UCSF researchers have successfully used protease inhibitors to restore to normal levels a key protein involved in early brain development. Reduced levels of that protein have been shown to cause the rare brain disorder lissencephaly, which is characterized by brain malformations, seizures, severe mental retardation and very early death in human infants.
The findings offer a proof-of-principle, at least in mice, that the genetic equivalent to human lissencephaly, also known as "smooth brain" disease, can be treated during pregnancy and effectively reversed to produce more normal offspring. Findings are reported in the September issue of "Nature Medicine" and found online at http://www.nature.com.
While the progress is still in animal models, the work is significant in being the first successful attempt to use protease inhibitors to reverse a severe brain defect that is known to be caused by limited quantities of one key gene, the researchers say.
The hope is that this approach also could be used to treat other defects in utero, or even those manifesting after birth, when caused by a partial deficiency in one gene, according to Anthony Wynshaw-Boris, MD, PhD, who is chief of the UCSF Division of Genetics in the Department of Pediatrics, and a member of the UCSF Institute for Human Genetics.
"Researchers have not considered it possible to treat such a pervasive, early developmental brain disorder as lissencephaly," said Wynshaw-Boris, who collaborated on the paper with Shinji Hirotsune, MD, PhD, in the Osaka City University Graduate School of Medicine. "Not only were we able to show a clear cellular effect from using these protease inhibitors, but also were able to treat the disorder in utero."
The work is the culmination of 15 years of collaborative research in the Wynshaw-Boris and Hirotsune labs into the cause and mechanisms of lissencephaly, which is caused by a deletion o
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University of California - San Francisco