The proposed research is designed to foster the development of new therapies for the treatment of Rett syndrome (RTT), a severe and currently untreatable neurodevelopmental disorder that affects approximately 1 in 10,000 females worldwide. RTT is caused by loss-of-function mutations in a single gene, MECP2, and is characterized by developmental regression, loss of speech, abnormal locomotion and hand use, autistic behaviors, cardiorespiratory and gastrointestinal dysfunction, and an increased risk of seizures. Genetically engineered mice carrying Mecp2 mutations develop symptoms that closely mimic human RTT, thereby providing a powerful tool for developing potential therapies. Our laboratory recently found that key aspects of abnormal brain function can be reversed in symptomatic Mecp2 mice following acute treatment with sub-anesthetic doses of ketamine, an antagonist of the NMDA subtype of glutamate receptors. Ketamine, which is widely used in children and adolescents for sedation, pain management and other indications and for treating major depressive disorder in adults, has never been evaluated for treatment of RTT. Therefore, the primary goal of the proposed research is to provide sufficient preclinical data on the efficacy and safety of ketamine in Mecp2 mutants to determine whether or not a clinical trial may be justified. We will use Mecp2 mutant mice to define the acute and long-term effects of ketamine treatment on 1) behavioral outcome measures relevant to clinical endpoints in RTT patients, including breathing, motor function, cognition and anxiety, 2) epileptiform activity, including spontaneous seizures and seizure threshold and 3) molecular and cellular biomarkers of treatment effects on brain growth and function. Moreover, because ketamine can have effects that may limit its utility in some patients, the proposed research will also determine whether any observed therapeutic benefits of ketamine are reproduced by traxoprodil (CP-101606), a potentially safer drug that exhibits selectivity for the NR2B subunit of the NMDA receptor. The proposed studies will require diverse approaches and will draw upon the combined expertise of Dr. Katz's laboratory (plethysmographic analysis of breathing dysfunction in mice, Western blot and immunohistochemical analysis of cell signaling molecules and quantitative analysis of neuronal and dendritic morphology), Dr. Najm's laboratory (continuous EEG analysis in mice) and the Neurosciences Department Rodent Behavioral Phenotyping Core Facility. If our studies demonstrate that ketamine is efficacious and safe for the treatment of murine RTT, we will seek FDA approval for its use in a clinical trial with RTT patients. If we find that CP-101606 also has significant benefit, pharmacokinetic, pharmacodynamic and safety data will help inform our decision about the clinical development path. These issues will be vetted with our Therapy Development Advisory Board, which includes experts in 1) clinical trials for pediatric neurological disorders, 2) CNS drug development and trial design, including NMDA antagonists, 3) clinical management of RTT patients and 4) mouse behavior and preclinical trial design.
The proposed research is designed to foster the development of new pharmacological therapies for the treatment of Rett syndrome (RTT), a severe and currently untreatable neurodevelopmental disorder that affects approximately 1 in 10,000 females worldwide. Specifically, we will evaluate the ability of two drugs, ketamine and traxoprodil, to reverse symptoms of neurologic dysfunction in mouse model of RTT, based on strong preliminary data as well as clinical studies in which these drugs have been used for other indications. This proposal grows out of a strategic collaboration between Dr. Katz's laboratory, RTT clinicians and clinical trialists and the Rett Syndrome Research Trust that will provide the infrastructure to support a subsequent clinical trial in RTT patients if warranted by the outcome of the proposed studies.