Disease 'in a dish' is a new tool for studying ALS
An MDA-supported research team has created a human cellular model of ALS using cells taken from people with the ALS8 subtype of the disease, a familial (inherited) form of ALS (amyotrophic lateral sclerosis) caused by mutations in the VAPB gene.
This so-called “disease in a dish” research model was made possible by recent advances in stem cell technology, including the ability to generate induced pluripotent stem cells (iPSCs). (An iPSC is an adult cell that has been “reprogrammed” back to an immature stem-cell-like state, after which it can be prompted to develop into any type of cell in the body.)
The research team, which was led by MDA grantee Alysson Muotri, assistant professor at the University of California, San Diego in La Jolla, described the new model in an online report published June 17, 2011, in Human Molecular Genetics.
Although the model is based on one inherited subtype of ALS, its value could extend to other familial forms of the disease, as well as to noninherited (“sporadic”) forms that make up the majority of ALS cases.
’Inhibitor’ molecule increases strength, life span in ALS mice
Treatment with an experimental compound called trichostatin A (TSA) has shown benefit in mice with an ALS-like disease.
TSA belongs to a family of chemical compounds called HDAC (histone deacetylase) inhibitors, which keep genetic instructions “open” and ready to be read and used in protein production, rather than “closed,” which results in the silencing of the gene.
The findings were reported online June 20, 2011, by a team of scientists, including MDA-supported Chien-Ping Ko at the department of biological sciences, University of Southern California in Los Angeles.
In the study, the researchers found that compared to untreated (control) mice, TSA-treated mice showed an increase in levels of the glutamate transporter GLT1 in the spinal cord. More GLT1 protein may have reduced a toxic buildup of the neurotransmitter glutamate, which can lead to motor neuron damage and death. Research has shown that people with ALS have raised levels of glutamate in the brain and spinal cord.
The TSA-treated mice showed improved motor function as measured by grip strength, and improvement on performance tests that evaluated endurance, balance and coordination.
Furthermore, TSA treatment significantly increased the average survival time from disease onset to end stage and prolonged overall life span in the mice.
Scientists refine understanding of correlation between ataxin 2 gene and ALS risk
In 2010, scientists working in the United States and Germany found that small DNA expansions in the ataxin 2 gene significantly increase the risk for developing ALS.
Until now, however, researchers haven’t been sure whether the mechanism linking longer-than-normal ataxin 2 protein molecules and an increased risk of developing ALS is unique to the ataxin 2 protein or whether it applies to other proteins containing similar DNA expansions.
Now, results from several new studies not only confirm that the phenomenon so far is unique to the ataxin 2 protein, but indicate that the risk appears to be related to a change in this protein’s function, not to the presence of the expansions themselves.
Aaron Gitler, assistant professor of cell and developmental biology at the University of Pennsylvania in Philadelphia, and colleagues published their findings online May 11, 2011, in the journal Neurology.
Stem cell trial set to advance
Maryland biotherapeutics company Neuralstem on June 14, 2011, announced favorable results from the first part of a phase 1 trial to test the safety of its experimental spinal cord stem cell treatment in ALS. The trial’s safety monitoring board has given unanimous approval to advance the trial to the next stage; the U.S. Food and Drug Administration (FDA) also must grant approval before the trial can progress.
Neuralstem’s ongoing phase 1 human clinical trial is being conducted at Emory University in Atlanta, under the supervision of neurologists Eva Feldman and Jonathan Glass, and is designed to test the safety and feasibility of injecting neural stem cells into the spinal cords of people with ALS. (Glass directs the MDA/ALS Center at Emory, but MDA is not funding this trial.)
The phase 1 Neuralstem trial, which uses human neural cells, is being progressively tested over incrementally increasing risk levels in 18 people with ALS, depending on safety results at each stage. The levels of risk correspond to trial participants’ disease severity, and the number and location of injections into the spinal cord.
Although the study remains primarily a safety trial, the investigators hope that cervical injections may show some benefit with breathing and swallowing in ALS.
CK-2017357: Second phase 2 trial under way
San Francisco biotechnology company Cytokinetics announced June 21, 2011, the opening of a new clinical trial of CK-2017357 at three different dosage levels in people with ALS.
The new trial marks the second phase 2 study for CK-2017357, and is designed to assess the safety and tolerability of the drug, although researchers also will evaluate participants’ motor function, pulmonary function, muscle strength and fatigue.
CK-2017357 is thought to increase the sensitivity of muscle fibers to calcium, resulting in a potential increase in muscle force generation. It was granted orphan drug status on March 10, 2010, by the U.S. Food and Drug Administration (FDA). (Orphan drug status provides financial incentives for the development of drugs for rare diseases.)
For information on study center locations and eligibility requirements for participation in this trial, visit ClinicalTrials.gov and search for trial ID NCT01378676. Or, email firstname.lastname@example.org, or call (650) 624-2929.
Israeli stem cell trial in ALS may open U.S. trial sites
Biotechnology company BrainStorm Cell Therapeutics announced July 22, 2011, that it has signed an agreement with PharmaNet, an organization that will assist with development of clinical trial procedures and preparation of an investigational new drug (IND) application for submission to the U.S. Food and Drug Administration (FDA) in its early steps toward obtaining approval to bring its ALS human clinical trials to sites in the United States.
BrainStorm’s ongoing phase 1-2 clinical trial is testing its experimental treatment in people with ALS in Jerusalem. The trial is sponsored by the Hadassah Medical Organization in Jerusalem, in collaboration with BrainStorm which is based in New York and Petach Tikva, Israel.
BrainStorm signed a “memorandum of understanding” (an agreement to collaborate) July 17, 2011, with two American institutions to test its experimental “NurOwn” stem cell technology in people with ALS in the United States. The institutions are Massachusetts General Hospital in Boston and the University of Massachusetts Medical Center in Worcester, Mass.
Neurologist Merit Cudkowicz will lead the Massachusetts General Hospital team. Cudkowicz has received MDA research funding, is a member of MDA’s translational research and medical advisory committees, and directs the MDA/ALS Center at Massachusetts General.
The University of Massachusetts Medical School team will be led by Robert Brown, a previous MDA grantee who preceded Cudkowicz as director of the MDA/ALS Center at Massachusetts General Hospital.
For more about the ongoing trial in Israel, visit ClinicalTrials.gov and search for trial ID NCT01051882. You also may contact Dimitrios Karussis at email@example.com, or +972-2-6776939.