Date: October 3, 2011
Nothing can keep Payton Mueller down, not even the spinal muscular atrophy (SMA) that continues to take its toll on his young body. Doctors here share his optimism. Thanks to rapid advances in research and clinical care, the future for patients with SMA has never looked brighter.
By Christen Brownlee
Photos by Mike Ciesielski
The mood was light at the start of 10-year-old Payton Mueller’s recent exam. While his mother and grandmother chatted with Hopkins pediatric neurologist Tom Crawford about Payton’s recent activities and the family’s trip from their home in North Dakota, the brown-haired boy fidgeted as only a pre-teen in a motorized wheelchair can—knocking the chair’s joystick back and forth, repeatedly swinging it in little side-to-side arcs. He alternately grinned and dramatically grimaced as Crawford led him through a series of tests that measured strength all over his body. “Pull, pull, pull! Great job!” the doctor encouraged.
But near the end of the hourlong visit, the atmosphere took a somber turn. Payton, whose hips and knees are locked into right angles from muscle shrinkages called contractures, lay face down on the exam table. He groaned in pain as Crawford showed his mother how to press on his back to stretch these joints.
After Payton was back in his wheelchair, blinking away tears, Crawford explained why these agonizing stretches, along with all the other painful efforts to take care of his body, were necessary: “I’m planning on you doing a lot—college, a job, having a family, all that normal stuff,” said Crawford. “You don’t get out of anything.”
That future wasn’t always the case for kids with spinal muscular atrophy (SMA), the condition that Payton has. Not long ago, parents were often told to take their SMA kids home, and love and coddle them, since it wasn’t likely that these children would live long. But now, with the help of better clinical care and new research, the potential has never been brighter for people with this disease. SMA patients are living longer and longer, and treatments that could radically improve their lives and outlooks hover tantalizingly on the horizon.
“SMA has gone from being one of the most hopeless of the neuromuscular diseases to one of the most hopeful,” Crawford says.
Earlier that day, 60-year-old SMA patient Joan Palmer arrived at the Johns Hopkins Outpatient Center for her appointment with adult neurologist Charlotte Sumner. Unlike Payton Mueller, who has used a motorized wheelchair for most of his life, Palmer just started using her wheelchair five years ago—a fact evident as the bespectacled patient with neatly bobbed hair cautiously backed her chair into a tiny exam room.
“Kids these days, they just naturally know how to use a toggle stick,” Palmer says. “There’s a bit of a learning curve for me.”
Palmer is the rare SMA patient, in that she has lived well into adulthood. Unlike the vast majority of people with this disease, she has had enough strength to be, at various points, a high school cheerleader, a mom of three, a Girl Scout leader, and the chairwoman for her church’s antique sale. “I’ve done what everyone else has done,” she says.
That’s because Palmer has what’s known as SMA type-3. Though they’re still plagued by muscle weakness, type-3 patients generally fare much better than type-2 patients like Payton, who can sit but not stand, or type-1 patients, who never sit or stand. About 1 in 6,000 people has SMA, with the devastating type-1 making up more than half of cases.
Although survival past their second birthdays remains difficult for type-1 patients, several advances in the past few decades now keep type-2 patients alive for decades longer than they’ve survived in the past—exactly how long is yet to be known as current patients grow older. For example, like most type-2 patients, Payton Mueller has undergone spinal fusion surgery to straighten his back—in the past, scoliosis was a major cause of death, with weakened back muscles causing the spine to curve dramatically, eventually crushing the lungs. Payton and most other kids also use a “cough machine,” which helps clean out lungs too weak to cough up mucus that can make patients sick.
Though care advances such as these have slowly evolved over the last few decades, scientists only zeroed in on the reason for these disparities between SMA types relatively recently, explains Sumner. In 1995, French researchers discovered a pair of nearly identical genes, named survival motor neuron (SMN), that cause the disease through a unique mechanism in which each plays a role. About 1 in 40 people carries a single flawed copy of the first of these, termed SMN1, usually unknowingly. SMA is caused when a child inherits two copies of the flawed SMN1 gene, so a couple in which each member is a carrier has a 1 in 4 chance of having a child with the disease.
