Abstract
ABSTRACTReduced expression of brain-derived neurotrophic factor (BDNF) and impaired activation of the BDNF receptor, tropomyosin receptor kinase B (TrkB; also known as Ntrk2), are thought to contribute significantly to the pathophysiology of Rett syndrome (RTT), a severe neurodevelopmental disorder caused by loss-of-function mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2). Previous studies from this and other laboratories have shown that enhancing BDNF expression and/or TrkB activation in Mecp2-deficient mouse models of RTT can ameliorate or reverse abnormal neurological phenotypes that mimic human RTT symptoms. The present study reports on the preclinical efficacy of a novel, small-molecule, non-peptide TrkB partial agonist, PTX-BD4-3, in heterozygous female Mecp2 mutant mice, a well-established RTT model that recapitulates the genetic mosaicism of the human disease. PTX-BD4-3 exhibited specificity for TrkB in cell-based assays of neurotrophin receptor activation and neuronal cell survival and in in vitro receptor binding assays. PTX-BD4-3 also activated TrkB following systemic administration to wild-type and Mecp2 mutant mice and was rapidly cleared from the brain and plasma with a half-life of ∼2 h. Chronic intermittent treatment of Mecp2 mutants with a low dose of PTX-BD4-3 (5 mg/kg, intraperitoneally, once every 3 days for 8 weeks) reversed deficits in two core RTT symptom domains – respiration and motor control – and symptom rescue was maintained for at least 24 h after the last dose. Together, these data indicate that significant clinically relevant benefit can be achieved in a mouse model of RTT with a chronic intermittent, low-dose treatment paradigm targeting the neurotrophin receptor TrkB.
Highlights
Rett syndrome (RTT) is a complex neurological disorder caused by loss-of-function mutations in the gene encoding methyl-CpGbinding protein 2 (MeCP2)
The present study reports on the detailed characterization of one such derivative, PTX-BD4-3, in which the terminal hydroxyl groups in the three side-chain moieties were substituted with methyl groups (Fig. 1), and on the in vivo efficacy of PTX-BD4-3 in a mouse model of RTT, a severe neurodevelopmental disorder characterized by reduced brain-derived neurotrophic factor (BDNF)–tropomyosin receptor kinase B (TrkB) signaling (Katz, 2014)
The present findings demonstrate that a low-dose, chronic intermittent treatment paradigm targeting the neurotrophin receptor TrkB can yield significant, clinically relevant symptomatic benefit in a mouse model of RTT
Summary
Rett syndrome (RTT) is a complex neurological disorder caused by loss-of-function mutations in the gene encoding methyl-CpGbinding protein 2 (MeCP2) MeCP2 deficiency results in dysregulated expression of synaptic signaling molecules (Shepherd and Katz, 2011), which, together with structural synaptic deficits, leads to abnormalities in excitatory/inhibitory synaptic balance and network connectivity (Shepherd and Katz, 2011) and, thereby, neurological dysfunction
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