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The story of a childâs illness, a scientistâs quest, and the circumstances that made possible the successful development of a life-saving treatment, a miracle drug.
Itâs not a question any mother wants to ask herself.
When Dianne Larson gave birth to her daughter, it was a joyous occasion. In fact, the entire first year was joyous. She was learning to be a mother, and little Emma was just beginning to develop the innocent wanderlust of a newborn. She would lift her head and explore the room with startling amber eyes. Right on schedule, she began to crawl—thrusting herself into a new world full of curiosities.
âAt her 12-month pediatrician appointment she was moving her legs, beginning to bear weight on them, as kids are supposed to do. They said, âSheâs great, sheâs perfect. Take her home.ââ
âThat was 12 months,â Dianne recalls. âAt 13 monthsâŠthatâs when all hell broke loose.â
Thatâs what it felt like, anyway.
âYou feel like the rug is ripped out from under you with this disease,â Dianne explains.
A native New Yorker, Dianne describes herself as an âopen bookâ—not the kind of person to hold back when she feels something is wrong. After seeking the opinion of numerous doctors and experts concerning her daughterâs deteriorating condition, tests were taken. The result? After little more than a year in this world, little Emma Larson was diagnosed with Spinal Muscular Atrophy (SMA)—a disease infamously known to be the deadliest genetic disease among infants. The most seriously affected are often gone before their 2nd birthday.
âHer diagnosis was. . .pretty grim,â Dianne says, wiping the tears from her eyes.
Even with it now all in the past, the emotions from the hardest time in her life still easily bubble to the surface. What happened next, from Dianneâs point of view, was a miracle. In reality, however, it was the fruit of tireless and exemplary science—with all the right people coming together in all the right ways to achieve something wonderful.
The first week after Emmaâs diagnosis was particularly hard for the Larsons. Dianne and her husband Matt had the unenviable task of informing family and friends about their daughterâs disease.
âIt was pretty devastating to keep repeating it.â
Matt places a hand on his wifeâs shoulder as she goes on to explain that eventually they decided to inform their friends through social media. It was with that decision, they say, that serendipity then took the reins.
"My husbandâs cousin saw the post, and then a friend commented that she worked with a doctor who was working on a treatment for Spinal Muscular Atrophy."
Matt and Dianne took the first opportunity they could to visit ¶¶Òő»Æ°æÏÂÔŰ, a major research facility near their Long Island home. There they met Dr. Adrian Krainer—a scientist who had been working toward understanding and coming up with a treatment for SMA.
âMeeting doctor Krainer was like a blast of fresh air,â Matt recalls. âIt was so relieving to meet someone who not only understood what was happening to our little girl, but was working to help. He gave us hope.â
Krainer also gave them peace of mind. After doing their own research and speaking with the right people, the Larsons had determined that Emma could be an ideal candidate for Nusinersen—an experimental treatment for SMA that was in the middle of clinical testing. However, they had been hesitant about moving forward. As the inventor of the drug in question, Krainer was able to explain how the drug would work to help their ailing little girl. The Larsons didnât hesitate to trust him.
"Enrolling your child in a clinical trial... itâs tough,â says Dianne. âItâs very tough on a parent because I donât want her to hate me for making the wrong decision. You know?...but at this point I feel like we made the best decision for her because sheâs doing great."
Emmaâs first injection in the nusinersen trial occurred in March 2015. At the time, Dr. Krainerâs words had left Dianne cautiously hopeful, but she and her husband Matt didnât expect a miracle.
âI even have it written down,â Dianne explains now, over the phone. The sound of papers shuffling crackles over the speaker. âHere it is. She went through all the screenings. Passed them. She had her first injection...I think it was March 3rd. Second injection was at the end of March. Third injection was in May.â
She pauses for a second, then presses on excitedly.
âBy this time...This was an amazing thing. It was in April—after the second shot, before her third. I was in the bedroom and she was in the den. Now, mind you she canât move. She couldnât crawl more than two feet, if that. She was talking and all of a sudden I hear her voice getting closer and closer.â
Dianne knew Emma had done something—she couldnât think of what—to make her tiny voice carry across the house. âEmma?â she called out.
âNext thing I know, sheâs right by the bedroom door, crawling on the floor. Iâm like, âWhat?!â I was freaking out. I couldnât believe it. She had crawled from the den to the bedroom! I picked her up and put her back in the den and said âOkay, come find mommy again.â I just couldnât believe it.â
Emma did find mommy again. And again. It had been just over a month since she had begun the experimental treatment.
A religious woman, Dianne admits that when Emma was first diagnosed with a potentially deadly condition, she started to doubt.
