ALS Research Roundup Nov.-Dec. 2009

by ALSN Staff on Sun, 2009-11-01 10:15
Article Highlights:

Research news as of October 2009:

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Trial of SOD1 blocker set to open soon

A phase 1 clinical trial of the experimental drug ISIS-SOD1-Rx (formerly ISIS-333611) in patients with the SOD1-related type of familial (inherited) ALS is expected to begin before the end of 2009 at Washington University in St. Louis and Massachusetts General Hospital in Boston. Eventually the trial will include four additional sites.

MDA provided support to Timothy Miller at Washington University in St. Louis to work with Isis Pharmaceuticals of Carlsbad, Calif., to develop ISIS-SOD1-Rx.

The trial will test the safety and tolerability of this “antisense” compound, which is designed to block production of the SOD1 protein in people who have developed ALS because of mutations in the SOD1 gene. Such mutations result in ALS in approximately 1 percent to 3 percent of cases.

The investigators will infuse ISIS-SOD1-Rx into the fluid that surrounds the brain and spinal cord, a delivery method that targets the cells that produce the toxic SOD1 protein.

Details of genetic testing will be discussed with potential study participants. For further information as it becomes available, see the clinical trials section of the MDA Web site by going to and selecting Clinical Trials from the home page.

Masking unwanted instructions with ‘Antisense’
Antisense Antisense
Antisense strands will be infused into the fluid surrounding the brain and spinal cord, where it is hoped they will stick to the flawed strands of RNA. There they are expected to block the RNA instructions that would otherwise result in ALS-causing superoxide dismutase 1 (SOD1) protein molecules. (When cells process a genetic recipe for a protein, they first convert DNA to RNA.)

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One lithium study stopped; MDA study continues for now

The investigators for one study of lithium carbonate in ALS announced Sept. 23, 2009, that they will stop their study after an interim analysis showed the drug was not beneficial. The study was funded by the National Institutes of Health, the ALS Association and the ALS Society of Canada; MDA was not a funder of this study.

As of October 2009, an MDA-supported study of lithium remains open. The MDA trial is separate from the canceled NIH trial, and the dosages and trial design are not the same.

Clinical trials of the effectiveness of lithium in ALS were undertaken after a small study in Italy was published in 2008, reporting that lithium appeared to dramatically slow the course of the disease.

However, recently published results of a study of lithium in ALS mice conducted at the MDA-supported ALS Therapy Development Institute in Cambridge, Mass., showed the drug lacked benefit on any measure.

The study was published online Aug. 3, 2009, in PLoS One.

Merit Cudkowicz, who directs the MDA/ALS Center at Massachusetts General Hospital in Boston, was an investigator on the NIH-supported study.

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First US trial of neural stem cells in ALS gets FDA green light

The U.S. Food and Drug Administration (FDA) has given a green light to a phase 1 trial to study the effects of injecting human neural stem cells into the spinal cords of people with ALS, the biotechnology company Neuralstem announced Sept. 21, 2009.

Neuralstem of Rockville, Md., will sponsor the study, which, if approved by an institutional review board at Emory University in Atlanta, will take place at that site. No participants will be recruited until Emory’s review board approves the study.

Stem cells
Neuralstem’s patented stem cells have the ability to develop into motor neurons and a type of support cell known as glia.

Jonathan Glass, neurologist and director of the MDA/ALS Center at Emory, is the onsite principal investigator, with Eva Feldman at the University of Michigan serving as the overall principal investigator. Emory neurosurgeon Nicholas Boulis, a pioneer in developing surgical methods for delivery of therapeutics to the spinal cord, will perform the surgical procedures at Emory.

“This is the first time in the United States that cells will be injected into a human spinal cord, although these cells have been tested in several models of spinal cord injury in rats,” Glass said.

Neuralstem’s patented stem cells, developed from cultured neural stem cells derived from a single fetus, have the ability to mature into various types of cells in the nervous system. This includes motor neurons, the muscle-controlling nerve cells that are specifically lost in ALS, and nervous system support cells known as glia.

“This study will be focused on the safety of the procedure for introducing stem cells for the treatment of ALS,” Glass said of the phase 1 trial. “Our hope is to find a surgical approach that is manageable in humans with no negative effects. As with any phase 1 clinical trial, a patient may benefit from treatment, but that is not the focus of this study.”

The proposed study would include 18 ALS patients and, if approved, recruitment is expected to begin by the end of 2009.

“We are very excited about the possibilities this study may bring,” said Glass, “and are hopeful this is the first step toward a new way of treating ALS.”

Details of the proposed trial, including selection of participants, will be posted as they become available on an Emory Web site at and on MDA’s Web site (click on Clinical Trials).

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New type of ALS research mouse now available

Mice carrying a mutation in the gene for the TDP43 protein that’s known to cause ALS in humans have been developed by MDA-supported scientists at Washington University School of Medicine in St. Louis. The mice may provide an important new research tool in this deadly disease.

Iga Wegorzewska and colleagues published their findings online the week of Oct. 12, 2009, in Proceedings of the National Academy of Sciences. MDA grantee Robert Baloh coordinated the research team.