Though a second, similar gene, called SMN2, can make up for some of SMN1’s function, it does so much less efficiently, making significantly less of the necessary protein. However, says Sumner, people carry a varying number of SMN2 copies in their genome, ranging from one to four. These copy numbers loosely correlate to SMA type. Those with the lowest number of copies—and, therefore, with the least SMN protein—have the most severe forms of SMA, and those with the highest copy numbers generally have the least severe forms. Though extraordinarily rare, sometimes people with two copies of the faulty SMN1 gene, but a high SMN2 copy number, don’t realize they have the disease at all.
“I once had a professional wrestler from Canada, who was a sibling of one of my adult SMA patients, come into one of my studies as a control,” Sumner says, referring to people who don’t have the condition being studied and are used for comparisons. After analyzing the wrestler’s genes, however, Sumner found that he had SMA, too.
SMA first caught Sumner’s eye during a neuromuscular fellowship at Johns Hopkins in 2000, soon after excitement over SMN1’s discovery started spreading throughout the field. Later, at a research fellowship at the National Institutes of Health, she started working on her first research project on the disease by chance, taking over for another researcher who left the lab. When she was offered a faculty position at Johns Hopkins in 2006, she continued that work here.
Though she’d originally planned to research other genetic neuromuscular diseases, such as some forms of ALS, the intriguing nature of SMA—and the promise of someday effectively treating this disease, possibly through harnessing the power of the SMN2 gene—commanded her attention. She and Crawford now lead the SMA charge here at Hopkins, seeing around 50 patients with this disease every year.
“It’s such an incredibly important disease, and it has such interesting biology and a real chance for therapeutics. There are also such close collaborations between families affected by SMA, clinicians, and researchers—it feels like we’re all in this together.
“Why wouldn’t you want to work on this problem?” says Sumner. “I am so grateful that I ended up in this field. I thank my lucky stars every day.”
Though she sees adult SMA patients, including Palmer, in the clinic, Sumner mostly deals with mouse models of the disease in the lab. These mice—genetically modified so that their own mouse version of the SMN gene has been removed, replaced by a single copy of the human SMN2 gene—are meant to mimic the most severe form of the disease.
Showing a visitor these animals in her lab, Sumner places a couple of SMA mice side by side with a pair of healthy mice that are about the same age, roughly 10 days old. The SMA mice look frail and sickly compared to their healthy brethren, measuring about a head shorter and about half their weight. With the tip of her index finger, she rolls one of the healthy mice onto its back. It immediately flips onto its feet, righting itself as if spring-loaded. After she does the same with an SMA mouse, the animal flounders like a bug stuck upside down, helplessly pawing the air in slow motion.
“He just doesn’t have the strength to move his trunk,” Sumner explains.
Animals like these are incredibly important for understanding exactly why SMA exacts the toll it does. Though pinning down the responsible gene was a huge breakthrough, many questions remain about why patients develop their specific deficits. For example, though the same genetic quirk that causes SMA exists in every cell in the body, researchers don’t yet know why the nerve cells that control muscle movement—specifically those that affect muscles in the trunk and parts of arms and legs closest to the trunk—seem to be uniquely affected. Additionally, these so-called motor neurons don’t exist in isolation. Could the muscles they connect to, or the spinal cord they spring from, be part of the problem?
Using SMA mice, Sumner and her colleagues are trying to uncover the earliest events that distinguish these sick mice from healthy ones. Several years ago, they discovered that at two weeks of age, near the end of the animals’ lives and at their weakest point, these mice still had plenty of living motor neurons—a stark contrast to many other neuromuscular diseases including ALS, in which weakness arises from the loss of these cells. That led Sumner’s team to wonder whether that meant that SMA-addled motor neurons could live significantly longer than researchers had thought, but weren’t functioning normally.