âYou kind of lose faith, like, âWhy is this happening?â I stopped praying, soâŠwhen this medicine came, it changed.â
When she and Matt revisited Dr. Krainer and his lab in the summer of 2016, they were all smiles and hugs. Little Emma was a bundle of energy, scooting around in her wheelchair faster than Matt could keep up. With a smile on her face, Dianne explained that these days, sheâs praying again, but not for your run-of-the-mill miracle.
"You do pray, I pray for these four people," she adds, gesturing toward Dr. Krainer and the people in his lab. âBecause without them there wouldnât be any hope for my daughter...so they are a miracle for us.â
Dianne calls it âcruising.â According to the proud mother, Emma braced herself against an ottoman to stand. Then she sidestepped around it in order to reach different parts of the den. She did this without leg braces, opting to stand entirely on her own budding strength.
Itâs important to note that before the trial, Emma had never stood. SMA struck too early—before the average newborn takes her first steps.
And now she was standing.
âDoctors havenât put a limit on it,â Dianne adds. âAt this point, weâre just waiting to see how far she can go!â
It was a gift to the world. On December 23, in the midst of 2016âs holiday season, the drug officially known as nusinersen—commercially branded as SPINRAZA™—was approved by the US Food and Drug Administration. Some went so far as to call it a âmiracle drugâ—the result of âperfectâ fast-tracked clinical trials.
Dr. Darryl De Vivo of Columbia University was involved in trials for nusinersen from the start. He was a prominent player in the drugâs testing and witness to the miraculous recovery of patients much like Emma Larson and —children who previously would have been doomed to suffer from acute neurodegeneration caused by (SMA).
âLet me tell you. We treated the very first patient with nusinersen in December of 2011,â De Vivo explains over the phone from his office in upper Manhattan. âIt was a pretty exciting moment, when you think about it. We didnât know for certain whether it was going to be as good as we know it is. It could have been a disaster. Thatâs just the nature of clinical trials. But it worked out fantastically!â
And why was that? According to De Vivo, beautiful results are the fruit of beautiful science.
âIn 1995, we, the medical community, were introduced to for the first time. Only after this occurred did people increasingly start to say, âIf we can do something about that mutation, then maybe we can find a perfect treatment for this disease.â â
âEnter people like Adrian Krainer who are masters of RNA splicing...â
âLo and behold,â said De Vivo, a path to a drug for SMA patients could suddenly be seen.
âIn 1999, it—Spinal Muscular Atrophy—was a disease I knew almost nothing about,â Professor Krainer admits with a bashful shake of his head.
Heâs sitting in an armchair at ¶¶Òő»Æ°æÏÂÔŰâs historic library. A bust of Francis Crick, co-discoverer of the structure of DNA, peers over his left shoulder with stoic indifference. Itâs easy to imagine the Nobel laureateâs likeness is actually listening in, subtly turning an ear toward our conversation even as his polished granite eyes pretend to browse titles on a nearby bookshelf.
âIt was 1999, and I was invited to attend a workshop at the NIH's National Institute of Neurological Disease and Stroke.â
Krainer was asked to attend the workshop, despite his lack of knowledge on SMA, because he was internationally recognized as one of the worldâs leading experts on the molecular process known as âsplicingâ—a process, his peers had just determined, that plays a critical role in causing SMA.
âThe NIH workshop was a watershed moment for me,â Krainer explains. âThe splicing errors these people were observing were so obviously similar to what I had been studying.â
So at that meeting in Washington DC, surrounded by experts of a disease he barely understood, Krainer decided to start blazing a path that eventually would lead to a new drug and many lives saved.
How did Krainer reach that point? How does one become an expert on something other scientists were just figuring out?
Thatâs according to Nobel laureate Richard Roberts—a man whose decades of work in the lab have certainly taught him a thing or two about serendipity...and Adrian Krainer for that matter. In 1977, 20 years before Krainer had his epiphany, Roberts and Phillip Sharp had one of their own that changed the history of the life sciences. In different labs at different institutions, they co-discovered the process of RNA splicing.
According to Roberts, he never intentionally set out to discover RNA splicing. Instead, that big discovery was the accidental fruit of a search for other things—research that required two attributes above all: curiosity and an open mind.
âWhy should we celebrate this aspect of scientific discovery?â science writer Peter Tarr recently asked Roberts. They were sitting in Robertsâ office at New England Bio Labs, where he has served as Chief Science Officer (CSO) for the past 25 years.
âWhy should we celebrate...â
âSerendipity?â Roberts provided.
âWell, yes, but also the patience that is so characteristic of scientists. It takes time. Itâs not a straight line.â
âNo, never. Never. And if it was, it would be rather boring,â Roberts cut in. He was grinning at this point. âAnd I donât think youâd get particularly talented people to come along and do it.â
— James Watson, Nobel laureate and co-discoverer of the double-helix structure of DNA
To really press his point home, Roberts provided an example from his own mark on history.
