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UNUSUAL APPROACH TO fALS THERAPY CLEARS FIRST ANIMAL STUDIES The article describing the research appears in the August issue of the Journal of Clinical Investigation. “Our work suggests that this technique can be an effective, regulatable way to treat types of ALS and other neurodegenerative diseases where we know the causative gene and the protein it produces,” Cleveland says. The study, in conjunction with researchers at California’s Isis Pharmaceuticals, used therapeutic molecules called antisense oligonucleotides delivered to the brain and spinal cord of disease-bound rats, as well as healthy controls, via a tiny pump implanted beneath the skin. Carried in the cerebrospinal fluid that bathes the central nervous system, the specially tailored oligonucleotides were designed to block effects of the mutant SOD1 gene that causes roughly 20 percent of inherited ALS. Diffusing into brain and spinal cord tissues usually harmed by the disease, the antisense oligonucleotides attached to the very molecules that carry out the mutant gene’s bidding, making them vulnerable to destructive enzymes. In test cultures of cells, antisense lowered mutant SOD1 protein — the gene’s byproduct — to 20 percent of what’s typical. And in the ALS model rats given antisense oligonucleotides a month before symptoms of disease typically appear, the effect could be seen as a 37 percent increase in the animals’ survival. It slowed the rate of the insidious advance of paralysis. “Antisense had no effect on the illness’s onset in the animals,” Cleveland says. They still developed symptoms. And some mutant SOD1 protein still accumulated, even as high as 5 percent of protein in the brain. “But even with that, remarkably, there was dramatic slowing of the disease’s progress.” Much of the study was dedicated simply to proving the principle that antisense oligonucleotides, given this way, can squelch protein production. So Cleveland’s team showed that was the case in healthy rats and also in the healthy Rhesus monkeys they tested. Animals apparently suffer no ill effects from being without some, most, or even all normal SOD1 protein, Cleveland says. One arm of the research also depleted a protein thought responsible for much of disease progression in Alzheimer’s disease. So it shows the potential of antisense therapy for a number of neurodegenerative illnesses, including Parkinson’s and Huntington’s disease. As for its use in humans, nothing, so far, discourages continued research. “Safety of local and systemically given oligonucleotides is well established,” Cleveland adds. More than 500 human subjects in other studies have had exposure to oligonucleotides similar to those used in this one. “Our results support infusing antisense oligonucleotides as a treatment for familial ALS, especially for patients with the SOD1-A4V mutation which accounts for about 50 percent of SOD1 mutations in this country and which has an unusually rapid disease course after onset,” says Cleveland. If the formal safety studies underway in animals and the planned Phase I trials, to be carried out with Packard Center Clinicians, in human familial ALS patients support it — both, admittedly clear hurdles for a new technique — antisense could have genuine impact on the disease. Richard Smith, of the Center for Neurologic Study, La Jolla, CA., and Tim Miller, a colleague of Cleveland’s at UCSD, were also co-investigators in the study. Cleveland is a consultant at Isis Pharmaceuticals Inc., which will manufacture the agent used in clinical trials. |
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