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Killer disease,
Miracle drug

The story of a child鈥檚 illness, a scientist鈥檚 quest, and the circumstances that made possible the successful development of a life-saving treatment, a miracle drug.

Chapter 1

"Am I just going to watch my child die?"

It鈥檚 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.

鈥淎t her 12-month pediatrician appointment she was moving her legs, beginning to bear weight on them, as kids are supposed to do. They said, 鈥楽he鈥檚 great, she鈥檚 perfect. Take her home.鈥欌

鈥淭hat was 12 months,鈥 Dianne recalls. 鈥淎t 13 months鈥hat鈥檚 when all hell broke loose.鈥

It took her legs overnight

That鈥檚 what it felt like, anyway.

鈥淵ou feel like the rug is ripped out from under you with this disease,鈥 Dianne explains.

A native New Yorker, Dianne describes herself as an 鈥渙pen book鈥—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 daughter鈥檚 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.

鈥淗er diagnosis was. . .pretty grim,鈥 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 Dianne鈥檚 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.

It started with a Facebook post

The first week after Emma鈥檚 diagnosis was particularly hard for the Larsons. Dianne and her husband Matt had the unenviable task of informing family and friends about their daughter鈥檚 disease.

鈥淚t was pretty devastating to keep repeating it.鈥

Matt places a hand on his wife鈥檚 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 husband鈥檚 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 麻豆传媒社区, 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.

facebook post

Meeting Dr. Krainer

鈥淢eeting doctor Krainer was like a blast of fresh air,鈥 Matt recalls. 鈥淚t 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.鈥

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 didn鈥檛 hesitate to trust him.

"Enrolling your child in a clinical trial... it鈥檚 tough,鈥 says Dianne. 鈥淚t鈥檚 very tough on a parent because I don鈥檛 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 she鈥檚 doing great."

鈥淚f every parent said no...鈥

Emma鈥檚 first injection in the nusinersen trial occurred in March 2015. At the time, Dr. Krainer鈥檚 words had left Dianne cautiously hopeful, but she and her husband Matt didn鈥檛 expect a miracle.

鈥淪he鈥檚 doing better than great鈥

鈥淚 even have it written down,鈥 Dianne explains now, over the phone. The sound of papers shuffling crackles over the speaker. 鈥淗ere 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.鈥

She pauses for a second, then presses on excitedly.

鈥淏y 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 can鈥檛 move. She couldn鈥檛 crawl more than two feet, if that. She was talking and all of a sudden I hear her voice getting closer and closer.鈥

Dianne knew Emma had done something—she couldn鈥檛 think of what—to make her tiny voice carry across the house. 鈥淓mma?鈥 she called out.

鈥淣ext thing I know, she鈥檚 right by the bedroom door, crawling on the floor. I鈥檓 like, 鈥榃hat?!鈥 I was freaking out. I couldn鈥檛 believe it. She had crawled from the den to the bedroom! I picked her up and put her back in the den and said 鈥極kay, come find mommy again.鈥 I just couldn鈥檛 believe it.鈥

Emma did find mommy again. And again. It had been just over a month since she had begun the experimental treatment.

Dianne Larson's diary
Click image to enlarge

An amazing moment for Emma

Faith restored

A religious woman, Dianne admits that when Emma was first diagnosed with a potentially deadly condition, she started to doubt.

鈥淵ou kind of lose faith, like, 鈥榃hy is this happening?鈥 I stopped praying, so鈥hen this medicine came, it changed.鈥

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, she鈥檚 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. 鈥淏ecause without them there wouldn鈥檛 be any hope for my daughter...so they are a miracle for us.鈥

By June she was standing

Dianne calls it 鈥渃ruising.鈥 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.

It鈥檚 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.

鈥淒octors haven鈥檛 put a limit on it,鈥 Dianne adds. 鈥淎t this point, we鈥檙e just waiting to see how far she can go!鈥

Chapter 2

A gift from science

It was a gift to the world. On December 23, in the midst of 2016鈥檚 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 鈥渕iracle drug鈥—the result of 鈥減erfect鈥 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 drug鈥檚 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).

鈥淟et me tell you. We treated the very first patient with nusinersen in December of 2011,鈥 De Vivo explains over the phone from his office in upper Manhattan. 鈥淚t was a pretty exciting moment, when you think about it. We didn鈥檛 know for certain whether it was going to be as good as we know it is. It could have been a disaster. That鈥檚 just the nature of clinical trials. But it worked out fantastically!鈥

And why was that? According to De Vivo, beautiful results are the fruit of beautiful science.

