Protease Inhibitor Treats Rare Genetic Brain Disorder

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Lissencephaly (literally “smooth brain”) describes a set of rare conditions in which the foetal brain does not develop normally beyond the third or fourth month of pregnancy and, instead of the usual folds and grooves, the cerebrum has a partially or completely smooth appearance. The severity and range of symptoms varies, but include mental retardation, failure to thrive, difficulty swallowing, seizures, and psychomotor problems. A number of factors are believed to cause lissencephaly including viral infection during pregnancy, an interrupted blood supply to the foetus, and genetic mutation. Loss of one copy of the gene LIS1 prevents migration of immature nerve cells from deep in the brain to the surface of the emerging cerebral cortex and US and Japanese researchers have now shown, in mice at least, that the results of this mutation can be reversed during pregnancy, leading to more normal offspring.

human brainIn mice with only one copy of the LIS1 gene, the enzyme calpain reduces LIS1 protein levels to less than half of normal near the surface of cells, leading to abnormal brain development similar to that seen in human lissencephaly. Daily intraperitoneal injections of the small molecule calpain inhibitor, ALLN (N-Acetyl-Leu-Leu-Nle-CHO), to pregnant mice restored levels of LIS1 protein and resulted in offspring with more normal brains and no signs of mental retardation. Although the technique will not be easy to extend to humans, this study is the first successful attempt to use a protease inhibitor to reverse a severe brain defect caused by a partial deficiency in one key gene, and offers a proof-of-principle that the genetic equivalent to human lissencephaly can be effectively reversed during pregnancy to produce more normal offspring.

The authors hope that the approach could be extended to in utero treatments for other defects in which a protease plays a role in degrading an essential developmental protein.

The study was published online on September 6th in the journal Nature Medicine.

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