Functional recovery with recombinant human IGF1 treatment in a mouse model of Rett Syndrome

Abstract

Rett Syndrome is a neurodevelopmental disorder that arises from mutations in the X-linked gene methyl-CpG binding protein 2 (MeCP2). MeCP2 has a large number of targets and a wide range of functions, suggesting the hypothesis that functional signaling mechanisms upstream of synaptic and circuit maturation may contribute to our understanding of the disorder and provide insight into potential treatment. Here, we show that insulin-like growth factor-1 (IGF1) levels are reduced in young male Mecp2-null (Mecp2 −/y ) mice, and systemic treatment with recombinant human IGF1 (rhIGF1) improves lifespan, locomotor activity, heart rate, respiration patterns, and social and anxiety behavior. Furthermore, Mecp2-null mice treated with rhIGF1 show increased synaptic and activated signaling pathway proteins, enhanced cortical excitatory synaptic transmission, and restored dendritic spine densities. IGF1 levels are also reduced in older, fully symptomatic heterozygous (Mecp2 −/+ ) female mice, and short-term treatment with rhIGF1 in these animals improves respiratory patterns, reduces anxiety levels, and increases exploratory behavior. In addition, rhIGF1 treatment normalizes abnormally prolonged plasticity in visual cortex circuits of adult Mecp2 −/+ female mice. Our results provide characterization of the phenotypic development of Rett Syndrome in a mouse model at the molecular, circuit, and organismal levels and demonstrate a mechanism-based therapeutic role for rhIGF1 in treating Rett Syndrome. molecular therapeutic | respiration | synaptic function | male mice | female mice R ett Syndrome (RTT) is a devastating, rare neurodevelopmental disorder that primarily afflicts girls. Over 90% of individuals with RTT have sporadic mutations in the X-linked gene coding for methyl-CpG binding protein 2 (MeCP2). Affected girls are initially asymptomatic, but later develop a wide range of symptoms. Mouse models of RTT with deletion of Mecp2 recapitulate many of the key physiological, autonomic, motor, and cognitive aspects of the disorder (1, 2).MeCP2 binds widely across the genome and has complex roles that encompass activating or inhibiting gene transcription, repressing methylation, regulating chromatin remodeling, and altering noncoding RNAs (3). This wide range of functions has led to the proposal that a focus on functional signaling pathways is needed to drive an understanding of RTT and its possible therapeutics (1, 2, 4). Several lines of evidence indicate an arrested brain maturation phenotype in RTT, suggesting that loss of functional MeCP2 leads to immature synapses and circuits in the brain (5). Importantly, mouse models have suggested reversibility of specific symptoms once MeCP2 function is restored (6, 7). One well-documented target of MeCP2 is brain-derived neurotrophic factor (BDNF), which is known to be critical for neuronal and synaptic maturation and is down-regulated in Mecp2 mutant mice and RTT patients (8, 9). BDNF exerts influence on neurons and synapses mainly via the phosphoinositide 3-kinase (PI3K)/Akt pathway ...

Placebo‐controlled crossover assessment of mecasermin for the treatment of Rett syndrome

“…Prominent among these are compounds that modulate synaptic development and function, such as insulin‐like growth factor 1 (IGF‐1), which shares many features with brain‐derived neurotrophic factor (BDNF), including activation of the AKT signaling pathway 17, 18. Evaluation of IGF‐1, and its active N‐terminus peptide, in MECP2 mouse models, has rescued many RTT‐like symptoms 19, 20, 21. These experimental findings have led to two phase 2 trials with the IGF‐1 peptide analog trofinetide (NCT01703533 and NCT02715115) and one phase 1 trial with recombinant human IGF‐1 (rhIGF‐1) also termed mecasermin 22…”

Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome

“…Among the latter are locomotor function impairment, breathing abnormalities, and heart rate irregularities. These improvements seem to reflect IGF-1's effect on defective synaptic maturation and maintenance secondary to Mecp2 deficit (14).…”

“…Furthermore, administration of IGF-1 restores dendritic spine dynamics in Mecp2-deficient mice (12). The most compelling data supporting IGF-1 as a treatment for RTT come from two studies demonstrating that systemic administration of either full length IGF-1 or its active peptide fragment reverses, at least partially, many RTT-relevant features in Mecp2-deficient mice (13,14). Among the latter are locomotor function impairment, breathing abnormalities, and heart rate irregularities.…”

Glutamate Delta-1 Receptor Regulates Metabotropic Glutamate Receptor 5 Signaling in the Hippocampus

“…GluD1 Regulates mGlu5 Signaling model (Calfa et al, 2011;Guy et al, 2011;Castro et al, 2014). In this study, we found that GluD1 KO have upregulated AktmTOR signaling (Fig.…”