鈥淚n 1995, we, the medical community, were introduced to for the first time. Only after this occurred did people increasingly start to say, 鈥業f we can do something about that mutation, then maybe we can find a perfect treatment for this disease.鈥 鈥

鈥淓nter people like Adrian Krainer who are masters of RNA splicing...鈥

鈥淟o and behold,鈥 said De Vivo, a path to a drug for SMA patients could suddenly be seen.

Nobody鈥檚 dropped out of treatment, nobody鈥檚 had a significant side effect, and everybody has continued to make normal gains for age... It鈥檚 just beautiful.

Dr. Darryl De Vivo
— Dr. Darryl De Vivo
Columbia University

A young scientist's unforeseen path

鈥淚n 1999, it—Spinal Muscular Atrophy—was a disease I knew almost nothing about,鈥 Professor Krainer admits with a bashful shake of his head.

He鈥檚 sitting in an armchair at 麻豆传媒社区鈥檚 historic library. A bust of Francis Crick, co-discoverer of the structure of DNA, peers over his left shoulder with stoic indifference. It鈥檚 easy to imagine the Nobel laureate鈥檚 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.

鈥淚t was 1999, and I was invited to attend a workshop at the NIH's National Institute of Neurological Disease and Stroke.鈥

Krainer was asked to attend the workshop, despite his lack of knowledge on SMA, because he was internationally recognized as one of the world鈥檚 leading experts on the molecular process known as 鈥渟plicing鈥—a process, his peers had just determined, that plays a critical role in causing SMA.

鈥淭he NIH workshop was a watershed moment for me,鈥 Krainer explains. 鈥淭he splicing errors these people were observing were so obviously similar to what I had been studying.鈥

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?

Dr. Adrian Krainer 1998

Adrian Krainer, 1998

It was pure serendipity

That鈥檚 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.

鈥淲hy should we celebrate this aspect of scientific discovery?鈥 science writer Peter Tarr recently asked Roberts. They were sitting in Roberts鈥 office at New England Bio Labs, where he has served as Chief Science Officer (CSO) for the past 25 years.

鈥淲hy should we celebrate...鈥

鈥淪erendipity?鈥 Roberts provided.

鈥淲ell, yes, but also the patience that is so characteristic of scientists. It takes time. It鈥檚 not a straight line.鈥

鈥淣o, never. Never. And if it was, it would be rather boring,鈥 Roberts cut in. He was grinning at this point. 鈥淎nd I don鈥檛 think you鈥檇 get particularly talented people to come along and do it.鈥

It was a once-in-a-lifetime event that completely transformed all of biology.

— James Watson, Nobel laureate and co-discoverer of the double-helix structure of DNA

Dr. Richard Roberts: why curiosity-driven research is so important.

War. What it's good for

To really press his point home, Roberts provided an example from his own mark on history.

鈥淚 mean, think of Nixon鈥檚 War on Cancer! If it wasn鈥檛 for the War on Cancer there never would have been a biotech industry. Really! And we would have never discovered splicing.鈥

鈥淏ut did we get an answer to cancer?鈥 he asked. 鈥淣o...not at all.鈥

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.

image of Richard Roberts and Phillip Sharp

Richard Roberts (l) and Phillip Sharp (r)

麻豆传媒社区鈥檚 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.

One of nature's greatest inventions

Both scientists applied their skills to a basic mystery that molecular biology was then tackling: When an activated gene鈥檚 鈥渕essage鈥 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 麻豆传媒社区) soon concluded that a preliminary, raw copy of a gene first had to be edited, or 鈥渟pliced,鈥 before it could be used to direct protein production.

The research baton is passed

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 Laboratoryto promote a new generation of young scientists to the forefront of efforts to more completely understand splicing.

鈥淔or me, I look for enthusiasm,鈥 Robert鈥檚 explained.

鈥淚f people are enthusiastic...鈥

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, Laboratorywas 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 Roberts鈥 advice, Adrian Krainer became the very first in a distinguished line of LaboratoryFellows that also includes Nobel laureate .

A podcast about Adrian Krainer. See all Base Pairs podcasts.

麻豆传媒社区's president on investing in young scientists.

"Relentless pursuit"

Under Roberts鈥 tutelage, Krainer was able to flourish, beginning what he describes as a 鈥渞elentless pursuit of RNA splicing鈥 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 he鈥檇 beat that disease.

Rich Roberts describes his first impressions of prot茅g茅 Adrian Krainer.

Chapter 3

A disease of helplessness

Imagine that when you鈥檙e born, there is a hand lightly pressing on your chest. At first, it鈥檚 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, it鈥檚 a life that won鈥檛 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...

