Cells throughout the human body are constantly being damaged as a part of natural life, normal cellular processes, UV and chemical exposure and environmental factors — resulting in what are called DNA double-strand breaks. Thankfully, to prevent the accumulation of DNA damage that could eventually lead to cell dysfunction, cancer or death, the healthy human body has developed ways of locating and repairing the damage.
Unfortunately, these DNA repair mechanisms themselves are not impervious to genetic errors. Genetic mutations that disrupt DNA repair can contribute to devastating disease.
Across the early-stage progenitor cells that give rise to the human brain’s 80 billion neuronal cells, genomic alterations impacting DNA repair processes have been linked to neuropsychiatric disorders and the childhood brain cancer medulloblastoma. But until now, it was not known exactly which disruptions in DNA repair were involved.
A mouse surrounded by computer screens turns its head when it notices lines moving across one of them, as a camera captures this evidence of visual acuity. A chamber similarly equipped with video cameras tests social interaction between mice. A small swimming pool, with shapes on its walls as navigational cues, lets scientists gauge a mouse’s spatial memory. A pint-sized treadmill, with a tiny camera to watch foot placement, measures gait.
Here in the Neurobehavioral Developmental Core at Boston Children’s Hospital, managed by Nick Andrews, PhD, the well-tended mice also have opportunities to play: “If you have a happy mouse,” says Andrews, “researchers get better, more consistent results.” …
Families of children with autism spectrum disorder have long noted sensory processing difficulties such as heightened sensitivity to noise, touch or smell—or even specific foods or clothing textures—earning sensory processing a place in the official DSM-5 description of the disorder.
“A high proportion of kids with autism spectrum disorder will have difficulty tolerating certain kinds of sensory inputs,” says Carolyn Bridgemohan, MD, co-director of the Autism Spectrum Center at Boston Children’s Hospital. Others, she adds, are less sensitive to certain stimuli, showing a higher tolerance for pain or excessively hot or cold temperatures.
Maitreyi Mazumdar, MD, MPH, practices pediatric neurology at Boston Children’s Hospital. She leads a research program in Bangladesh that studies the effects of the epidemic of arsenic poisoning on neurological outcomes in children.
Neurodevelopmental disorders, including autism and attention deficit/hyperactivity disorder (ADHD), affect many millions of children and appear to be increasing in frequency worldwide. Improved diagnosis and changes in diagnostic criteria explain a portion of the rise, but not all. In other words, the increase in neurodevelopmental disorders seems to be “real.”
To date, research has mainly invested in finding genetic causes, implicating biological pathways that affect, for example, the formation of synapses and the production of neurotransmitters. Such discoveries improve our understanding of the basic biology of neurodevelopmental disorders and may ultimately lead to new therapies. But genetic variants alone cannot explain the recent rise; if they did, population rates of neurodevelopmental disorders would be expected to stay the same, or even decrease over a 30- to 40-year period, due to affected people likely having fewer children. Instead, reported rates have steadily increased over the past several decades. Something else is going on. …
Translational neuroscience research has seen a disappointing streak of failed clinical drug trials. While the need for therapeutics that target the nervous system is growing, recent results in diseases like Alzheimer’s and autism have disappointed, and many companies have begun to downsize their R&D investments. Prospects are glum for patients who need new therapies to help manage their disorders.
The frustration is that drug candidates that have shown promise in animal models have not demonstrated efficacy in humans. Mouse models are not proving to be sufficient surrogates for human neurologic disease. Human brains and brain cells are built and function differently, and many neurodevelopmental disorders—hard enough to diagnose in human children—don’t have identifiable behavioral counterparts in mice. As I hear over and over from scientists, there is no such thing as a mouse with autism.
When I tell people I work at the Technology and Innovation Development Office at Children’s (TIDO), they usually think I work to commercialize patented blockbuster drug candidates. But many of the most satisfying projects I help promote are innovations that don’t involve as much risk, time and investment, yet make a big difference for patients. Commercializing these innovations can help the greater good, and is part of what propels me to work at a licensing office at a pediatric hospital.
And sometimes it doesn’t take much to help them along.
Angelman syndrome (AS) is a rare, neurogenetic condition characterized by severe developmental delay, movement disorder, speech impairment (often with a complete lack of speech) and an unusually happy demeanor. Nearly every individual with AS faces at least two major challenges in their daily life: cognitive or intellectual disability, and movement disorder, usually in the form of ataxic (uncoordinated) gait, unsteadiness, jerky movements or tremors. Seizures are also common, and present a daunting health challenge.
Arising in one out of every 10,000 to 20,000 children from the loss of an enzyme on chromosome 15 called Ube3A, AS falls in the category of orphan diseases: ones that affect fewer than one in 200,000 Americans. There is no cure for AS, but there are therapies and medications that can help the symptoms. Seizures can be controlled with the right medications, physical therapy can improve ataxia, and speech therapy helps improve communication skills.
Like nearly all orphan diseases, research on AS has historically not been well-funded, but orphan diseases have lately gained growing attention, especially at Children’s Hospital Boston. …
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, such as the one we posted about yesterday for Rett syndrome, 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. …
In 2007 an extraordinary paper was published, suggesting that developmental disorders, including autism spectrum disorders, aren’t necessarily a done deal. Working with a mouse model of Rett syndrome, a disorder causing severe cognitive, motor and language problems and autistic behaviors, mostly in girls, researchers in Scotland restored the function of MeCP2, the mutated gene. The mice showed a striking reversal of their neurologic symptoms.
The paper has had an impact around the world, changing how scientists think about disorders that have been thought to be untreatable. …