Robin Kleiman, PhD, is Director of Preclinical Research at Boston Children’s Hospital’s Translational Neuroscience Center.
One of the hardest parts of developing new treatments for autism spectrum disorder (ASD) is that almost every patient has a different combination of environmental and genetic risk factors. This suggests that every patient could take a unique path to their diagnosis. It is hard to come up with a single treatment that will help patients with fundamentally different root causes of ASD.
One way to approach this problem is to look for ways to cluster sub-types of autism for clinical trials, based on genetic risk factors or the types of neural circuits that are affected. If circuit dysfunction could be monitored and diagnosed easily in patients, it might be possible to develop treatments to reverse the dysfunction that cut across genetic and environmental causes of ASD. That is the hope of research on well-defined “syndromic” causes of autism such as tuberous sclerosis complex, Fragile X syndrome and Rett syndrome.
Accelerating research collaborations to design clinical trials for children with brain disorders, including ASD, is a major mission of Boston Children’s Hospital’s Translational Neuroscience Center (TNC). A recent study in Translational Psychiatry, led by Mathew Alexander, PhD, in the Boston Children’s lab of Lou Kunkel, PhD, in collaboration with the TNC and Pfizer, is a prime example. It suggests that patients with Duchenne muscular dystrophy (DMD) may constitute another subset of ASD patients — one that could benefit from phosphodiesterase (PDE) inhibitors, a family of drugs including Viagra.
From muscle to brain: Duchenne muscular dystrophy and autism
The findings provide evidence that mice lacking dystrophin, if treated with PDE5 or PDE9 inhibitors, do not develop social deficits. While ASD affects 1 in 42 boys born in the U.S., it affects roughly 1 in 4 boys born with DMD, a genetic neuromuscular condition that Kunkel discovered in the 1980s to be caused by the loss of the dystrophin gene. The primary pathology of DMD is a reduced capacity for muscle cells to recover from contraction-induced damage and a gradual replacement of functional muscle with non-functional fibrotic tissue (generated when the body tries unsuccessfully to repair the muscle).
The dystrophin protein is also found in select neuronal cells in the brain. Mouse studies have shown that the absence of dystrophin in specialized cerebellar Purkinje cells and in some cortical neurons leads to disturbances in the cerebellar circuit, which has been implicated in learning normal social behavior. The circuit can be easily monitored in animals and humans using quantitative functional measures.
Kunkel’s lab has long been involved in testing potential therapeutic approaches to treating the muscular degeneration in animal models of DMD. The phosphodiesterase 5 (PDE5) inhibitor known as sildenafil, made by Pfizer, has been proposed to increase blood flow to muscle and to improve muscle oxygen consumption during exercise.
PDE5 inhibitors work by preventing the degradation of the signaling molecule cGMP. The resulting accumulation of cGMP is thought to compensate for signaling deficits caused by the loss of dystrophin. The idea that PDE5 inhibitors could improve muscle function has recently been evaluated in clinical trials (using a different PDE5 inhibitor made by Eli Lilly), although no definitive benefit has been described to date.
Reversing social deficits in dystrophin-deficient mice
In collaboration with Pfizer and the TNC, Alexander and colleagues in the Kunkel lab began to explore whether either PDE5 inhibitors or the related PDE9 inhibitors developed by Pfizer might improve social behavior deficits. The study used mice that lacked the dystrophin protein but had not yet developed any muscle degeneration. In behavioral assays, these mice displayed less social behavior than control mice and had no preference for interaction with other mice.
The researchers hypothesized that PDE5 and PDE9 inhibitors might improve social behavior through specific effects on the Purkinje cells that express very high levels of dystrophin. While these cells are especially vulnerable to dystrophin disruption, they also express very high levels of PDE5 and PDE9 enzymes. Inhibiting one of these enzymes, the reasoning goes, could produce a compensatory cGMP signal and potentially reverse ASD caused by impairment in this cerebellar circuit.
The study’s findings indeed provide evidence that mice lacking dystrophin, if treated chronically with PDE5 or PDE9 inhibitors, do not develop the social deficits observed in placebo-treated mice. We need further confirmation, but the study exemplifies how centers like the TNC can advance the development and testing of new therapeutic hypothesis for neurodevelopmental disorders. The disease expertise of both academic faculty and industry collaborators is essential to develop the next generation of treatments for our patients.