Translating mouse research into clinical trials
Two rare neurological disorders—tuberous sclerosis complex (TSC) and Rett syndrome—have a clear genetic basis first defined in mouse models over the last decade. There are currently no drug treatments for patients with these disorders, which often cause cognitive impairment in the form of intellectual disability, development delay or autism.
Historically, physicians have thought these disorders irreversible and have only used drugs to treat behavioral symptoms, such as irritability or aggression. But with a deepened molecular understanding bolstered by animal studies, researchers have identified targets for drug treatments, causing a paradigm shift in how the disorders are viewed. Two of these pioneering researchers—Mustafa Sahin, MD, PhD and Omar Khwaja, MD, PhD at Children’s Hospital Boston—are leading a new wave of clinical trials to test drug treatments in human patients.
“Using pharmacotherapy to improve neurocognition is a novel idea,” says 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.”
TSC is a disorder marked by noncancerous tumors in a variety of organs, including the brain, which may cause epilepsy and autism spectrum disorders in about 50% of patients. Sahin’s research points to brain miswiring as the disorder’s root cause. In a healthy nervous system, one axon grows to a neuron, but in patients with TSC, the loss of an enzyme called mTOR promotes growth of multiple axons in vitro. This leads to disorganized and structurally abnormal axon tracts seen in brain imaging.
BRAIN MISWIRING The disorganization of nerve fibers in a 5-year-old girl with tuberous sclerosis complex (left) as compared to a healthy girl of the same age (right). Click each image for larger version. Courtesy: Simon Warfield, PhD
Remarkably, by inhibiting mTOR in mouse models, Sahin reversed the anatomic abnormalities and brain defects, including epilepsy. Now he hopes to do the same in humans. A recently launched phase II clinical trial tests an mTOR inhibitor, called RAD001, in TSC patients. The goal is to shrink the tumors and reverse neurocognitive deficits.
Changing how we see Rett syndrome
Rett syndrome, the leading known cause of autism in girls, was thought to be an irreversible X-linked disorder caused by the degeneration of nerve cells. Although affected children appear normal during their first six months of life, severe cognitive symptoms emerge, tragically, between 6 and 18 months of age. Children can exhibit repetitive, stereotyped hand movements; slowed brain and head growth; and heart-rhythm and breathing problems.
But researchers like Khwaja and others have shed light on the Rett brain as structurally normal, but having synapses that are unable to respond to the environment. Without the ability of the synapses to adapt, brain circuitry cannot mature, which is why Rett patients have severe cognitive defects.
“Before, it was thought that if there ever was a treatment, it would have to be given before symptoms appeared and that once the disease started it couldn’t be reversed,” says Khwaja, who directs the Rett Syndrome Program at Children’s.
Recent animal studies have shown, though, that these deficits can be reversed. Underlying the Rett syndrome is the mutation or deletion of a master ‘control’ gene called MeCP2, which regulates a group of genes responsible for synaptic maturation. Restoring MeCP2 function in mouse models has improved cognitive and other impairments.
Khwaja focused on insulin-like growth-factor 1 (IGF-1) as a candidate for restoring MeCP2 function in humans. A 2009 animal study suggested that raising levels of IGF-1 reversed neurologic symptoms of Rett syndrome. Interestingly, IGF-1 is indirectly regulated by MeCP2 and has been show to enhance synaptic maturation in vitro.
The next step
In December 2010, Khwaja launched a three-year pilot randomized study testing mecasermin, a synthetic form of IGF-1. Forty girls, ages 2 to 12, with Rett syndrome will participate in the study for five months. IGF-1 is already approved for use in children with short stature.
The study will use a cross-over design, allowing girls assigned to placebo to switch to active treatment after a six-week “washout” period. The main outcome measures will be improvement in neurodevelopment and in cardiorespiratory function.
“Now that work has been done in reversing symptoms in a mouse model, it has revolutionized our thinking about therapy—not just for Rett syndrome, but for many other neurogenetic disorders,” says Khwaja.