“This could have huge implications for therapy,” says Sumner. “It’s a lot easier to rescue a neuron that’s there but dysfunctional compared to one that’s dead.”
Sure enough, recent research at her lab showed that the connections between neurons and muscles are abnormal in SMA mice. Over time, these bad connections cause muscles to have less activity, then weaken and shrivel. Further research suggests that problems with the connections between neurons, known as synapses, are widespread throughout the animals’ bodies.
“It’s showing that we can’t just rely on fixing the motor neurons in isolation and hope this solves the problem. It’s really more complicated than that,” Sumner says.
Besides just looking at the source of the problem, her lab is testing potential solutions, including a number of promising compounds. However, Sumner points out, it’s important to remember that mice aren’t people. Though some treatments, such as antisense oligonucleotides and gene therapy, have shown incredible promise in mouse models—sometimes even appearing to cure them of the disease—the same therapies may not work in the different physiology of humans. That’s one reason why she frequently works with human tissue samples that she and Crawford collect during autopsies.
Dawn Kershner, whose son Oliver died from SMA three years ago, agreed for him to be autopsied for the two scientists’ research. The blond-haired, blue-eyed infant seemed completely healthy when he was born.
“We counted 10 finger and 10 toes and thought he seemed just perfect,” she recalls.
But as the weeks went on, Kershner, a cardiologist at Union Memorial Hospital in Baltimore, and her husband realized that he wasn’t gaining the same strength that she remembered seeing in her older son. Oliver’s neck stayed floppy, and he eventually lost the ability to bring his hands up to his face. His pediatrician referred Oliver to Crawford, who diagnosed him with SMA at two months of age.
Kershner and her husband decided on hospice care for Oliver. Giving him a ventilator, feeding tube, and other life-extending but potentially uncomfortable treatments “just felt very unnatural to us,” she says. Oliver died at 4 1/2 months old, on his brother’s third birthday.
When Crawford asked Kershner and her husband whether they’d be willing to have Oliver autopsied, it was an easy decision for them. As a physician, she says, she knew how useful autopsies can be for furthering researchers’ understanding of diseases—knowledge that can’t be attained in any other way.
“SMA is a horrible disease. If something as small as using Oliver’s body for an autopsy could change the future for other families, so they wouldn’t have to suffer from this experience,” Kershner says, “we wanted to help.”
Crawford assists in the specific portions of autopsies that relate to SMA on his own patients, work that he admits often feels awkward, uncomfortable, or incredibly sad. “I can’t be there when they do the initial portion of it,” he says. “But when they get to the actual tissues, they’re not my patients, they’re a science question.”
Each tissue collected from these autopsies is actually being used to answer a variety of science questions, Sumner says. She and her colleagues are studying fresh or frozen sections from muscles or the spinal cord to measure gene expression and protein levels. Tissues preserved in fixatives are shedding light on differences in structures between SMA and healthy patients. Taken together, Sumner says, autopsy tissues from SMA patients represent an invaluable gift for research that might eventually help countless other families.
Hannah Fallon and her mother, Kathy, also hope to help other families with SMA. Hannah, a blonde 14-year-old who likes to act, sing, and play video games—and happens to be in a wheelchair—is one of six siblings. She and her older brother Lance, now 24, both have SMA type-2.
By the time Hannah was diagnosed, around the time of her first birthday, Kathy Fallon and her husband had already amassed loads of expertise in dealing with SMA, painstakingly gathered from more than a decade of finding the right physicians, equipment, and programs for Lance. They freely share their knowledge nowadays with other families dealing with the same issues.
“With Hannah, there hasn’t been nearly as much guesswork,” Fallon says, comparing her daughter’s childhood to the often confusing and frustrating time she and her husband spent trying to figure out the best options for Lance.
