, and on budget, and we reported on these AIMs in our previous progress report. During this reporting period we have made progress on AIMs 3, 4 and 5. In AIM 3, we transplanted hESC-derived motor neuron progenitor cells into sites of motor neuron death in adult rats. We experienced minor technical difficulties that have set us back by a few months, due to sub-optimal expression of a growth factor in muscles, which is necessary to draw motor neuron axons out to muscles. We have fixed the problem and have confirmed long term growth factor expression in muscles. We have also confirmed that our toxin model induces motor neuron death using several methods, that transplanted motor neurons survive and connect with the spinal cord, and standardized all testing protocols to determine whether transplants along with growth factor addition to muscles will benefit the behavior of the treated animals. Our final experiment is in progress. This delay will not alter the project costs. With regards to AIM 4, we are well ahead of schedule. This AIM was to begin in Year 3, but we began the experiments in Year 2. In this AIM, we transplanted hESC-derived motor neuron progenitor cells into sites of spinal cord injury in adult rats. We have confirmed that transplanted motor neurons survive and connect with the spinal cord, that transplantation enhances the survival of the host spinal cord that otherwise would have been lost, that transplantation enhances axon branching of the host spinal cord, and that these ‘nursing’ effects cause behavioral improvement of locomotion. Our increased productivity has not affected the budget. With regards to AIM 5, are on track and on budget. We have generated FDA-compliant documents for all of the studies listed above.

Year 2

We are on schedule with our research plan, having made progress on the last two AIMs of the proposal according to schedule. The goal of the 4th AIM was to transplant cells to the spinal cord of rats and see if they connect to muscle in the limbs that had been engineered to express an attractant for the processes of the cells in the spinal cord. We confirmed that we can induce the muscle in the limbs to express the attractant, and have the cells in the spinal cord survive, differentiate appropriately, become connected in the spinal cord to other circuits, and extend processes. In addition, we have evidence that these treatments benefit the locomotor ability of the rats. We wrote a scientific article concerning some of this work, and it was accepted for publication in an excellent journal. The goal of the 5th AIM was to document regulatory oversight for the project, to ensure compliance with FDA policies. We have generated FDA-compliant paperwork for all of our studies to date. Thus, our progress is in line with the original proposal.

Year 3

This study tested the hypothesis that high purity motor neurons (MNs) derived from human embryonic stem cells could benefit spinal cord injury. In the first AIM, we proved that MNs could extend processes to muscle and cause it’s contraction, in a dish. In the second AIM, we proved that we could enhance process extension to muscle, in a dish. In the third and fourth AIMs, we proved that MNs transplanted into the diseased or injured spinal cord could integrate and benefit the function and spinal cord tissue structure of animals. In neither case did we see projection of MN processes to muscles, despite the provision of a MN process attractant in the muscles. Nonetheless, MN transplantation reduced tissue loss that normally results from injury or disease, and enhanced regeneration of the spinal cord and functional recovery of the animals.

© 2013 California Institute for Regenerative Medicine