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New Molecule Touches Key Bases in the ALS Therapy Pipeline Can a mimic of a natural neuroprotector work in humans? Here’s a progress report from the path. Just a few months ago, Packard Center scientists reported that an agent they’re testing — one that counters harmful excitotoxicity — has reached important milestones in ALS’s therapeutic pipeline. Yes, it’s still early and the compound is still in animal studies. And, no, it’s not something already prescribed for some other disease and, thus, already safe in patients. So, should it continue to slide down the pipeline, it would still face broad clinical trials. But the fact that GPI-1046 mimics a natural molecule in the body, one that protects nerves and nurtures nerve cell growth, and that it can reverse a well-known step in ALS’s downhill path makes it worth watching. One hallmark of ALS is the surge of glutamate. Normally a fleeting chemical released in small amounts — just enough to hit a target nerve cell and send a message — glutamate in excess is a liability. In ALS and some other neurological diseases, glutamate pools in the synaptic spaces that separate nerve cells. The flood of it overstimulates the chemical’s target receptors in nerve cell membranes. Their jangled activity, in turn, trips a harmful biochemical cascade in the cells — excitotoxicity — long suggested as a key cause of motor neuron death in ALS. Normally, glutamate is cleared from synapses by the nervous system’s astrocytes, cells well-stocked with molecules called glutamate transporters which act like sponges. But earlier studies by Jeffrey Rothstein, Packard Center director, showed that both ALS patients and animal models of the disease lose glutamate transporters, with drastic results.
So along comes GPI-1046. According to Rothstein, who lead the research team, the molecule is a designer version of a brain immunophilin protein. Molecules in that family support neuron survival and, in some situations, promote growth. “We’ve followed others’ studies that describe immunophilins’ ability to enhance nerve growth, as well as their usefulness a Parkinson’s disease therapy,” he says. “Based on good signs there, we thought we should look into them for ALS.” So recently, Rothstein, Scottish collaborator Mandy Jackson, fellow Packard scientist Nicholas Maragakis and other Johns Hopkins colleagues studied GPI-1046's effects in cell cultures, spinal cord models and live rodents. In the first experiments, the drug was applied to rodent spinal cords kept alive in culture. After two weeks, the glutamate transporters in spinal cord astrocytes more than doubled. Later work with spinal cords (now ground-up for ease of study) showed a 50 percent increase in actual glutamate uptake — a sure sign of transporters at work. Studies in living rodents kept up the trend: given orally to adult male mice, GPI-1046 increased glutamate transporters by 300 percent in three weeks. When infused directly into rat brains, the molecule also created a jump in transporter protein there. Even more telling was the molecule’s activity in situations mimicking disease. When a chemical that trips excitotoxicity was introduced into the rodent spinal cord cultures, GPI-1046 protected neurons there in a dose-dependent way, that is, the more drug added, the greater the protection. In the SOD1 mice most often used as models of ALS, oral GPI-1046 increased survival, though modestly. “The neuroprotection we saw in cultures seems to carry over to live animal models,” Rothstein explains. And though the way this neuroimmunophilin works isn’t yet clear, he says, “it certainly warrants keeping in the pipeline as a possible way to block the damage from the excitotoxicity that’s a cellular threat in ALS.” Funding for this study came through the Robert Packard Center for ALS Research, from the NIH and the Muscular Dystrophy Association. First author is Raquelli Ganel. Tony Ho, Mandy Jackson and Joseph Steiner rounded out the scientific team. |
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