CSHL researcher-inventor hails FDA approval of new SMA drug

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Within a week of Christmas day, a drug called nusinersen will be in the hands of doctors across the nation, who will use it, most urgently, to treat young children with a severe and potentially fatal illness called spinal muscular atrophy (SMA).

The leading genetic cause of infant mortality, SMA is a motor neuron disease that leads to the wasting of young muscles, impairing the ability of newborns and toddlers to walk, crawl, or even hold their heads up, and in the most severe cases, failure of muscles that enable them to breathe.

"Some are understandably calling the FDA's announcement of nusinersen's approval 'a Christmas surprise,'" Dr. Krainer commented. "For those of us who have had the thrilling experience of working on this drug from the very beginning, and have watched it succeed in reversing SMA pathology in animals -- and more recently in young people with the illness -- news of the approval is simply thrilling. Most gratifying to me is the thought that thousands of families will now be able to see their loved ones benefit from the drug's therapeutic effects."

"This drug will save lives of young people with severe SMA, and will improve the lives of many thousands of older children and adults who have disabling forms of the disease," said Bruce Stillman, Ph.D., President and CEO of CSHL. "This is a fantastic example of how fundamental research exploring the mechanisms of cells can lead to important clinical developments."

Ionis says nusinersen's FDA approval clears it for use in both pediatric and adult SMA patients. The drug performed impressively in clinical trials testing its impact across a wide range of SMA patients, from just after birth to age 12 and beyond. The earlier the drug is administered in patients, the more it appears to help them.

SMA patients no longer have a working copy of a gene called SMN1 ("survival of motor neuron"), which encodes a protein essential for the development of motor neurons. Without it, patients must rely on a nearly identical gene called SMN2. It's a poor backup, though: the SMN2 gene (in all people) has a DNA error that usually prevents cells from manufacturing functioning SMN protein. [click here to see a cartoon explaining the problem and how the drug fixes it]

Dr. Krainer, a world authority on a cellular process called RNA splicing - the editing of RNA "messages" copied from our genes - conceived of a way to compensate for the error in SMN1 by correcting the defect in SMN2, which is caused by a failure of the splicing mechanism to "edit" the gene's RNA message properly.

With Ionis scientists, Krainer's team designed, synthesized and tested tiny molecules of modified RNA called antisense oligonucleotides (ASOs), which, when delivered to cells, bind at a specific site on the unedited RNA message made from the SMN2 gene. The ASO's binding has the effect of fixing the splicing error responsible for non-functional SMN protein. Human testing sponsored by Ionis began in 2011.

One child who has benefited is Emma Larson, a lively 3½-year-old from Long Island, whose parents sought Dr. Krainer's counsel when she was diagnosed with Type 2 SMA. Dianne and Matthew Larson later enrolled Emma in a clinical trial, when she reached her 2nd birthday, at which point she was losing the ability to crawl and to hold her head up without assistance. Within 2 months of receiving her first injections of nusinersen, Emma began to improve. "It was a miracle," Dianne Larsen recalls. Today, Emma continues to improve, graduating from a walker to crutches and getting ready to join her peers in preschool.

"We are in tears over here, along with the rest of the community! Amazing! Still numb," Dianne said in an email the morning after the drug's FDA approval. "Thank god for Adrian Krainer and all the people who made this drug possible!"

Dr. Stillman, echoing Dianne Larson's joy, took the occasion to note that the applied research leading to nusinersen was preceded, in Krainer's case, by some 15 years of basic research to determine the mechanisms that underlie RNA splicing. And those discoveries, Stillman noted, followed closely upon another great scientific triumph, occurring simultaneously at CSHL and MIT almost exactly 40 years ago.

"In the spring of 1977, Drs. Richard Roberts of CSHL and Phillip Sharp, then of MIT, first described RNA splicing - a fundamental mechanism in cells that regulates how our genes are expressed." Roberts and Sharp shared the 1993 Nobel Prize for that work, which provided a point of departure for investigators like Adrian Krainer who worked on the mechanism. "This is a perfect example of how basic research -- with no specific purpose other than uncovering the mysteries of life - is the precondition for all the marvels of applied science that we enjoy, wonders that now include the development of nusinersen."

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