Reversal of Rett Phenotype: A screen for compounds that enhance KCC2 expression

Rudolf Jaenisch, MD | Whitehead Institute

$180,000 AWARDED

There are numerous strategies to target Rett Syndrome. Curative strategies target MECP2 itself through gene therapy or protein replacement or by activating the backup copy of MECP2. An alternative treatment strategy is to activate or stimulate a molecular pathway that is disrupted in Rett but that does not involve MECP2.

K+/Cl- cotransporter-2 (KCC2), an essential gene for proper brain function, is one such pathway. Dr. Jaenisch’s previous published work has demonstrated that restoration of the decreased KCC2 expression level in Rett Syndrome mouse model neurons leads to the recovery of impaired neuronal functions. They have developed a robust in vitro screening platform in human Rett neurons based on KCC2 expression that will allow the identification of compounds that rescue the cellular phenotypes. Therapeutic effectiveness of the compounds will subsequently be assessed in Mecp2 mutant mice. KCC2-enhancing compounds identified from human reporter neuron screening that are further validated in the animal model of RTT, could provide the basis for a novel therapeutic strategy for symptom improvement.

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