Can drugs improve cognitive deficits in developmental disorders

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Can drugs improve cognitive deficits in developmental disorders? 

Clinical trials for strongly genetic developmental disorders linked to autism take aim at symptoms previously considered irreversible

By Parizad Bilimoria


Ryan Long with mother Jody Long and neurologist Mustafa Sahin in the Clinical and Translational Study Unit at Children’s. Ryan is participating in a Tuberous Sclerosis Complex (TSC) research study pioneered by Sahin. It is hoped that the drug being tested in this study, RAD001, will improve cognitive outcomes in patients with TSC, a genetically-based developmental disorder.

Six-year-old Ryan is an expert chef. He especially likes cooking turkey in the toy microwave in the playroom of Children’s Hospital Boston’s Clinical and Translational Study Unit. As he gathers his ingredients, Ryan works hard to string together his words and formulate sentences. His microwave sometimes doesn’t work, but fortunately his neurologist, Mustafa Sahin, MD, PhD, is a talented microwave repairman.

The two are collaborating on more than cooking turkey. Ryan is taking part in a neurologic research study pioneered by Sahin. His speech difficulties are part of a developmental delay caused by tuberous sclerosis complex (TSC), a rare genetic disorder marked by noncancerous tumors in a variety of organs, including the brain. Many patients with TSC experience developmental delay or intellectual disability in addition to seizures, and about 50 percent have an autism spectrum disorder.

Sahin, who directs Children’s Tuberous Sclerosis Program, is investigating a drug treatment that he hopes will not only reduce the growth of one Ryan’s brain tumors, but actually lessen his developmental delay. And for others with TSC, maybe even their intellectual disability or autism. “For some of these kids, even a little bit of gain makes a big difference in quality of life,” says Jody Long, Ryan’s mother. “For us, getting a little more language, or a little more understanding, would be huge.”

Currently, there are no drugs to treat developmental delay, intellectual disability or autism, but only drugs to treat the behavioral symptoms, such as irritability or aggression. But a new wave of clinical trials—many led by researchers at Children’s—are raising the possibility of treating the actual disorders, previously considered irreversible.

From mouse to man

In the last decade, scientists have gained molecular insights into rare neurodevelopmental disorders where the genetic basis is clear, such as TSC, Rett syndrome, Fragile X syndrome and Angelman syndrome. Each of these disorders can impair cognition and place a child on the autism spectrum.

The deepened molecular understanding is suggesting targets for drug treatment, and causing a paradigm shift in how these conditions are viewed. Some of the drugs now being tested appear to improve cognitive symptoms in mouse models, and some are already FDA-approved for other indications.

“Using pharmacotherapy to improve neurocognition is a novel idea,” says Sahin. “It is an idea that’s based upon mouse studies, which have really given hope that we can do the same thing in humans.”

Although the animal studies didn’t specifically look at autism symptoms, Sahin’s bench research on TSC supports the emerging notion that autism is a “developmental disconnection syndrome” in which brain circuits are miswired. In TSC, the growth of axons, or nerve fibers, is thought to be deregulated due to the loss of an important molecular brake on an enzyme called mTOR, which promotes cell growth. In neurons cultured in a dish, loss of this mTOR brake causes the cells to grow multiple axons, where usually they grow one.

Further evidence comes from brain imaging. Sahin and collaborator Simon Warfield, PhD, associate professor of Radiology, found that patients with TSC have disorganized, structurally abnormal axon tracts that appear to have diminished coating by myelin, the fatty insulating material that promotes their ability to transmit electrical signals.

Brain miswiring in tuberous sclerosis and autism
These diffusion tensor images of the brain illustrate the disorganization of nerve fibers in a 17-year-old girl with tuberous sclerosis complex (TSC) and autism as compared with a healthy girl of the same age. In the affected girl, the tracts of nerves that carry information from the brain's thalamus to the visual cortex are less organized, with far fewer axons connecting to the cortex. The brighter colors in the healthy brain illustrate greater structural integrity of the tracts. Courtesy Simon Warfield, PhD.

