Research Roundup updates as of Feruary 2009:
ALS TDI and Asklepios collaborating on gene therapy development
The MDA-supported ALS Therapy Development Institute (ALS TDI) in Cambridge, Mass., and Asklepios BioPharmaceutical in Chapel Hill, N.C., which also receives MDA support, are working together to develop viral delivery vehicles (vectors) that could be used to deliver therapeutic genes in ALS.
Potentially therapeutic genes under consideration in ALS include those that carry instructions for neuroprotective proteins or for blockers of harmful proteins.
The project will use custom-constructed “biological nanoparticle” (BNP) vectors, designed by Asklepios. These vectors are known for their ability to penetrate tissues without eliciting a strong unwanted immune response.
The ALS TDI will evaluate the BNP vectors in a tightly managed mouse colony in which the animals have a mutation in the SOD1 gene known to cause a familial form of ALS in humans and a similar disease in mice. Scientists there will analyze samples from animals treated with BNP vectors to determine the cells and tissues in which these vectors localize.
The partnership combines the extensive experience of Asklepios in developing gene-delivery technology with the expertise of the ALS TDI in screening ALS therapeutic leads.
The project is part of a three-year, $36 million funding and scientific collaboration involving MDA’s Augie’s Quest initiative and the ALS TDI.
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FDA approves embryonic stem cells for use in study of spinal cord injury
The U.S. Food and Drug Administration (FDA) has said yes to a small safety trial of nervous system stem cells in people with recently sustained injuries to the middle (thoracic) part of the spinal cord, the biopharmaceutical company Geron Corporation of Menlo Park, Calif., announced Jan. 23.
Although this trial has no immediate implications for ALS patients, it’s seen as a major step toward developing stem cell treatments for conditions that damage the spinal cord, including ALS.
In a news release Geron said it will move forward with the “world’s first study of human embryonic stem cellbased therapy in man.” Although the primary goal of the study is to test safety, the investigators will also test for any functional improvement as a result of the treatment.
The cells used by Geron were derived from a single early-stage embryo a decade ago. They are treated in the laboratory to become an immature form of the cells that produce myelin, a coating that surrounds nerve fibers and is needed for their normal function, and they’ll be tested in this trial for their ability to repair damaged nerves in the spine of people injured seven to 14 days prior to treatment.
Although the myelin-producing cells to be used in the Geron trial are probably not the cells that might ultimately be tested in ALS, they and the processes used to produce them are similar to those under development for this disease.
“Embryonic stem cell treatments have been widely praised for their potential application in the repair and restoration of disease or injury damaged tissues and organs,” said Chris Airriess, chief operating officer at California Stem Cell (CSC) in Irvine, Calif., where he has MDA support to develop stem cell-based therapies for ALS. “This huge milestone reached by Geron is a watershed in the development of the field of regenerative medicine.”
CSC Scientific Advisory Board Chairman Hans Keirstead and member Gabriel Nistor are co-inventors of Geron’s experimental treatment for spinal cord injury.
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Dogs found with SOD1 mutations and ALS-like disease
Researchers at several institutions in the United States and Sweden have found that a mutation in the gene for superoxide dismutase 1 (SOD1), known to cause ALS in 1 percent to 3 percent of human cases and to cause an ALS-like disease in rodents, also can cause an ALS-like disease in dogs.
The investigators, coordinated by Gary Johnson and Joan Coates at the University of Missouri in Columbia, analyzed DNA samples from 38 Pembroke Welsh corgi dogs with an ALS-like disease and 17 related, clinically normal dogs and found a mutation in the SOD1 gene that was significantly associated with the illness.
Unlike most human cases, however, this SOD1-related disease is recessive, not dominant, meaning an animal must have a mutation in both its two SOD1 genes in order to show symptoms. Humans generally only need one SOD1 mutation to show disease symptoms.
The investigators went on to identify a similar disease caused by the same SOD1 mutation in boxers, Rhodesian ridgebacks, German shepherds and Chesapeake Bay retrievers.
The dogs showed clinical signs of degenerating upper (brain) and lower (spinal cord) motor nerve cells (motor neurons), as in human ALS. When the dogs’ spinal cords were examined microscopically, they revealed loss of nerve fibers and SOD1-containing clumps in their nerve cells, which are also seen in ALS patients.
The dogs are the first spontaneously occurring animal model of ALS discovered, the researchers say in their paper, published online Feb. 2 in Proceedings of the National Academy of Sciences.
Dogs may be better predictors of human responses to experimental ALS treatments than mice, because they’re closer in size to humans than rodents are, their nervous systems are more similar to humans in structure and complexity, and they’re unlikely to possess the very high levels of mutated SOD1 protein found in some mice but not in humans with the disease.
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Type B botulinum toxin improves ALS-related drooling for four weeks
Injections of type B botulinum toxin, derived from Clostridium botulinum bacteria, seem to reduce the severity of drooling in people with ALS for up to a month in a recent, small study. There were no significant adverse events.
Carlayne Jackson, director of the MDA ALS Center at the University of Texas Health Science Center in San Antonio, with investigators at the University if Kansas Medical Center in Kansas City and Carolinas Medical Center in Charlotte, N.C., studied 20 ALS patients whose drooling was not responding to medical therapy.
Study participants were randomly assigned to receive one set of injections of either type B botulinum toxin, which is known to reduce saliva production, or a placebo (inactive substance), into two salivary glands (the parotids and submandibulars) on each side of the face.
Two weeks after the injections, 82 percent of the participants treated with botulinum toxin reported improvement in their drooling, compared to 38 percent of those who received a placebo. At four weeks post-treatment, 90 percent of the toxin-treated participants reported improvement, while 44 percent of the placebo-treated patients felt they had improved.
At eight and 12 weeks after the injections, study participants in the botulinum toxin group continued to report improvement more often than those in the placebo group, but these differences were not statistically significant.
“We conclude from these results that it is likely that BTxb [type B botulinum toxin] is effective in improving sialorrhea [drooling] in patients with ALS, although these results need to be confirmed in a larger study,” the authors report in the February 2009 issue of Muscle & Nerve. They say higher doses may be needed to sustain the beneficial effect.
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