ALS Research Roundup Nov.-Dec. 2007

by Margaret Wahl on Thu, 2007-11-01 09:16
Article Highlights:

Research Roundup updates as of October 2007:

New studies strongly support ALS-angiogenin connection

A study conducted by investigators at several institutions in Boston has added additional support to an existing hypothesis based on earlier studies that mutations in the gene for angiogenin can cause ALS, or at least increase susceptibility to the disease. Angiogenin is a protein that participates in the formation of new blood vessels (angiogenesis).

David Wu at Brigham and Women’s Hospital, with colleagues at Harvard Medical School and Massachusestts General Hospital, identified mutations in the angiogenin gene in four out of 298 North American ALS patients whose DNA had previously been screened and found not to contain ALS-causing abnormalities in a gene called SOD1.

Last year, Matthew Greenway and Orla Hardiman at the Royal College of Surgeons in Dublin, Ireland, led a team that studied 1,629 people with ALS and 1,265 without ALS, identifying angiogenin mutations in 15 people in the ALS-affected group and in only one person in the unaffected group. (See “Angiogenin Mutations,” Research Roundup April 2006.)

Wu and colleagues, reporting online Sept. 20 in Annals of Neurology, say the four variants they identified in the four individuals all cause a complete loss of function of the angiogenin protein.

A deficiency of the protein known as vascular (blood-vessel) endothelial growth factor (VEGF) also has been implicated as a possible ALS susceptibility factor, and angiogenin works in the same biological pathway as VEGF.

The researchers speculated that the role of angiogenin in protecting neurons might extend beyond its effect on blood vessels that support these cells.

On Oct. 4, Vasanta Subramanian and colleagues at the University of Bath, United Kingdom, announced online in Human Molecular Genetics their findings that angiogenin is involved in maintenance of motor neurons and in the growth of nerve fibers, and that three ALS-associated angiogenin variants were toxic to lab-grown motor neurons.

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Progranulin deficiency leads to toxic TDP-43 behavior

When progranulin is deficient, TDP-43 breaks up and leaves the cell nucleus.
When progranulin is deficient, TDP-43 breaks up and leaves the cell nucleus.

Last spring, Ian Mackenzie at the University of British Columbia and colleagues announced they had identified a key difference between ALS caused by a mutated SOD1 gene (a “familial” or inherited form) and other forms of ALS.

They found that motor neurons (nerve cells that control muscle action) from people with nonfamilial ALS, ALS with dementia (cognitive impairment), and non-SOD1 familial ALS all had clusters containing a protein called TDP-43. In contrast, samples from people with SOD1-related familial ALS didn’t show this protein in their nerve cells.

Now, Yong-Zie Zhang at the Mayo Clinic College of Medicine, with colleagues in the United States, United Kingdom and Italy, have taken those observations a step further by finding that a deficiency of the protein known as progranulin is one cause of mislocation and clustering of TDP-43.

The researchers, who announced their findings in the Sept. 26 issue of the Journal of Neuroscience, found that when the progranulin protein is deficient because of a mutation in the progranulin gene, the TDP-43 protein molecule behaves abnormally. It splits into two pieces and appears in the main part of the cell (cytoplasm) instead of in its normal location in the cell nucleus; and it forms disease-related clusters.

The investigators write that the new data provide insight into the mechanisms linking the chromosome-17 gene for progranulin with disease-related TDP-43 abnormalities, at least in some cases of ALS. They say their work will set the stage for screening of compounds that can prevent TDP-43 fragmentation and redistribution.

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Knopp Neurosciences to pursue development of ‘mirror-image’ molecule

S(-) pramipexole (left) mimics the actions of dopamine and is used to treat Parkinson disease. Its mirror image, R(+) pramipexole (right), doesn’t imitate dopamine but has antioxidant and anti-cell-death properties that may be beneficial in ALS.
S(-) pramipexole (left) mimics the actions of dopamine and is used to treat Parkinson disease. Its mirror image, R(+) pramipexole (right), doesn’t imitate dopamine but has antioxidant and anti-cell-death properties that may be beneficial in ALS.

Knopp Neurosciences, a Pittsburgh drug discovery and development company, has announced it will develop an orally administered small molecule for the treatment of ALS that it calls KNS-760704.

The molecule is a mirror image of pramipexole (Mirapex), which is approved for the treatment of Parkinson disease and restless legs syndrome. Mirapex is referred to as S(-) pramipexole, and KNS-760704 is known as R(+) pramipexole.

Pramipexole mimics the actions of dopamine, a carrier of signals in the brain. It also acts as an antioxidant, reducing a cell-damaging process known as oxidative stress, and combats a process called programmed cell death, or apoptosis. Mimicking dopamine is not considered desirable in ALS, and the mirror image form of the drug doesn’t do that. It does, however, have antioxidant and anti-apoptosis properties.

In 2005-2006, investigators at the University of Virginia in Charlottesville conducted studies of the mirror image form in people with early-stage ALS, using a variety of dosage levels. Results of those trials are expected soon.

“Knopp and I are pursuing parallel but separate courses,” says James Bennett, the University of Virginia professor of neurology and of research in psychiatric medicine who was the first to observe the differences between the two forms of the pramipexole molecule.

Bennett says Knopp Neurosciences licensed the development of the mirror image form of pramipexole from the University of Virginia Patent Foundation and is developing it commercially, while he and others at his university have concentrated on small studies to determine the biological effects of the drug.

For information about the University of Virginia studies, see the clinical trials section of the MDA site at www.mda.org; or contact Dr. Ted Burns at (434) 924-5361 or tmb8r@virginia.edu.

“Knopp will be able to raise funding for the expensive efficacy studies that ultimately will have to be done,” Bennett says, but he also notes that his small trials “enabled Knopp to move much faster into human studies, which will hopefully get this drug to the ALS community more rapidly. That’s everyone’s goal.”

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Researchers probe use of MRIs in diagnosing ALS-related cognitive decline

Magnetic resonance images (MRIs) may one day be useful for monitoring the dementia that occurs in a small proportion of people with ALS, say researchers in Japan.

Eiji Matsusue at Tottori University in Yonago, Japan, and colleagues, studied three people with ALS and dementia, comparing their MRI findings with microscopic analyses of their brain tissue after death.

In all three cases, they found MRI abnormalities in the form of a more-intense-than-normal signal on the images correlated well with loss of nerve fibers and an excess of support cells (glia) found when the brain was examined microscopically.

The researchers, who published their findings in the September issue of the American Journal of Neuroradiology, say MRIs showed changes in signal intensity that appear to reflect microscopic changes in brain tissue in ALS-related dementia.

They say further studies, comparing large numbers of people with and without ALS-related dementia and following them through time, are needed to clarify the diagnostic value of MRIs in this condition.

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Ceftriaxone trial still open

A multicenter trial of ceftriaxone remains open to ALS patients who are at least 18 and have a forced vital capacity of at least 60 percent of normal.

Ceftriaxone is an antibiotic used to treat certain types of infections. It has shown evidence in laboratory experiments that it can increase the transport of a potentially toxic chemical called glutamate away from spaces between nerve cells. It has to be given intravenously.

The first two stages of the study will last at least 20 weeks, and there will be a third stage if the results from the first two warrant it.

Contact Amy Swartz or Fran Murphy at Massachusetts General Hospital at (617) 643-3980; or send e-mail to alswartz@partners.org or fmurphy@partners.org.

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Margaret Wahl
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