In the future, she adds, kids with SMA may have even more options. Four years ago, Hannah participated in a multicenter drug trial to test a combination of compounds that showed promise in animal studies: an anticonvulsant drug called valproic acid and levo-carnitine, a compound derived from an amino acid.
Five times over the course of a year, she came to Johns Hopkins to evaluate the effects of medication she was taking at home—either the real compounds or a placebo—through physical exams and blood tests. The hope was that researchers would see a marked improvement for those who received the real drugs in the ability to perform basic tasks, such as lifting their heads or rolling over.
Unfortunately, they didn’t, says Crawford, who led Hopkins’ portion of the study. But the researchers did learn a lot—not about treating SMA, Crawford explains, but about how to design a useful study to more accurately test future SMA therapeutics.
“It sounds so simple, but how do you measure something that’s useful to patients and researchers?” he asks. “Patients are concerned about practical things, like feeding themselves, but researchers need something they can measure consistently in all the study subjects. It would be easy if everyone had exactly the same problem, but each of these kids is different, with different deficits.”
One thing this study taught researchers, Crawford explains, is that the same activity can be defined in a variety of different ways by different researchers, thereby potentially impacting their reports on the effectiveness of test drugs. For example, whether a patient rolls over, sits up, or lifts his head isn’t cut and dried—researchers use their own subjective guidelines to evaluate the success or failure of each of these actions. Additionally, SMA kids can devise workarounds by performing an activity in a way that doesn’t truly measure what researchers had hoped.
For future studies, he says, researchers need a way to measure whether an intervention is truly effective in a way that everyone can agree on. That universal measure, he believes, is strength.
Though he and other neurologists who work with SMA patients often check their strength at exams using dynanometers, instruments that measure force, those tests are only consistently accurate if delivered by the same physician, Crawford explains. How a doctor wields the dynanometer—resisting a patient’s pushes and pulls—can make a difference in measurements, he says, in a way that could lead to inconsistencies between measurements at different clinical trial sites.
“I do it my way, you do it your way. I can’t train everyone to do it my way,” he says.
To solve that problem, Crawford is developing a new device that researchers might eventually use as a standard measuring tool in future clinical trials. Its design is deceptively simple, he says: a piece of plywood with a post through the center and a stirrup attached. Painted red, the device looks like a fun toy to kids, rather than an odious task. Kids naturally want to yank on the stirrup, which connects to an internal dynanometer connected to a computer that records results.
“All you have to say is ‘ready,’ and kids want to pull as hard as they can,” he says.
Crawford is currently building 12 of these devices and applying for a grant to evaluate them in a multicenter trial. If they prove useful, Crawford’s strength testers could eventually be put to use in measuring the effects of other promising medicines on the forefront of SMA research, such as quinazoline, a drug that the FDA recently approved to be tested in Phase 1 trials in healthy volunteers.
This particular drug has an unusual story, Crawford explains. Rather than being the brainchild of a big pharmaceutical company, quinazoline was plucked out of thousands of other compounds after an advocacy group called Families of SMA paid a company to test these compounds on cells. Searching for a compound that raised the amount of SMN protein in cells, the company’s scientists soon discovered that quinazoline did the trick.
Having paid the company for its work, Families of SMA held the rights to this drug. They eventually sold it to a small drug development company called Repligen for a nominal amount, with the agreement that Repligen would usher this compound quickly and effectively into clinical trials. If the company changes its mind, it’s required to return rights to the drug back to Families of SMA so they can try to sell it to another development company.
Sumner and her colleagues are currently further testing quinazoline in SMA mice in the lab to better understand how it works and how to best follow its effects during a clinical trial. Eventually, says Crawford, it might be tested in his patients in a clinical trial at Hopkins. This drug, or others, might just be the break that SMA patients have been waiting for, Crawford says.
“When I started out in this field, the story was that kids with SMA type-2 died in their school years. Now they’re getting older with me,” he says. “Now we get a chance to see how this plays out. It’s been an incredible ride.”