LOS ANGELES (May 16, 2017) -- Scientists for the first time have assembled a "disease in a dish" model that pinpoints how a defect in the blood-brain barrier can produce an incurable psychomotor disorder, Allan-Herndon-Dudley syndrome. The findings point to a path for treating this syndrome and hold promise for analyzing other neurological diseases.
The blood-brain barrier, formed by blood vessels, protects the brain from toxins circulating in the body's blood system. It also can keep out therapeutic drugs and, when defective, biomolecules that are needed for healthy brain development. The latter is what happens in Allan-Herndon-Dudley syndrome, according to investigators from Cedars-Sinai and the University of Wisconsin-Madison. The rare, congenital syndrome causes cognitive disability, impaired speech and underdeveloped muscles, among other symptoms.
Clive Svendsen, PhD, director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute, said the model developed by the collaborative team's study, published May 16 in the journal Cell Stem Cell, may shed light on other neurological conditions that involve possible dysfunctions in the blood-brain barrier. These conditions include Alzheimer's disease and Huntington's disease, which together affect millions worldwide. A related paper, involving Svendsen, his colleague Gad Vatine, PhD, and a team from University of California, Irvine, published the same day in the journal Cell Reports, used a similar approach to study Huntington's disease.
"This model could have far-reaching implications to advance the understanding and treatment of neurological disorders," said Svendsen, senior author of the Cell Stem Cell study.
To develop their "disease in a dish" model, the team took skin cells from patients with Allan-Herndon-Dudley syndrome and reprogrammed them into induced pluripotent stem cells, which then can be developed into any type of tissue in the body. Using these cells, the team modeled the patients' neurons and blood-brain barrier in a laboratory dish.
"To our surprise, the neurons were normal," said Vatine, a postdoctoral scientist in Svendsen's laboratory and first author of the study. "But the blood-brain barrier was not."
The dish model showed that the thyroid hormone, which is critical to neuron development, wasn't getting into the brain. This hormone requires a biomolecule to transport it across the blood-brain barrier. Due to a gene mutation in Allan-Herndon-Dudley patients, there was not enough of the biomolecule in the barrier to do the job.
"The blood-brain barrier forms pretty early in gestation, so the thyroid hormone, even from the mother, is probably not getting through the barrier and into the brain, likely leading to developmental deficits," said Eric Shusta, a professor of Chemical and Biological Engineering at the University of Wisconsin-Madison and a senior author of the study.
One potential way to treat Allan-Herndon-Dudley syndrome, based on this model, may be to develop an artificial version of the thyroid hormone that does not need the biomolecule to cross the blood-brain barrier, Vatine said. It also may be possible in the future to repair the gene mutation using gene-editing technology, which the investigators were able to do in the laboratory dish, he added.
Research reported in this publication was supported by grants from the Cedars-Sinai Board of Governors Regenerative Medicine Institute and the National Institutes of Health under award numbers NS083688, AA020476, NS085351 and R37DK15070.