July 7, 2006

Research Update — from ALSA’s National Office

The ALS Association Funds Project to Create and Characterize ALS Motor Neurons

Roberta Friedman, Ph.D., ALSA Research Department Information Coordinator

The ALS Association announced today it is funding a project led by Harvard researcher Tom Maniatis, Ph.D., to establish motor neurons living in lab dishes that could reflect what goes wrong in Lou Gehrig’s disease. The studies would compare the electrical and chemical properties of motor neurons derived from mouse stem cells as a prelude to the possibility of similar work in human cells that reflect the genetics of ALS patients. This latter aspect would involve a process called nuclear transfer.

The initial effort in mice aims at the degenerative condition, ALS (amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease for the famous ballplayer who died of it in 1941). Motor neurons growing in the lab with the genetic instructions of cells obtained from ALS mice or humans might show the disease process more accurately than any other model of the disorder available today. Motor neurons are the cells that reach from the spinal cord to muscles and are the cells that die in the disease.

The first steps would be to study stem cells from mouse with and without the mutation that produces some inherited forms of ALS. The stem cells would be prompted in the lab dish in which they are growing to form motor neurons. For the cells derived from mutant mice, the motor neurons would have the genetic change that produces death of motor neurons in the mice and in some people with ALS.

A major thrust of the project is to fully study the electrical and chemical behavior of such motor neurons as they form connections in the lab dishes, which might differ in ALS. Minute electrodes can show the impulses generated by a single cell. Chemical analysis can determine the balance of nerve cell messenger molecules that are active or overactive. Microarrays are gene chips that survey which genes are turned on within a cell. With these techniques, researchers will be able to see any differences in the behaviors of cells that could show how ALS arises and progresses.

The award is part of the grant program that The ALS Association uses to recruit and retain experts who will focus on finding effective therapies for the disease. The ALS Association is pleased to be able to support the proposal by Maniatis, chair of the scientific advisory board for research projects initiated by The ALS Association. He has through this contribution aided such notable progress as a transgenic rat as a model for the disease.

Maniatis is currently serving on The Drug Discovery and Development steering committee for The Association’s new initiative TREAT ALS (Translational Research Advancing Therapy for ALS), a program to accelerate entry of promising candidate therapies into clinical trials.

Marking his own entry into direct research toward a treatment for ALS, Maniatis will collaborate with several groups in the forefront of nuclear transfer and stem cell biology participating in the program announced recently by the Harvard Stem Cell Institute. The ALS Association is funding Maniatis and his collaborators for a particular project aimed at ALS that falls under the umbrella of the research planned by members of the Institute.

The ALS Association project brings together collective expertise in placing nuclei from adult cells into donated egg cells and establishing stem cells, as well as derived motor neurons. Collaborators including the groups of Thomas Jessel, Ph.D., of Columbia University in New York, and Kevin Eggan, Ph.D., at Harvard. The teams will work with motor neurons generated from stem cells of mice with the so called SOD1 mutation. These mice express a change in the gene for the protein, copper-zinc superoxide dismutase, a mutation present in some of the ALS that runs in families.

This mouse model of the disease has provided a first step toward understanding the disease process but has not yet yielded a therapeutic solution. A more accurate and comprehensive laboratory model of the disease might dovetail with studies on the SOD1 mice to reveal a precise therapeutic target for ALS.