In mice, mTOR inhibition can reverse these sorts of anatomic abnormalities, as well as functional brain defects such as epilepsy and learning difficulty. The drug Ryan may now be taking, called RAD001, is an mTOR inhibitor, and Sahin is launching a phase II clinical trial to assess its ability to reverse neurocognitive deficits, as well as autistic symptoms, in TSC patients. The trial is expected to begin at Children’s Hospital Boston and Cincinnati Children’s Hospital in January 2011.

Revolutionized thinking

Omar Khwaja, MD, PhD, is principal investigator on a similarly-aimed clinical trial for Rett syndrome, the leading known genetic cause of autism in girls. It, too, is based on striking results in a mouse model of the disease.

“We always believed that to treat Rett syndrome, you would have to diagnose it before the onset of symptoms,” says Khwaja, who directs the Rett Syndrome Program at Children’s Hospital Boston. “And now that work has been done in reversing symptoms in a symptomatic mouse model, it has revolutionized our thinking about therapy—not just for Rett syndrome, but for many other neurogenetic disorders.”


Lillian Courtney, a young girl with Rett syndrome, with neurologist Omar Khwaja. Rett is the leading known genetic cause of autism in girls. Khwaja has now launched a clinical trial for a drug expected to improve developmental outcomes in Rett syndrome.

Khwaja’s team has just begun a three year pilot study of Increlex, a synthetic form of insulin-like growth factor-1 (IGF-1), in girls with Rett syndrome. Beyond examining the safety and optimal dosing of the drug, this clinical trial—aiming to enroll 40 patients—will examine the drug’s ability to improve cardiorespiratory functions anda wide range of neurodevelopmental symptoms, including features of cognitive disability and autism. Like RAD001, Increlex is already FDA-approved for other indications. The animal studies suggest that it may reverse Rett symptoms by enhancing maturation of synapses, the points of communication between brain cells.

Children’s is also leading a trial aimed at improving neurocognitive outcomes in Angelman syndrome, a neurodevelopmental disorder characterized by severe developmental delay, with extremely limited speech and motor difficulties, and sometimes autistic behaviors. Patients are often distinguished by their apparently happy disposition.  

A team led by Wen-Hann Tan, BMBS, of the Genetics Program at Children’s, is completing a phase I clinical trial examining the safety and dosing of levodopa, a drug commonly used for Parkinson disease, in patients with Angelman syndrome. The results will inform a planned phase II treatment trial, to be conducted in collaboration with University of California San Francisco, University of California San Diego, Vanderbilt University, Baylor College of Medicine and Greenwood Genetic Center. [For more information on Angelman research and events, check out this Facebook page.]

Research suggests that levodopa may increase the activity of an important brain enzyme known as CaMKII, which is involved in learning and memory, and that may be decreased in Angelman syndrome. In a mouse model of Angelman syndrome, low activity of CaMKII is associated with neurologic defects. Levodopa reverses the chemical modification that underlies decreased CaMKII activity. When this same modification is reversed in mice by genetic means, they show improvement in neurologic deficits, and it’s hoped that levodopa can do the same in humans.

The story is similar for Fragile X syndrome, the leading inherited cause of mental retardation and autism. Studies in mice suggest that a brain molecule called mGluR5 is unregulated in this disorder, causing too much protein to be made at the synapse. Drugs to counteract this excess activity are being developed; one, R-baclofen (Seaside Therapeutics), has initial study results that are now being analyzed for follow-up. Jonathan Picker, MD, PhD, director of the Children’s Fragile X Program, is investigating the possibility of a clinical trial with another mGluR5 inhibitor with a major drug company, looking at behavioral outcomes in Fragile X patients.

From the rare to the common

Though these genetic diseases are relatively rare, they present an opportunity to create mouse models in the laboratory. These models are now paying off, and may have implications that go well beyond these specific disorders.

“The animal studies all essentially show the same thing,” says Sahin. “You can take a mouse that is genetically deficient in a certain protein, that has a pretty severe phenotype, and by either pharmacologic or genetic means you can normalize the neurologic phenotype.”

The mouse models of TSC, Rett syndrome, Angelman syndrome and Fragile X each show that some of the neurologic outcomes of the genetic deficiencies can be improved. Many scientists believe these rare genetic disorders may be a kind of “Rosetta stone”: the key to deciphering the brain processes that go awry more generally in autism or intellectual disability in general. If so, a world of new research and options for families could open up.

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