Researchers have identified the putative gene for the familialform of Lou Gehrig's disease, or amyotrophic lateral sclerosis(ALS).

Collaborating research teams led by Robert Brown of Boston'sMassachusetts General Hospital and Teepu Siddique ofNorthwestern University in Chicago report in today's issue ofNature that the gene responsible for many cases of familial ALS(FALS) codes for copper-zinc superoxide dismutase (SOD). It islocated on the long arm of human chromosome 21.

ALS is a degenerative disorder of motor neurons in the cortex,brain stem and spinal cord. It's a uniformly fatal disease thatoccurs in adults. Death usually claims the victims, who sufferfrom generalized weakness, progressive muscle wasting andparalysis, within five years. The familial form of ALS, which isinherited as an autosomal dominant trait, is thought toconstitute roughly 5 percent to 20 percent of all reported cases.But in most instances, the authors state, sporadic ALS isclinically similar to the familial version.

Brown, Siddique and their colleagues identified 11 differentmutations in the gene coding for SOD in 13 different FALSfamilies. They hypothesize that "the mutations we haveidentified in the SOD1 gene cause FALS."

As to whether these results pertain to individuals withsporadic ALS, Brown told BioWorld: "We're passionatelyinterested in that. We are just starting the non-familial studies,but the data are too preliminary" for any comment.

So what is the connection between superoxide dismutase andALS? SOD's role in the cell seems to be to catalyze theconversion of the toxic superoxide anion radical to hydrogenperoxide. Reactive free radicals such as superoxide can bedirectly toxic to cells, and have even been proposed to causeneuronal injury in Parkinson's disease and ischemic braininjury. Thus, if the activity of SOD in FALS patients is reduced,it could lead to the accumulation of superoxide radicals andsubsequent tissue damage.

However, "why a SOD1 abnormality might selectively damagemotor neurons is unclear," according to the scientists.

Brown, Siddique and colleagues concluded, "If indeed toxicitycaused by oxygen free radicals is the primary pathogenicmechanism for motor neuron death in FALS and perhaps insporadic ALS as well, measures that diminish this toxicitymight blunt the devastating course of this disease."

Several companies are already in clinical trials with potentialtherapies for ALS. Cephalon Inc. (NASDAQ:CEPH) of WestChester, Pa., is developing a recombinant form of insulin-likegrowth factor (IGF-1). And both Regeneron PharmaceuticalsInc. (NASDAQ:REGN) of Tarrytown, N.Y., and Synergen Inc.(NASDAQ:SYGN) of Boulder, Colo. -- in collaboration with SyntexCorp. -- are exploring the potential of ciliary neurotrophicfactor (CNTF).

As to why such therapies might work, Mark Furth, Regeneron'svice president of technology, told BioWorld: "We know from ourstudies and those of others that treatment with neurotrophicfactors stimulates some of the detoxifying efforts (of cells) indealing with free radicals. Neurotrophic factors can protect cellsfrom the kind of insult that SOD might cause."

As well, "while neurotrophic factors act on specific nerve cells,the protection they provide neurons from injury is rathergeneral," explained Leonard Schleifer, Regeneron's presidentand chief executive officer.

Siddique, one of the authors on the Nature paper, is one of theinvestigators in Regeneron's clinical trials, which includespatients with both familial and sporadic ALS, Furth said.

-- Jennifer Van Brunt Senior Editor

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