By Quinn Eastman
In some ways, Samuel is like many other little boys. He likes swimming, riding in his grandfather's boat, and playing games on the family's Wii. His face lights up when he sees an image of Lightning McQueen from the movie Cars.
However, learning to talk has been slow for him. Now six years old, Samuel learned to count before he could say "Mommy." His parents noticed something was different early in his development.
"He still learns and grows. He just does those things differently," says Samuel's father, John McKinnon.
For one thing, Samuel tends to flap his arms when excited—one reason that his pediatrician first suspected he might have a type of autism spectrum disorder. In 2008, Samuel was diagnosed with fragile X syndrome, the most common inherited form of intellectual disability and also the most common single-gene cause of autism.
His parents threw themselves into supporting him. They taught him sign language to help his communication skills. His mother, Wendy McKinnon, puts many miles on her car getting him to appointments with several therapists—speech, physical, and occupational as well as a specialist in applied behavior analysis.
Now, Samuel is one of the youngest participants in a clinical study testing arbaclofen, a drug that scientists think could compensate for the changes in the brain caused by fragile X syndrome. His parents say they are keeping their expectations in check.
"Our family and our therapists are telling us the same thing—not to put too much hope in the trial," says Wendy McKinnon. "We're trying hard not to read too much into it if Samuel says a new word or plays more with other kids."
The majority of children with fragile X syndrome have some kind of developmental delay, and their behavior varies widely. Behavior problems can include hyperactivity, inattentiveness, aggression, or social withdrawal. The average age of diagnosis is approximately 3-1/2 years.
In 1991, a team led by Stephen Warren, Emory's chair of human genetics, discovered the gene whose inactivation is responsible for fragile X. Two decades later, a potential strategy for treating fragile X based on Warren's landmark work is reaching a critical phase in human clinical trials. Three pharmaceutical companies—Seaside Therapeutics, Hoffmann-LaRoche, and Novartis—are sponsoring multi-center studies of drug therapies that take the same biochemical approach, and Emory is participating in all three.
While some children with fragile X syndrome take antidepressants or attention-focusing stimulants, the medications in these studies are the first treatments that scientists think can specifically target the molecular changes caused by fragile X inactivation. Previously tested with promising results in adults with fragile X syndrome, the drugs are now being tested in children and teens with the disorder—some as young as five. Clinicians expect these studies to answer important questions about whether learning and behavior deficits can improve with the medications.
"It's exciting that the research has gotten to this point," says Jeannie Visootsak, principal investigator for the fragile X clinical trials at Emory. "Childhood is when the behavioral problems typically start, so earlier intervention could potentially make more of a difference."
Small steps of progress
In the fall of 2011, Samuel's study was in the "blind" phase, with neither parents nor doctors knowing who was getting the active drug and who was receiving placebo. There was a one-in-four chance of getting the placebo. An open-label (meaning the mystery is over) phase of the study started in January 2012 to monitor how well children tolerate the medication over longer periods.
"Our family and our therapists are telling us the same thing—not to put too much hope in the trial," says Wendy McKinnon. "We're trying hard not to read too much into it if he says a new word or plays more with other kids."
Being able to judge whether the various drugs are working is complicated, Visootsak says. In Samuel's study, parents regularly fill out a questionnaire about the child's behavior, self-help skills, and sleep patterns, and the child undergoes cognitive tests and receives a comprehensive exam by a physician.
Previous behavioral studies with ar-baclofen suggested that the drug's strongest impact came in helping people with fragile X engage socially. So children in this study are being scored on an "aberrant behavior checklist" with an emphasis on the social withdrawal domain.
Samuel's parents describe him as trusting, flexible, and easygoing, and they recall how he climbed into Visootsak's lap the first time they met.
Just as Samuel is different in some ways from other boys with fragile X, it follows that not all patients with fragile X syndrome will benefit from the same drug, says Visootsak. Small-scale studies have already shown that patients with fragile X vary in their responses to one of the drugs being tested by Novartis, called AFQ056. It also is possible that a single drug may be unable to address all fragile X-related symptoms, she says.
To understand why, it helps to look at what the inactivated gene in fragile X normally does. It produces a protein called FMRP that regulates a host of genes. As a result of FMRP's absence, fragile X neurons turn those genes on more easily—and indiscriminately— than typical neurons.
Several years ago, in collaboration with Mark Bear from MIT, Emory's Steve Warren identified a type of drug (glutamate receptor antagonists) with the potential to calm one type of hyperactive signal in the brain caused by a lack of FMRP. Even so, drugs can't exactly replace FMRP. They can only push back against some of the changes generated by its loss.
If the ar-baclofen or glutamate drugs are successful, Visootsak says, such drug treatment still cannot be considered a "cure." She says the medications could potentially make learning and social adjustment easier, and they might improve some behavior problems.
"Individuals with fragile X are still going to need educational support and ongoing therapies, including speech and physical therapy," Visootsak says. "With these medications, the goal is to help them adapt better in social situations and ultimately enhance academic performance and independence."
For the McKinnons, that's a welcome start. "Some people we talk to think it will be a magic bullet and will ‘fix' him," says Samuel's mom. "But I think if we can find something that maybe helps him adjust better or communicate more, we have to try it out—for his sake."
WEB CONNECTION: Erica Johnson was an adult before she ever received her diagnosis of fragile X syndrome. Now at 33, she is participating in a clinical trial for fragile X at Emory. Her parents believe that the medication she is receiving is helping her communicate better and hold down a job. To hear the Johnsons and McKinnons discuss their experiences with fragile X, visit bit.ly/McKinnonfragileX and bit.ly/JohnsonfragileX.
Calming the overexuberant protein
While clinical research on treatments for fragile X proceeds at Emory, research exploring a different approach to treating fragile X is taking off in the laboratory.
Cell biologist Gary Bassell and colleagues have found a way to tamp down the runaway protein production seen in brain cells of people with fragile X syndrome. A class of drugs they identified could be complementary or alternative to those now moving through clinical trials.
Working with Bassell, postdoc Christina Gross has found that the enzyme PI3 kinase is regulated by FMRP and is more active in its absence.
The "overexuberant" protein production in fragile X neurons leads to structural changes in the brain, including a hyper-abundance of dendritic spines (small protrusions that transmit electrical signals to adjacent cells). Gross showed that reducing PI3 kinase activity with drugs in cells from fragile X mice can restore normal levels of both protein production and dendritic spine density.
PI3 kinase inhibitors are already under investigation for their anti-cancer properties, and some drugs of this type can be toxic to normal cells. Bassell says that newer drugs that preferentially inhibit the type of PI3 kinase found only in neurons hold greater promise as a new therapy than those inhibiting P13 kinase indiscriminately. He and Gross are working with pharmaceutical companies to test the inhibitors in animal models of fragile X.
Bassell says the study is "an important first step toward a new therapeutic strategy for fragile X syndrome that treats the underlying molecular defect. We are excited about the possibility that it may be more broadly applicable to other forms of autism."
Recent research shows that mutations in other genes that can lead to autism also disturb PI3 kinase activity. This connection suggests that PI3 kinase inhibitors might be viable for treating autism spectrum disorders beyond fragile X, Bassell says.
Gross and Bassell already have observed that PI3 kinase levels in the blood cells of children with fragile X are measurably different from normal cells, a finding that opens the door to biochemical tests for other disorders. They recently received a "Trailblazer Award" from the charity organization, Autism Speaks, to support their continued exploration of P13 kinase inhibitors.