Lauren Orefice, PhD, assistant professor in the Department of Genetics at the Blavatnik Institute at Harvard Medical School and the Department of Molecular Biology at Massachusetts General Hospital, discusses steps toward translating promising science into novel treatments for autism.
Autism spectrum disorders (ASDs) have long been ascribed to altered brain circuitry believed to give rise to well-recognized core symptoms, such as social impairments, sensory hypersensitivity, and anxiety. Now, a series of elegant experiments in animal models suggest that gene mutations or alterations in peripheral sensory neurons that lie outside the brain influence certain ASD behaviors. What’s more, GABA receptors on these somatosensory nerves may provide a target for therapeutics that circumvent the blood-brain barrier.
Lauren Orefice, PhD, principal investigator of the Orefice Lab, is an assistant professor in the Department of Genetics at the Blavatnik Institute at Harvard Medical School and the Department of Molecular Biology at Massachusetts General Hospital. She answers questions about her research studying altered somatosensory processing in animal models of autism and collaborative work with David D. Ginty, PhD, a neurobiologist in the Blavatnik Institute at Harvard Medical School and Howard Hughes Medical Institute Investigator. Their goal is to develop novel therapeutics for ASD and launches the first project in an innovative R&D alliance with Deerfield Management.
Interview edited and condensed for clarity
My lab studies the development and function of the somatosensory system, focusing on peripheral sensory neurons that receive inputs from the skin and the gastrointestinal tract and then transmit this information to the spinal cord and, ultimately, the brain. We’re interested in how dysfunction in somatosensory circuits may impact certain diseases and disorders, specifically autism spectrum disorders (ASDs).
When I was a postdoctoral fellow in the Ginty Lab, we were struck by the observation that people with ASDs often report abnormal responses in sensory modalities: seeing or hearing, smell or taste, and touch, which David’s lab has studied extensively. We undertook a project to understand whether or not somatosensory circuits were disrupted in animal models for autism. If so, what parts of the circuits are disrupted? And is it possible to treat circuit dysfunction to improve how an animal –– or a person –– feels the sense of touch?
Most people assume ASD-associated genes only function in the brain. But when we mutated each of three distinct ASD-associated genes in peripheral sensory neurons in mice, we found this causes touch overreactivity. This is really surprising because these gene mutations are localized just to the peripheral neurons. Their expression in the brain and spinal cord are normal. So, these genes were necessary in peripheral neurons for normal touch behaviors. Further, when we selectively delete these same ASD-associated genes only in peripheral sensory neurons during early development, mice go on to develop some social impairments and anxiety-like behaviors in adulthood (see here and here).
Each of the mutated genes has a distinct way of affecting peripheral sensory neurons, yet they ultimately converge on the same phenotype: increased sensory input to the spinal cord. We think this is what causes the overreactivity to touch.
So, in animal models, we identified ASD-related gene mutations associated with dysfunction in peripheral sensory neurons that led to altered sensory input to the spinal cord and touch overreactivity in mice. If those neurons are essentially overactive, can we perhaps turn down the volume, reducing touch overreactivity and possibly related ASD symptoms in mice?
We like this approach because it’s very simple. It’s based on affecting excitability in the peripheral neurons rather than complex signal transduction pathways in the brain. We want to identify drugs that actually do not get into the brain, compounds that will act selectively on peripheral neurons. This is particularly attractive because drugs that pass through the blood-brain barrier can have significant side effects.
The compound we started with is isoguvacine, a GABA mimetic — it acts like GABA and binds to the GABA-A receptor, but it does not cross the blood-brain barrier. When we gave mice an acute injection of isoguvacine, we found it reduced touch overreactivity in a range of animal models despite different pathophysiologies or types of dysfunction in the peripheral somatosensory neurons. Even in control mice without any genetic mutations, this compound reduces the sensitivity of neurons that respond to light touch.
In another experiment, we treated mice with isoguvacine for six weeks starting the day after they were born, then looked at brain development and touch overreactivity, as well as social impairments and anxiety. We saw an improvement in touch overreactivity and anxiety-like behaviors. We also saw partial improvement in social impairments and some improvement in microcircuit function in the brain.
Currently, David and I are working in collaboration with colleagues at BIDMC and BCH to develop better quantitative metrics of touch overreactivity in people with ASD. We’re developing assays based on work we did in adult mice — so we’re going backward and trying to develop those behavioral assays for use in humans now. We’d like to be able to identify touch overreactivity very early because it’s likely best to treat it early. While you can improve touch overreactivity in adults with ASDs, we’d hope to administer these types of compounds early for maximal benefits.
We are the first project to be part of an exciting translational research alliance with Harvard Medical School, and Deerfield Managementcalled Lab1636. Partnering with them has been incredible for us because it allows us to see this project through the many stages of drug discovery and development in a way we couldn’t do by ourselves.
I’m a basic scientist. I’ve been working with mice throughout my career. But the ultimate goal for these studies is to use our scientific findings to improve the quality of life for people with ASD. We don’t think of this as a cure for autism. We’re hoping to improve some of the symptoms of autism that may affect quality of life for people or may make certain situations or interactions more difficult. If we can alleviate some of those stresses, that would be wonderful.
— Francesca Coltrera
Continue the conversation with us @HMS_ExecEd or with Dr. Orefice @lauren_orefice