鈥淭ake that, SMA!鈥

Today, you might say that SMA has been 鈥渂eat.鈥

Approved in the United States and European Union (Japan, Canada, Australia, Switzerland, and Brazil聽pending), the drug known as nusinersen compensates for the insidious problems within an SMA patient鈥檚 genome.

Sold under the brand name SPINRAZA™, the drug has been hailed as the 鈥渇irst-ever treatment for SMA,鈥 and a 鈥渉uge win鈥 for molecular biology. In fact, SPINRAZA™ was named the "best biotechnology product of 2017" by the prestigious Galien Foundation.

鈥淭here has never been a disease-altering therapy for a neurodegenerative disease,鈥 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 drug鈥檚 inventors did, before you can understand how this miracle drug works, you first must understand SMA.

image of Science Magazine SMA article
Science 16 Dec 2016:
Vol. 354, Issue 6318, pp. 1359-1360

A protein we can鈥檛 live without

Working with our friends at Youreka Science, Laboratoryhas 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 鈥淪urvival of Motor Neuron鈥 (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, there鈥檚 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.

Turning to the backup gene

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, wouldn鈥檛 that halt SMA?

Enter Dr. Adrian Krainer. A curiosity-driven researcher, Krainer鈥檚 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.

鈥淣ow suddenly here鈥檚 a common disease which I鈥檓 learning about in which all the patients have the same defect [in SMN2],鈥 says Krainer. 鈥淚t was really apparent that if we could find a solution, it would apply to all SMA patients.鈥

Much of the work Krainer had done as a LaboratoryFellow 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.

A magical discovery

鈥淚t was almost magic—the way things ended up working,鈥 says Dr. Frank Bennett, a leader of drug development at Ionis Pharmaceuticals.

However, Bennett, who was instrumental in nusinersen鈥檚 development, knows that it was hard work, not magic, that got the drug to the patients who need it.

鈥淲orking with Adrian [Krainer] has been one of my most enjoyable collaborations,鈥 he explains. 鈥淚t was like two streams of basic research coming together.鈥

Like most basic research, Krainer鈥檚 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. 鈥淢y first real breakthrough,鈥 he recalls, 鈥渨as to purify a single protein, which is now called SRSF1.鈥

An excerpt from Base Pairs episode 5: Dr. Krainer explains how an exhausting method to isolate specific proteins helped him make discoveries that later led to a drug for SMA. See all Base Pairs podcasts.

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 SMN2鈥檚 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 that鈥檚 what got Bennett鈥檚 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.

Dr. Adrian Krainer in his lab

Pleasant surprises

There were more surprises still in store. After Krainer鈥檚 identification of SRSF1 as the missing splicing activator that caused exon 7 to be skipped—impairing the SMN2 鈥渂ackup鈥 gene—he realized that the corrective molecule used in ESSENSE was also able to correct exon skipping when stripped down to a short, 鈥渘aked鈥 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 gene鈥檚 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 SMN2鈥檚 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 wasn鈥檛 disaster that struck. Instead, it was success.

Dr. Krainer describes a key moment during clinical trials that exemplifies nusinersen's success in treating SMA.

Those results were indeed 鈥済ood enough to convince the FDA,鈥 and in December 2016, the once-experimental treatment became commercially available to SMA patients for the first time.

image of Yimin Hua
The most promising of the antisense molecules was identified by Krainer lab postdoc Yimin Hua (pictured). Originally designated ASO 10-27, it was then chosen by Ionis.

Meet a superhero

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.

鈥淲hen 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,鈥 Krainer explains. 鈥淚t's something you strive for, and now it seems to actually be happening and it's like a dream come true, very rewarding."

Emma Larson was treated with nusinersen during clinical trials. Today, as she and her parents visit Dr. Krainer at 麻豆传媒社区, she's stronger than ever!


Product of LaboratoryCommunications Department

Written by

Brian Stallard

Edited by

Peter Tarr, Sue Runkowski, and Philip Renna

Produced by

Sue Runkowski and Brian Stallard

VP Communications

Dagnia Zeidlickis

"Sink or Swim" Base Pairs podcast episode 5

Written by Andrea Alfano and produced by Brian Stallard

Photo and video material (CC BY):

Photo and video material (CC BY-NC):

The Larson family
Nikita No Komment
, , &

Additional video & photography ©:

LaboratoryCommunications Department

Kathy Kmonicek, 2016/麻豆传媒社区
T5G Productions & Christopher Gazzo

Special thanks to:

Emma, Dianne, and Matt Larson
Sir Richard Roberts, Ph.D.
Darryl C. De Vivo, M.D.
C. Frank Bennett, Ph.D.
Professor Adrian Krainer, Ph.D.