Investigating a candidate therapeutic for Rett Syndrome

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The X-chromosome harbors hundreds of disease genes whose associated diseases predominantly affect males. However, a subset — including neurodevelopmental disorders, Rett (RTT), Fragile X (FXS), and CDKL5 Syndromes — also or only affects females. Autism is a frequent manifestation. Because female cells carry a second copy of the X-chromosome, an emerging treatment strategy has been to reawaken the healthy allele on this inactive X (Xi) to reverse disease symptoms. An obstacle has been that the Xi is subject to a very robust silencing mechanism and, for decades, it was thought that Xi-reactivation would not be possible. However, recent work from our lab and other groups indicates that Xi reactivation can be achieved. We have been focusing on Rett Syndrome (RTT) and leveraging our understanding of XCI biology to develop Xi- reactivating drugs. RTT is a severe neurodevelopmental disorder that affects ~1:10,000 girls throughout the world. Affected girls inherit one defective copy of methyl-CpG-binding protein 2 (MECP2), a chromatin- associated gene product that is crucial for neuronal development. RTT girls are born normal and develop normally for the first few months of life, but begin to regress between 6-12 months of age. RTT is associated with severe autism and seizures, and is one of the most debilitating genetic disorders. There is no disease- specific treatment at present, as the standard of care treats only general symptoms. In a landmark discovery of 2007, scientists demonstrated in a mouse model that restoring MECP2 expression after onset of RTT symptoms reverses the neurological disease. MECP2 restoration is therefore of major interest to the pharmaceutical industry. Because MECP2 is an X-linked gene subject to X-inactivation and nearly all patients are heterozygous for the MECP2 gene, every affected girl carries a good copy of MECP2 on the Xi of her sick cells. Our goal is to unlock the Xi and restore expression of MECP2. With seed funding from foundations and an expired/non-renewable NIH grant, my lab has worked on this problem for the past 7 years. Critical for testing Xi-reactivating drugs is a female mouse model for RTT, because existing Mecp2+/- female mice have variable disease penetrance, only a mild disease later in life, and are therefore not suitable as a model for the Xi-reactivation platform. We have now created a new female RTT mouse model that carries wildtype Mecp2 on the Xi, phenocopies the severe disease seen in male RTT mice, and is therefore an ideal model for testing Xi- reactivating drug candidates. Moreover, we have identified a first-in-class, mixed modality drug capable of reactivating MECP2 up to 30,000-fold in a cellular model. The goals of our proposed research are (i) optimization and preclinical development of the lead candidate in a mouse model, (ii) PK/PD studies and longitudinal evaluation of potential drug toxicities in vivo, and (iii) determination of efficacy in the new disease- relevant animal model. By the end of the 5-year project, we hope to secure proof-of-concept for in vivo MECP2 upregulation and phenotypic rescue, and establish industry partnerships to develop the drug for the clinic.