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Death Be Not Programmed
by John Fleischman
The ordered chain of events that is cell necrosis can be blocked to curtail the effects of some crippling diseases.
If the drug works in dogs with an aggressive form of MD, Jeffery Molkentin is hopeful that it will help children as well.
Necrosis is not subtle. One of the body’s natural forms of cell death, it can be likened to a ship hitting an iceberg, exploding the boiler, and capsizing, all at once. Cell necrosis occurs as a result of sudden death by trauma, by pathogenic infection, or by the proverbial last straw laid on accumulated damage.
Underneath all that seeming chaos, however, cell necrosis is actually an ordered chain of steps, says Jeffery Molkentin, an HHMI investigator at Cincinnati Children’s Hospital Medical Center. Moreover, Molkentin and others are crafting treatments for several “untreatable” degenerative diseases by uncoupling key steps that drive necrosis forward.
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Blocking a Protein’s Punch
Cyclophilin D isn’t just important in Duchenne MD, but a variety of other diseases.
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Although he made his first discovery in the field of necrosis while studying damaged heart cells, Molkentin is focusing on Duchenne muscular dystrophy (MD). The most common form of the genetic muscle-wasting disease affects one in every 3,500 males born in the United States; boys with Duchenne MD typically live only into their late teens and early 20s.
Molkentin has used engineered transgenic mice to show how the relentless muscle damage that drives Duchenne MD can be interrupted. Now, he has a “proof of principle” drug study underway in Brazil, using a small colony of golden retriever dogs that spontaneously develop an aggressive form of MD similar to human Duchenne MD. The drug is related to the immune suppressant cyclosporine, but instead of targeting the immune system it blocks a crucial step in the cell necrosis pathway in skeletal muscles, according to Molkentin.
This drug does not correct the genetic defect that drives MD—mistakes in a giant muscle-connecting protein called dystrophin—so it is no cure for the disease. But stopping cell necrosis could curtail MD’s crippling effects. Though results are not in, Molkentin believes that “if this drug fixes the golden retrievers, it’s going to work in kids.”
Photo: Jonathan Willis
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