Until now, most ALS research not conducted in humans has utilized mice with various mutations in the SOD1 protein, which also cause human ALS. However, since mutations in any particular gene only cause a small percentage of human ALS cases, the availability of a new “mouse model” of the disease is expected to broaden scientists’ ability to observe disease progression and the effects of experimental treatments.

Mice carrying the TDP43 gene mutation develop a disease resembling human ALS. They appear normal up to about 3 months of age, after which they develop a gait abnormality. By about 4.5 months, the mice with the TDP43 mutation begin losing weight and develop a “swimming” type of locomotion, dragging their bellies on the ground and using their limbs to propel them. Their average survival time is 154 days, or about five months. Normally, mice live about two years.

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Three new DNA variants ID’d that may raise ALS risk

A large, multinational study to identify genetic risk factors associated with ALS has found two DNA sequences on chromosomes 9 and one on chromosome 19 that are significantly different in people with ALS compared to those without the disease.

The identified DNA regions on both chromosomes contain genes for biological processes that could have an effect on the disease. Gene variations in the chromosome-9 region have been associated with ALS in combination with the cognitive disorder frontotemporal dementia.

For the first time, a specific DNA variant on chromosome 19 was identified as having a possible ALS association. The investigators say the variant is in the same DNA region as a gene that helps regulate transmission of signals between nerve cells and between nerve and muscle fibers.

Leonard van den Berg and Roel Ophoff at the University Medical Center Utrecht in the Netherlands coordinated the study team, which published its findings online Sept. 6, 2009, in Nature Genetics. MDA supported Simon Cronin and Orla Hardiman at the Royal College of Surgeons in Ireland for portions of the study.

The new findings represent the latest in a series of “whole-genome” (all genes in a person’s makeup) association studies, also known as “genome-wide” association studies. This type of study looks for small variants in DNA sequences that are significantly more common in people with ALS, although the strategy is still in development. (See “How Reliable Are Genetic Association Studies?” in the September-October 2009 ALS Newsmagazine.)

This latest study included an analysis of all the DNA from an initial group of 2,323 people with ALS and 9,013 unaffected people, followed by further investigation of potentially significant findings in another group of 2,532 ALS patients and 5,940 people without the disease. The study subjects were from the United States, the Netherlands, Ireland, Sweden, Belgium, the United Kingdom, France, Poland and Germany.

A surprise discovery in the new study is the association of a variant in a gene known as UNC13A on chromosome 19 that’s more common in people with sporadic ALS than in unaffected subjects. Since the UNC13A protein made from the gene is known to play a role in the transmission of signals among nerve cells and nerve-to-muscle signals, its influence on ALS development seems like a potentially productive research lead.

Also surprising and potentially valuable was the discovery that genetic variants on chromosome 9 that are known to be linked to a form of familial ALS accompanied by dementia also may be linked to sporadic ALS. The investigators found two specific variants in this region that are significantly more common in sporadic ALS patients.

Among earlier whole-genome association studies conducted in ALS are an MDA-supported study by the Phoenix-based Translational Genomics Institute (TGen) and another by the U.S. National Institutes of Health (NIH) in Bethesda, Md.

The TGen study suggested genes associated with the connections between nerve and muscle fibers might be different in people with and without ALS. However, critics charged the statistical methods used in this study might not have identified true differences between the two groups. The NIH study investigators found no significant differences between ALS and non-ALS genomes.

The differing results from the multiple whole-genome association studies in ALS have led to the conclusion that there may be no single “smoking gun” to be identified from this type of analysis. Study results support the idea that ALS is not one but many diseases, with differing combinations of causal factors. This understanding and the leads provided by the findings from each study are important for investigators to take into account as they work to develop treatments.

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Athena Diagnostics offers new group of DNA tests for FALS

A new test panel that may detect up to 35 percent of the genetic flaws that can cause familial ALS (FALS, an inherited form of the disease) has been released by Athena Diagnostics ( of Worcester, Mass. Athena is a commercial laboratory specializing in DNA testing for neurological disorders.

The panel tests for mutations in the SOD1 gene, FUS gene, TDP43 gene (also known as the TARDBP gene), angiogenin gene and FIG4 gene. Each test, except the FIG4 test, also can be performed individually.

A blood sample, which can be drawn locally and shipped to Athena, is required. For details, contact Athena at (800) 394-4493 or through the company’s Web site.

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ALS TDI research symposium posted online as webcast

A webcast is now available of the fourth annual research symposium held as part of the ALS TDI Leadership Summit 2009 on Oct. 5. The symposium was conducted at the MDA-supported ALS Therapy Development Institute in Cambridge, Mass.

The webcast of the symposium, an update on research in ALS, is free but requires registering via the Web site. Go to

Among the highlights of the presentation are discussions of gene therapy strategies for ALS, a discussion of RNA interference (a method of blocking genetic information), drug development strategies in general, and specific plans to develop ALS TDI-00846, an experimental compound that blocks the immune system protein CD40 and improves survival in ALS mice.

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ALSN Staff
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