Neurotic Disorders

The researchers studied decisions that more than 150 children ages 10 to 13 made while playing games that offered opportunities to risk a little and explore for potential gains. Trying something new is a risk every child undertakes as they explore and learn about the world. While risk can be costly, it can also pay off in rewards or knowledge. But new research suggests children without predictable support from the adults in their lives are less willing to take those risks -- and reap those rewards. "If you're in a resource-rich environment -- meaning for a child that you're safe, your meals are coming, someone is at home for you, you're surrounded by adults that are protecting you -- you'll try new things," says Seth Pollak, a University of Wisconsin-Madison professor of psychology who studies childhood adversity. "And that's how you discover and learn about the world." But not every exploration will be rewarding and, according to a new study of childhood exploration and parental predictability that Pollak and collaborators today published in the Proceedings of the National Academy of Sciences, kids who don't believe they have the support of reliable parents are less willing to risk the unknown. "What's unseen around that corner could be golden, but you could also end up in some bad situations," Pollak says. "You could end up ordering a bad meal or touching something that hurts you. You could end up in a bad relationship or with an empty wallet. And so, we thought, in order to have the confidence to try something new, you have to feel like you're supported and relatively safe -- like you can afford to make a bad call." The researchers studied decisions that more than 150 children ages 10 to 13 made while playing games designed by C. Shawn Green, a UW-Madison psychology professor. The games offered the children opportunities to risk a little and explore for potential gains. One game, fashioned after a pair of casino slot machines, gave players a history of payouts on just one of the machines -- information that helped them understand their expected winnings if they kept pulling that machine's handle. The other machine's history was a mystery, and investing a pull there was more of a risk, but also potentially a bigger return. The other game, in which the kids collected apples in virtual orchards, featured diminishing returns as players continued to pick from an individual tree. With limited time, would the players move to new trees, with unknown bounties? Or would they plug away at the tree they knew best? The kids and their parents also participated in a battery of surveys and assessments. The researchers gauged the stress the children experience and the predictability of their lives -- based on factors like parental job loss, divorce, death or illness in the family, and changing schools and homes -- as well as children's own views about whether or not their parents were reliable and predictable. Yuyan Xu, a UW-Madison graduate student and first author of the study, asked children to respond to questions about how they've experienced their relationships, such as: When my parents say they're going to pick me up, can I count on them to be there? When my parent makes a promise, do they follow through on it? Do I typically know how my parents are going to react to different kinds of situations? The less reliable and predictable the kids felt their parents were, the less likely they were to take exploratory risks in the games they played. They were less likely to give the mysterious slot machine a chance or choose to move to a different apple tree. "The children from more stable backgrounds, they play around and experiment in our games. They use that to get a sense of how things work, maybe earning them more money or more points," Pollak says. "Kids from unstable backgrounds just don't play that way. They stay within a narrower range of possibilities. They prefer to stick with what they already know, even if it's limited, rather than taking a chance at a higher possible reward." The researchers found those self-imposed limits on risk were not related to the more objective measures of stress and unpredictability on the kids' lives or even on parental reports that didn't necessarily agree with their child's perceptions of their relationships. There wasn't a correlation between lack of risk-taking and levels of anxiety or neuroses, or of the kids' feelings about the rest of the world outside their family. If they felt their parents were unreliable and unpredictable, they were less willing to explore. "I think it makes sense," Pollak says. "Their brains are doing exactly what we want our brains to do, right? If you really feel things are not predictable and you don't know how things are going to land, you'd stick to what works and what's familiar. You wouldn't waste your resources on something that could all fall apart." The researchers ran their experiments first with a group of nearly 80 kids, then repeated it with a second group of just over 80 more to confirm their results. "The interesting thing here is that there seems to be a way in which our early childhood experiences are calibrating how we decide to make these decisions years and years down the line and in these really different kinds of situations," says Xu. Openness to exploration wouldn't be the only important aspect of childhood enhanced by stability. Language development, sleep quality, stress regulation and other subjects of childhood development research have been tied to predictability in children's lives. Pollak plans to delve further into the relationship between predictability and exploration to see how rifts might be healed. "What can we do for kids who view their history of interpersonal relationships as unstable?" he says. "We might not be able to change the relationships by the time we understand them to be unpredictable. But could we change the way kids think about them, how they act on them? If that is flexible, maybe we can tune those kids into the benefits and rewards of exploration to help foster kids' learning." This research was supported by grants from the National Institutes of Health (R01MH61285 and P50HD105353).

