NEW RESEARCH SHEDS LIGHT ON SOD1 MUTATIONS
A study in the Jan. 26 issue of Science sheds light on the biochemical effects of mutations in the superoxide dismutase 1 (SOD1) gene, a cause of familial ALS.
In 1993, MDA researchers Robert Brown at Massachusetts General Hospital in Boston and Teepu Siddique at Northwestern University in Chicago found that mutations in a chromosome 21 gene for the SOD1 enzyme could cause the familial form of this disease.
Scientists already knew that superoxide dismutase acted as an antioxidant in cells, protecting cell parts, particularly the cell membrane, from oxidative damage, a deadly chemical reaction in which cell membranes can be destroyed.
A logical theory in 1993 was that flaws in the SOD1 gene would lead to a weakened SOD1 enzyme that wouldn't adequately perform its antioxidant function, leaving cells open to damaging oxidation reactions.
By 1995, more than 20 SOD1 gene flaws had been identified in familial ALS families. Although SOD1 enzyme activity was reduced with some of these mutations, indirect evidence began to build that the real problem wasn't a loss of function of the enzyme, but rather a new, toxic function that the gene flaws caused it to take on — what scientists call a "toxic gain of function.
" The Science article gives even firmer evidence that, in at least two types of SOD1 mutations, the enzyme produced is a toxic one.
Researchers at the University of California at Los Angeles and the La Jolla (Calif.) Cancer Research Foundation studied the effects of two SOD1 mutations found in human familial ALS. They found these mutations resulted in renegade SOD1 enzymes — proteins that not only didn't do their regular job of protecting against oxidative damage but actively contributed to it.
The research bolsters the idea of using antioxidants, such as vitamin E, in treating ALS.
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 MDA RESEARCHER'S MOUSE SHOWS VALUE OF DRUGS
Vitamin E delayed onset of ALS and slowed progression in the early stage of the disease in mice with a genetic defect known to cause the disorder in humans, says a new study by MDA-backed researcher Mark Gurney.
Gurney developed the mice in 1994 with MDA funding while he was at Northwestern University in Chicago, where he also did these drug studies. He's now at Upjohn Pharmacia Laboratories in Kalamazoo, Mich.
Gurney says the so-called SOD1 mouse model is a good model not just for genetic ALS, but probably for all ALS. The same study showed that two other drugs, riluzole and gabapentin, slightly prolonged survival in a later stage of ALS. Riluzole (brand name Rilutek), manufactured by Rhone-Poulenc Rorer, came on the market Jan. 10 as the first FDA-approved drug for treatment of ALS.
Gabapentin, which is thought to work somewhat like riluzole, is already on the market as Neurontin, for the treatment of epilepsy.
The Gurney study shows that ALS, at least in the mouse with an SOD1 defect, can be divided into two phases. The first phase, called the oxidative damage phase, involves "silent" damage to motor neurons in the brain and spinal cord by oxidation reactions. When the SOD1 gene and its protein, the SOD1 enzyme, are flawed, the reason for the oxidative damage is clear. When there's no genetic flaw, as is the case in most ALS, the trigger for oxidative damage in the early phase, if it occurs, isn't clear. Gurney believes the same oxidative damage occurs in non- genetic ALS as occurs in genetic ALS.
In this first phase, the antioxidant vitamin E was able to prolong function in the mouse. In the second phase, motor neurons already damaged by oxidation are vulnerable to lethal assault by normal levels of the central nervous system chemical glutamate, according to Gurney's theory. In this stage, the drugs riluzole and gabapentin prolonged survival in the mice.
The study confirms and complements the human research. Vitamin E is being tested in MDA centers and is already being recommended for ALS by many neurologists. Gurney's study appears in the Feb. 1 issue of Annals of Neurology.
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MDA, AMGEN DISCUSS ALS DRUG TRIALS
MDA's National Headquarters in Tucson, Ariz., played host on Jan. 24 to representatives of the global pharmaceutical company Amgen, which is developing BDNF (brain-derived neurotrophic factor) as a potential treatment for ALS.
MDA CEO Robert Ross, MDA Director of Field Organization Gerald Weinberg, MDA Director of Research and Patient Services Administration Ron Schenkenberger and other Association staff met with Amgen representatives. Speaking for Amgen were Senior Manager-Professional Services Jeanne Flynn, Product Development Team Leader for BDNF Jim Miller and Neurotrophic Product Managers Judy Doe and Tom Nusbickel.
The purpose of the meeting was for MDA and Amgen to confer on the status of BDNF and to discuss the possibility of MDA administering combination drug trials testing BDNF together with the recently approved ALS drug Rilutek and/or other substances. BDNF, which Amgen is developing in partnership with Regeneron, is one of a number of neurotrophic factors that occur naturally in the body and have the potential to protect motor neurons.
Amgen representatives said the company would take under advisement the proposal that MDA run combination trials including BDNF, but any such development might have to wait until phase III trials of BDNF are complete.
Phase III trials began last July, with 1,135 patients taking part at 38 sites in the United States and Canada, many of which serve as MDA-funded clinics.
"Although it's too early to know BDNF's potential, I believe we've built a possible foundation upon which Amgen and MDA may work together in the near future, serving the interests of individuals with ALS," MDA's Ross said.
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THE ALS NEWSLETTER
Muscular Dystrophy Association
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