Neurogenetic disorders: Dreaming the impossible dream

People with autism and most other disorders of brain development have never had medications to treat their core behavioral and cognitive symptoms. The best they can get are drugs targeting secondary problems, like irritability or aggression. But now, a new wave of clinical trials aims to change this.

In the last decade, scientists have discovered many of the molecular pathways in genetic disorders that can impair cognition and place a child on the autism spectrum—such as tuberous sclerosis complex, Rett syndrome, Fragile X syndrome and Angelman syndrome. These discoveries are suggesting targets for drug treatment, and is changing how these conditions—and perhaps neurodevelopmental disorders generally—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 Mustafa Sahin, who directs Children’s Tuberous Sclerosis Program. “It is an idea that’s based upon mouse studies, which have really given hope that we can do the same thing in humans.”

Tuberous sclerosis complex (TSC) is a rare genetic disorder marked by noncancerous tumors in a variety of organs, including the brain. It often causes developmental delay or intellectual disability in addition to seizures, and about 50 percent of patients have an autism spectrum disorder. Sahin’s team is launching a phase II clinical trial of a drug that might reduce cognitive deficits, as well as autistic symptoms, in TSC patients.  Sahin’s bench research, and human brain imaging studies conducted in collaboration with Children’s neuroradiologist Simon Warfield, reveal that brain circuits are miswired in TSC. Because of an over-active cell growth pathway called mTOR, nerve fibers grow in a wild, disorganized fashion and have structural abnormalities.

mTOR inhibition can reverse some of these abnormalities, as well as functional brain defects such as epilepsy and learning difficulty in mice. The clinical trial, expected to begin at Children’s Hospital Boston and Cincinnati Children’s Hospital in January 2011, will test a compound called RAD001, which inhibits the mTOR pathway.

Omar Khwaja, who directs the Rett Syndrome Program at Children’s, has just begun a similarly-aimed clinical trial for Rett—the leading known genetic cause of autism in girls. It, too, is based on striking results in a mouse model of the disease, including a loss of overt behavioral symptoms and increased long-term potentiation—a measure of the ability of neurons to adapt to certain patterns of stimulation, thought to be key in learning and memory.

“We always believed that to treat Rett syndrome, you would have to diagnose it before the onset of symptoms,” says Khwaja. “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.”

Khwaja’s trial, now recruiting, is a three-year pilot study of Increlex, a synthetic form of insulin-like growth factor-1 (IGF-1). The study will examine the drug’s safety, optimal dosing and its ability to improve cardiorespiratory functions and a 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 efforts to improve neurocognitive outcomes in Angelman syndrome, a disorder marked by severe developmental delay, extremely limited speech, motor difficulties and sometimes autistic behaviors. A phase I clinical safety trial of levodopa, a drug commonly used for Parkinson disease, is nearly complete; its results will inform a planned phase II multicenter treatment trial. The story is similar for Fragile X syndrome, the leading inherited cause of intellectual disability and autism. The drug R-baclofen, which counteracts core features of Fragile X in a mouse model, has been tested in an initial study, and the results are now being analyzed for follow-up.

Together, these trials signal the beginnings of a paradigm-shift in how we think about disorders of brain development. Basic research at the molecular level is aiding the development of drugs that get closer to the root of the problem—providing hope that symptoms once considered “irreversible” could actually be treated.