A Bluebird Bio gene therapy is now the first FDA-approved treatment for a neurodegenerative disorder that causes a progressive and irreversible functional decline that usually leads to death within five years. The late Friday approval of the therapy, elivaldogene autotemcel (typically shortened to eli-cel), covers boys ages 4 to 17 who have an early form of this disease, cerebral adrenoleukodystrophy (CALD). As the first FDA-approved therapy for CALD, the therapy, which will be marketed under the name Skysona, commands a premium price of $3 million. The approval comes with some qualifications. Though the Bluebird gene therapy is a one-time treatment, it is not a disease cure. The approval covers its use for slowing the progressive loss of neurologic function in CALD. Skysona’s label also carries a black box warning that cautions patients and physicians about the risk of blood cancer associated with the therapy. “We are confident that the risks of Skysona will be weighed carefully with the risks of other treatment approaches, and of CALD itself, as families and clinicians make these complex and deeply personal treatment decisions,” Bluebird CEO Andrew Obenshain said during a Monday conference call. Adrenoleukodystrophy stems from genetic mutations that lead to the accumulation of very long-chain fatty acids in the brain that damage myelin, the protective covering for nerve cells. That damage leads to a range of problems, such as losing the ability to walk, communicate, see, and control muscle movements, among other complications. CALD is the most severe form of adrenoleukodystrophy, with an onset in childhood. The X chromosome-linked disorder is found predominantly in boys. Somerville, Massachusetts-based Bluebird estimates that about 40 boys in the U.S. develop CALD annually. A stem cell transplant offers a treatment option that can slow the disease’s progression. However, this procedure can introduce dangerous complications, particularly in patients who do not have a matched donor. Bluebird makes Skysona from a patient’s own hematopoietic, or immature, stem cells. After those cells are collected, they are engineered in a lab. A lentiviral vector is used to insert a functional copy of a key gene into the patient’s stem cells. Those cells are then infused back into the patient, where they are taken up in the bone marrow to differentiate into various cell types that are capable of producing the protein needed to break down the very long chain fatty acids. Bluebird evaluated this gene therapy in a Phase 2/3 study and a Phase 3 clinical trial, both open-label studies that treated a total of 67 patients with early and active CALD. The FDA’s regulatory decision is based on results showing 24 months of improvement according to a test that assesses six major functions, such as communication and wheelchair dependence. Despite the positive clinical trial results, the studies did have a setback. Bluebird reported that three boys treated with Skysona developed myelodysplastic syndrome believed to be caused by the gene therapy. This cancer of the bone marrow can develop when a lentiviral-based gene therapy delivers its genetic payload in or near a gene that causes the growth of cancer cells. These cancer cases in the Skysona studies led the FDA to place the CALD therapy under a clinical hold last year. In June of this year, an FDA advisory committee unanimously voted to recommend approval of the therapy, concluding that its benefits outweigh its risks. Bluebird said the FDA lifted the clinical hold on Sept. 15, just prior to the Skysona approval. But the cancer risk is the basis for the black box warning on Skysona’s label. The affirmative decision for Skysona is the second regulatory nod for Bluebird in the span of one month. In August, the agency approved Bluebird gene therapy Zynteglo for treating the rare blood disorder beta thalassemia. That therapy carries a $2.8 million price tag and is being offered under an outcomes-based agreement that ties reimbursement to how well the therapy works in a patient. Skysona will not have a similar reimbursement program as the ultra-rare nature of CALD makes it too difficult to offer one, Obenshain said. The European Commission granted Skysona standard approval last year for treating CALD. The FDA’s decision for the gene therapy is an accelerated approval, which means that the biotech will need to provide the FDA with additional data to confirm the treatment’s safety and efficacy. Obenshain said that the accelerated approval pathway was chosen over a standard approval after the advisory committee and discussions with the FDA concluded that it was the fastest way to get the therapy to patients. He added that the company expects it will be able to meet the requirements of accelerated approval by using data from patients enrolled in a long-term follow-up study, which will track clinical trial participants for 15 years, as well as with data from those treated with commercially available Skysona. Skysona will be manufactured in the same facility that produces Zynteglo. Bluebird expects Skysona will launch by the end of this year, available through a limited number of qualified treatment centers that include Boston Children’s Hospital and Children’s Hospital of Philadelphia. Successful commercialization of both gene therapies is crucial for righting the course of Bluebird, which implemented a corporate restructuring earlier this year to save cash and focus on its two most advanced gene therapies. Approvals of both of Zynteglo and Skysona came with the award of a rare pediatric priority review vouchers. Such vouchers can be applied toward the speedy FDA review of a future drug for a rare pediatric disease. However, these vouchers have become commodities and many companies opt to sell them to raise cash. Obenshain said Bluebird has hired a bank to sell the vouchers; the company expects each of them will sell for about $110 million, bringing the company additional non-dilutive capital. In a note sent to investors on Monday, William Blair analyst Raju Prasad said CALD is already included in newborn screening in the U.S., currently covering about 75% of infants born. He added that the launch of both Bluebird gene therapies could be a bellwether showing how a small biotech can execute a commercial launch of its gene therapies. Prasad said the Skysona approval is a positive sign for Rocket Pharmaceuticals, a lentiviral gene therapies developer that is on track for two regulatory submissions with its lead therapeutic candidate.