âI mean, think of Nixonâs War on Cancer! If it wasnât for the War on Cancer there never would have been a biotech industry. Really! And we would have never discovered splicing.â
âBut did we get an answer to cancer?â he asked. âNo...not at all.â
What the war on cancer did do was provide an inspiring puzzle for some of 1970s' brightest and most ambitious scientists. Among them were Roberts and Sharp.
CSHLâs Jim Watson was among the scientific sages who realized cancer was a genetic illness, at its roots. Early in the cancer war, though, there was no way to easily study genes, or even know where specific genes were located on chromosomes. Roberts proposed to use a newly discovered class of proteins called to cut the enormously long DNA molecule into manageable bits that could then be mapped, if slowly, using a manual method. Similarly, Sharp had used the first of such enzymes to sequence parts of the genome of a cancer-causing virus.
Both scientists applied their skills to a basic mystery that molecular biology was then tackling: When an activated geneâs âmessageâ is copied from the original DNA into RNA—the first step in making a protein—how does the RNA message actually form?
Using powerful electron microscopes, Roberts and Sharp both noticed that RNA messages were not precise copies of genes. As they were processed in the cell nucleus, they formed odd shapes and eventually became looped and then broke into smaller pieces, as seen in the background image on this page.
Independently, using some of the same know-how and tools, Sharp's lab (at MIT) and Roberts with his team (at CSHL) soon concluded that a preliminary, raw copy of a gene first had to be edited, or âspliced,â before it could be used to direct protein production.
for the discovery of RNA splicing with a Nobel Prize in Physiology or Medicine in 1993. Just before then, Roberts found himself in a position at CSHL to promote a new generation of young scientists to the forefront of efforts to more completely understand splicing.
âFor me, I look for enthusiasm,â Robertâs explained.
âIf people are enthusiastic...â
Attending a large meeting on RNA splicing in the 1980s, Roberts had been impressed with a presentation made by a grad student from Harvard named Adrian Krainer with a clear passion for splicing research.
Fortunately, ¶¶Òő»Æ°æÏÂÔŰ was then in the midst of designing a program that would help spur promising postdoctoral researchers. It came to be called the Fellows program, and, on Robertsâ advice, Adrian Krainer became the very first in a distinguished line of CSHL Fellows that also includes Nobel laureate .
Under Robertsâ tutelage, Krainer was able to flourish, beginning what he describes as a ârelentless pursuit of RNA splicingâ that continues to this day.
In the early 1990s he made his first breakthroughs, identifying two proteins that would prove important in regulating the splicing process. Over time, more than 200 factors would be identified by labs around the globe.
And when that 1999 NIH workshop rolled around—with experts on Spinal Muscular Atrophy vaguely gesturing at examples of splicing in action—Adrian Krainer suddenly realized how all of his hard work might apply.
Serendipity had turned his scientific journey into the perfect key for a very specific lock. It would take more than a decade still, but heâd beat that disease.
Imagine that when youâre born, there is a hand lightly pressing on your chest. At first, itâs difficult to notice; perhaps it only stops you from looking around a room and maybe you have a little less interest in reaching for things. But as time goes on, that hand grows larger and presses down harder. Normally exploring limbs are leaden and breath is pushed from seemingly tiny lungs. You may never learn to sit up. Life with Spinal Muscular Atrophy is not a comfortable one, and if a child is born with a particularly severe version of the genetic disease, itâs a life that wonât last long.
A decade ago, Type 1 SMA would claim a staggering 90 percent of the children born with the affliction each year. Few would make it to their second birthday. Others, somewhat more fortunate, are born with less severe versions. Children with Type 2 SMA usually survive, but only to live with the weight of their own bodies proving too much for their failing muscles. Many lead a breathless, exhausting existence from the confines of a wheelchair.
That is, at least, how it used to be...
Today, you might say that SMA has been âbeat.â
Approved in the United States and European Union (Japan, Canada, Australia, Switzerland, and BrazilÂ pending), the drug known as nusinersen compensates for the insidious problems within an SMA patientâs genome.
Sold under the brand name SPINRAZA™, the drug has been hailed as the âfirst-ever treatment for SMA,â and a âhuge winâ for molecular biology. In fact, SPINRAZA™ was named the "best biotechnology product of 2017" by the prestigious Galien Foundation.
âThere has never been a disease-altering therapy for a neurodegenerative disease,â molecular neuroscientist J. Paul Taylor of St. Jude Children's Research Hospital excitedly told Science a few days before the drug became available. (Taylor is not involved with the drug or with the companies behind it.)
But just as the drugâs inventors did, before you can understand how this miracle drug works, you first must understand SMA.
Working with our friends at Youreka Science, CSHL has created a brief explainer video to help you understand SMA and how nusinersen treats it. We begin with what causes SMA.
SMA is caused by a lack of the aptly named âSurvival of Motor Neuronâ (SMN) protein. This protein is so important that our muscles cannot develop normally without it.
