April 5, 2006
AAN News: Genetic Findings Indicate Promising Therapies
Talks and posters presented Wednesday at the American Academy of Neurology (AAN) focused on new information on the genetics of ALS.
Researchers working with Teepu Siddique, M.D., Northwestern University, Chicago, show that a risk to develop ALS (amyotrophic lateral sclerosis) is associated with certain variants in the genes coding for a set of enzymes that detoxify nerve gas agents and chemically similar pesticides called organophosphates. This association might explain why the veterans of the Gulf War have been reported to be at a possible two-fold increased risk of developing ALS. Soldiers serving in that war may have been exposed to high doses of such chemicals, researchers have speculated. Genetic variations in the enzymes coded by the paraoxonase gene cluster are associated with a strong susceptibility for ALS, the investigators demonstrated.
Another research team led by Denise A. Figlewicz, Ph.D., University of Michigan, Ann Arbor, and Andrzej Szczudlik, M.D., Ph.D., Jagiellonian University Krakow, Poland, also reported similar findings on the paraoxonase (PON) genes and risk of ALS. The genes for three sets of the enzymes, referred to PON1, PON2 and PON3, are located together on chromosome 7. The activity of PON1 and PON2 are changed by a polymorphism, or a difference in the amino acid present at certain positions in the enzymes. A particular difference increases the odds of developing ALS by almost four fold, these researchers reported. Together these findings on the possible role of these detoxifying enzymes show how a person might be more susceptible to environmental influences due to his or her particular genetic makeup that could produce ALS in one person and not in another.
European and Australian investigators reported that mutations in the dynactin gene can produce a wide spectrum of motor neuron disease, from ALS to only lower motor neuron disease. But some mutations to this same part of dynactin, the p150 subunit, were detected in people without motor neuron disease, according to the report from the team which included Garth Nicholson, Ph.D., of Sidney, Australia, and Albert C. Ludolph, M.D., University of Ulm, Germany, and Reinhard Sedlmeier, Ph.D., Ingenium Pharmaceuticals AG, Martinsried, Munich.
Mutations to a protein called angiogenin also occur in some people with ALS. The gene was sequenced for 1,629 individuals with ALS and 1,264 controls from Ireland, Scotland, US, UK and Sweden. An association with a particular gene signpost, a single nucleotide polymorphism (SNP), was confirmed in Irish and Scottish patients, but no link to those from the US, England or Sweden emerged. Angiogenin mutations were also found in unrelated sporadic ALS patients and four people with ALS in their families. One of 1,264 controls screened also had a mutation to angiogenin. At least six of the mutations found in angiogenin should result in loss of the protein’s activity, reported the team led by Orla Hardiman, M.D., Beaumont Hospital, Dublin, Ireland.
A curious finding by Siddique’s group is that a mutation common in inherited ALS in North America, but rare in Europe, could have originated in the native Americans. The arginine to valine switch at amino acid number 4 (A4V) in the protein, copper-zinc superoxide dismutase (SOD1), is the mutation responsible for half of SOD1 changes associated with inherited ALS in North America, but this variant of SOD1 is uncommon in Europeans. The researchers now estimate that A4V was introduced into the North American population from the American Indians 400-500 years ago. It is possible that the natives of this continent have another, protective genetic factor that may not have transferred to the Caucasian host genome. If so, this could provide therapeutic insight.
A few presentations Wednesday in the genetics session reported some success with genetic therapy in rodents modeling ALS. Gyula Acsadi, M.D., Ph.D., Children’s Hospital of Michigan, Detroit, working with Jon A. Wolff, M.D., Waisman Center, University of Wisconsin, Madison, transferred a gene for Insulin-like growth factor (IGF-1) directly into the muscles by high-pressure injection into the bilateral great-saphenous veins. Treatment of SOD1 mice at six weeks of age gave increased survival equal if not better to that observed with vector delivery. Motor performance as measured by ability to remain on a rotating rod (Rotarod) also declined less rapidly in the treated mice than in the controls. This type of gene delivery has been tested in monkeys but not yet in people. The first human application may be for correcting hemophilia.
An antisense study aimed at boosting levels of the nerve cell messenger acetylcholine was presented in a poster by Marc Gotkine, MBBS, working with Hanna Rosenmann, Ph.D, Hadassah Hospital, Jerusalem, Israel. The antisense compound is made by Esther Neurosciences (EN101) and is already in Phase II studies in patients with another neurological disease. Mice with SOD1 mutation were treated starting at five weeks of age. These mice had a two week delay in motor impairment as determined by Rotarod performance and an 11-day delay in death when compared to control mice. An antisense treatment that shuts off a signal that triggers programmed cell death (apoptosis) was shown to prevent the loss of motor neurons in SOD1 mice, according to a talk by Federica Locatelli, M.D., working with Giacomo P. Comi, M.D., Milan, Italy
Role of SOD1 in Various Cells Can Help Guide Toward Improved Therapies for ALS Patients
On Wednesday, April 5, in a poster presentation at the AAN, investigators working with Siddique presented evidence that aggregation of the protein, copper-zinc superoxide dismutase (SOD1) is primarily neuronal, rather than glial in ALS patients and in mice with mutations in this protein altered in some inherited cases of the disease. The investigators looked at spinal cord sections from ALS patients with the SOD1I113T and SOD1G85R mutations and also examined transgenic mice with SOD1G93A and SOD1L126Z mutated proteins. The findings suggest that the SOD1 aggregates are primarily located in the large neurons and their fibers, rather than in glial cells.
Others reported on the role of microglia in ALS, including a poster presented by the Cleveland team Wednesday morning, showing that turning off the production of mutant SOD1 in microglia slows disease progression, extending survival after onset by 99 days. Finally, microglia that are not able to “switch off” their production of inflammatory mediators accelerate the damage in mice with the SOD1 mutation, especially the males, according to a poster presented by Erik Pioro, M.D., Richard M. Ransohoff, M.D., and colleagues at the Cleveland Clinic.
As presented in the Genetics of Motor Neuron Disease poster session Wednesday byinvestigators working with Raymond P. Roos, M.D., University of Chicago, mice that can produce a mutant SOD1 either in all cells or in specific cell types, including just in skeletal muscles, will give further information on the role of various cells in the disease. The Roos team has devised a way to switch off the production of the mutant protein to be able to see if the mouse can recover from the effects of the mutation, as is the case for the mutation that produces Huntington’s disease. If the mouse model of ALS also proved to be reversible, this could give important information toward developing a successful treatment for ALS.
To read more about ALS research at AAN, click here.
