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Spotlighting Rare Diseases Research Blog

Reactivating the Silenced X Chromosome: A Potential Therapeutic Approach to CDKL5 Deficiency and Rett Syndrome

Thursday, June 06, 2019



My lab has a long-standing interest in understanding gene regulation, or how genes are turned on or off in a cell. We seek to understand how misregulation of gene expression can contribute to human disease. One line of research in my lab investigates how modulating gene expression can be used as a therapeutic approach to certain disorders, such as the rare X chromosome-linked disorders CDKL5 Deficiency and Rett Syndrome, both of which are devastating neurodevelopmental diseases occurring primarily in females.      

Several years ago, we began investigating the mechanism by which genes are turned off on the X chromosome — a process termed X chromosome inactivation (XCI). In females, XCI is a naturally occurring phenomenon in which one of the X chromosomes is randomly turned off, or silenced, as a way to equalize the dosage of the X chromosome between females (who have two X chromosomes) and males (who have one). This process is relevant to CDKL5 Deficiency and Rett Syndrome, as both diseases are caused by mutations in one copy of an X chromosome-linked gene: CDKL5 Deficiency is caused by mutations in the gene CDKL5, whereas Rett Syndrome is caused by mutations in MECP2. Although these mutant genes are present in all cells, due to XCI only half of the patient’s cells express the mutant version. Notably, these cells retain a normal copy of the gene that is functional but silenced. Reactivating the normal copy of the CDKL5 or MECP2 gene is a potential therapeutic approach for these diseases.

We have identified a number of factors that are required for XCI, using genomic and proteomic approaches. On the basis of this information, we have found small molecule inhibitors (drugs) of these factors, which can block XCI, thus restoring expression of the silenced, normal CDKL5 or MECP2 gene. Our studies have shown that we can restore expression of CDKL5 or MECP2 in cultured cells of human patients and in cerebral cortical neurons of adult living mice. We hope that by restoring expression of normal CDKL5 or MECP2 in cells of the brain, we can ameliorate disease symptoms.

Research Impact on Rare Diseases

Currently, there are no effective treatments for CDKL5 Deficiency or Rett Syndrome. An attractive feature of our approach is that it addresses the root cause of the disease — the lack of CDKL5 or MECP2 — rather than a secondary, downstream consequence of the CDKL5 or MECP2 deficiency. We believe our research will lead to a new class of drugs to treat these diseases and will therefore have a major impact on the CDKL5 Deficiency and Rett Syndrome communities.

We are particularly excited about the possibility of repurposing existing drugs, which would offer a faster, cheaper, and safer way to develop new treatments. For example, we have identified small molecule drugs that, in clinical trials for other diseases, have shown to be well tolerated in humans, which is often a stumbling block in the drug development process. Repurposing these existing drugs can fast-track new treatments for rare diseases, including CDKL5 Deficiency and Rett Syndrome.

The Importance of Patient Participation in Rare Diseases Research

Because a rare disease afflicts so few people (by definition, fewer than 200,000 people nationwide), the information available is often insufficient to understand the causes of the disease and what can be done to treat it. The more information scientists are able to gather about a rare disease, the higher the chance of finding a cure.

Patients can take part in medical research on several different levels. First, patients can provide valuable resources for scientific research. For example, a patient’s fibroblasts, obtained through a relatively minor procedure (a skin biopsy), can be used to create patient-derived induced pluripotent stem cells (iPSCs), a powerful new research tool for modeling human diseases. This information not only helps scientists figure out what goes awry in the disease but also provides a platform for drug discovery. Second, patients can participate in clinical trials, for which it is often difficult to find sufficient numbers of participants.

A Personal Note

I received both an MD and a PhD. The typical career path for an MD-PhD graduate is to obtain additional medical training as an intern and resident, and ultimately become a practicing physician. However, I felt that the opportunities in research were so exciting that I decided to forego additional clinical training and become a full-time researcher.  I like working on rare diseases that are impacted by altered gene expression because I can apply my expertise in gene regulation to develop innovative new treatment strategies, which have the potential to make a real impact in the lives of patients. Through my association with foundations that support research for CDKL5 Deficiency and Rett Syndrome, I have met many patients afflicted with these rare diseases and their families, who have served as an inspiration for my work.

About Michael R Green

michael greenMichael R. Green, MD, PhD, is the Co-Director of The Li Weibo Institute for Rare Diseases Research. He is also a professor and Chair of the Department of Molecular, Cell, and Cancer Biology (MCCB); Vice Provost of Strategic Research Initiatives; and the Director of the Cancer Center at the UMass Chan Medical School. Dr. Green received an MD and PhD from Washington University School of Medicine and received postdoctoral training at Harvard University.