When a person is born without a properly working SMN1 gene, thereâs a serious problem, because it carries instructions for muscle cells to manufacture SMN protein. Deprived of the normal source of vital SMN protein, such a person falls back on a second, nearly identical gene called SMN2. But this gene is flawed. It only makes about 10% of the SMN protein needed by our muscles. These people have Spinal Muscular Atrophy. They usually begin to weaken at the very beginning of life, just as their muscles are developing.
Once the biological cause of SMA was discovered—a catastrophic flaw in the SMN1 gene—researchers quickly realized that a solution was not going to be easy. Even to this day, there are no approved drugs that repair broken genes. But what about that backup gene we just mentioned? If SMN2 were somehow to become an adequate producer of the vital SMN protein, wouldnât that halt SMA?
Enter Dr. Adrian Krainer. A curiosity-driven researcher, Krainerâs career has been motivated by his interest in the mechanism of a molecular editing process called RNA splicing that is central in the production of proteins. By the late 1990s—as we describe in Chapter 2—Krainer was known as a master of splicing.
Having worked directly under Nobel laureate Richard Roberts—who co-discovered splicing—Krainer was recognized by the research community as a promising candidate to tackle the RNA problem behind SMA.
âNow suddenly hereâs a common disease which Iâm learning about in which all the patients have the same defect [in SMN2],â says Krainer. âIt was really apparent that if we could find a solution, it would apply to all SMA patients.â
Much of the work Krainer had done as a CSHL Fellow and young lab leader would play a major role in the development of nusinersen. But it would take time to secure funding and introduce others in his lab to the idea of fixing the backup gene, SMN2, as a way of helping SMA patients.
âIt was almost magic—the way things ended up working,â says Dr. Frank Bennett, a leader of drug development at Ionis Pharmaceuticals.
However, Bennett, who was instrumental in nusinersenâs development, knows that it was hard work, not magic, that got the drug to the patients who need it.
âWorking with Adrian [Krainer] has been one of my most enjoyable collaborations,â he explains. âIt was like two streams of basic research coming together.â
Like most basic research, Krainerâs own stream started as a trickle, but grew into a torrent of insights into the molecular drivers of SMN.
In the late 1980s Krainer had sought to isolate the individual components that made splicing happen. âMy first real breakthrough,â he recalls, âwas to purify a single protein, which is now called SRSF1.â
Later, work in his lab with postdoc Akiya Mayeda determined that SRSF1 is a splicing activator.
As if by fate, it was this same essential activator that Krainer and postdoc Luca Cartegni determined is missing when SMN2âs RNA message is spliced, leading to the problematic skipping of one chunk of its message, called exon 7. Soon after, the pair developed a method called ESSENCE to correct this skipping problem.
And thatâs what got Bennettâs attention. There were plenty of kinks to be worked out of ESSENCE, and in 2004, Krainer and the Ionis drug developer worked to optimize the system.
There were more surprises still in store. After Krainerâs identification of SRSF1 as the missing splicing activator that caused exon 7 to be skipped—impairing the SMN2 âbackupâ gene—he realized that the corrective molecule used in ESSENSE was also able to correct exon skipping when stripped down to a short, ânakedâ sequence of RNA. Scientists call these tiny sequences antisense oligonucleotides, or ASOs. This was key in the design of the drug called nusinersen. Efforts began to synthesize an ASO with the greatest ability to promote the inclusion of exon 7, that missing part of the SMN2 geneâs message that prevented it from making normal amounts of SMN protein.
From there, things moved quickly. In April 2008, results from mouse trials proved the treatment could correct for SMN2âs major flaw in living cells. Subsequent research even showed that the drug could reverse symptoms of Type 1 SMA, the often fatal form of the disease that we mentioned at the start of this chapter. Soon, Ionis received permission to start testing the drug in people.
By 2015, several pivotal Phase 3 trials were in progress, and one—a trial for infants suffering from SMA—came to a sudden halt. However, it wasnât disaster that struck. Instead, it was success.
Those results were indeed âgood enough to convince the FDA,â and in December 2016, the once-experimental treatment became commercially available to SMA patients for the first time.
Of course, while wonderful results and FDA approval are successes of their own, Krainer would argue that his biggest success is all the young lives that get to continue thanks to basic research driven by curiosity about how cells work. This was a big dividend.
âWhen you do the research, you always hope that it's going to have a beneficial impact, but it always seems like that is a distant possibility,â Krainer explains. âIt's something you strive for, and now it seems to actually be happening and it's like a dream come true, very rewarding."
Product of CSHL Communications Department
Peter Tarr, Sue Runkowski, and Philip Renna
Sue Runkowski and Brian Stallard
Written by Andrea Alfano and produced by Brian Stallard
The Larson family
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