Development of therapeutic strategies for Rett syndrome

• Applicants: Professorin Dr. Jutta Gärtner; Professor Dr. Peter Huppke
• Subject Area: Pediatric and Adolescent Medicine
• Term: from 2004 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5433020

Rett syndrome, one of the most frequent causes of mental retardation in females, is caused by mutations in the MECP2 gene. The gene codes for the DNA binding protein MeCP2, which has a key role in the epigenetic control of gene expression. Surprisingly it was shown in conditional Mecp2 knockout mice that re-expression of Mecp2 can reverse the clinical symptoms indicating that Rett syndrome is a treatable disorder. Previously we have generated and characterized a mouse model that carries the nonsense mutation in the MECP2 gene most commonly found in patients with Rett syndrome (p.R168X). The aim of this research project is to develop therapeutic strategies for Rett syndrome that aim to re-express or replace MeCP2. Readthrough of nonsense mutations: We have shown previously that it is possible to induce significant expression of MeCP2 in transfected cells and in fibroblasts from the kockin mice by treatment with various aminoglycosides. Experiments in vivo, however, were so far unsuccessful due to the toxicity of the compounds and the low penetration of the blood brain barrier. To overcome these problems we will use novel compounds that enhance the readthrough and test synthetic aminoglycosides that have been altered to allow better penetration of the blood brain barrier. Moreover, we will administer the aminoglycosides intrathecally thereby circumventing the systemic toxicity and the blood brain barrier. Furthermore, we intend to treat the mice orally with Ataluren (Translarna®), a small molecule which was approved recently for readthrough therapy in Duchenne muscular dystrophy. Protein replacement therapy: The second therapeutic approach is aimed to replace MeCP2 directly. As MeCP2 cannot enter the cells a fusion protein was generated wherein the MeCP2 protein is fused to the protein transduction domain of the human immunodeficiency virus-1. To bypass the blood brain barrier the fusion protein will be given intrathecally. Bone marrow transplantation: Using the knockin mouse model we were able to show that other than previously reported, bone marrow transplantation does not lead to an extended survival in male mice. As Rett syndrome is a disorders that almost exclusively affects females, who due to the X-inactivation express a normal MECP2 allele in 50% of the cells, the experiments will now be carried out in female mice.

• DFG Programme: Research Grants