Repeated Insulin-Like Growth Factor 1 Treatment in a Patient with Rett Syndrome: A Single Case Study

Pini, Giorgio; Scusa, Maria Flora; Benincasa, Alberto; Bottiglioni, Ilaria; Congiu, L; Vadhatpour, Cyrus; Romanelli, Anna Maria; Gemo, Ilaria; Puccetti, Chetti; McNamara, Rachel; O’Leary, Seán; Corvin, Aiden; Gill, Michael; Tropea, Daniela

doi:10.3389/fped.2014.00052

Cited by 29 publications

(31 citation statements)

References 14 publications

(34 reference statements)

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“…The positive effects of the administration of IGF-I in RTT have been confirmed in mouse models [52,53], and in human patients [29][30][31][54][55][56], corroborating our results, although in those studies only IGF-I was used, and the treatment time and dose of this peptide were lower than in our case.…”

Section: Discussionsupporting

confidence: 90%

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Rett Syndrome: Treatment with IGF-I, Melatonin, Blackcurrant Extracts, and Rehabilitation

Devesa¹,

Devesa²,

Carrillo³

et al. 2018

Reports

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Abstract:(1) This study describes the good evolution of a 6-year-old girl genetically diagnosed (R106X) with Rett syndrome (RTT), after having been treated with IGF-I, melatonin (MT), blackcurrant extracts (BC) and rehabilitated for 6 months. (2) The patient stopped normal development in the first year of age. The patient showed short stature and weight and fulfilled the main criteria for typical RTT. Despite her young age, there was pubic hair (Tanner II), very high plasma testosterone, and low levels of plasma gonadotrophins. There were no adrenal enzymatic deficits, and abdominal ultrasound studies were normal. The treatment consisted of IGF-I (0.04 mg/kg/day, 5 days/week, subcutaneous (sc)) for 3 months and then 15 days of rest, MT (50 mg/day, orally, without interruption) and neurorehabilitation. A new blood test, after 3 months of treatment, was absolutely normal and the pubic hair disappeared (Tanner I). Then, a new treatment was started with IGF-I, MT, and BC for another 3 months. In this period, the degree of pubertal development increased to Tanner III (pubic level), without a known cause. (3) The treatment followed led to clear improvements in most of the initial abnormalities, perhaps due to the neurotrophic effect of IGF-I, the antioxidant effects of MT and BC, and the cerebral increase in the cyclic glycine-proline (cGP) achieved with administration of BC. (4) A continuous treatment with IGF-I, MT, and BC appears to be useful in RTT.

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Section: Discussionsupporting

confidence: 90%

“…The reason for using IGF-I in the treatment of RTT is based on the key role that this peptide plays in the development of the CNS; therefore, it could improve the symptoms of the syndrome at the expense of facilitating brain development [30,31] and increase the small number of dendrites that exist in this pathology [32,33].…”

Section: Introductionmentioning

confidence: 99%

Rett Syndrome: Treatment with IGF-I, Melatonin, Blackcurrant Extracts, and Rehabilitation

Devesa¹,

Devesa²,

Carrillo³

et al. 2018

Reports

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“…Further, administration of a TrkB ligand restores synaptic plasticity and memory in RTT mice 23 . Moreover, IGF-1 treatment was shown to improve the RTT syndrome in patient 24 . Because of the important roles of BDNF and IGF-1 in RTT, we first examined whether Wnt6 signaling regulates Bdnf and Igf-1 promoter activity.…”

Section: Overexpression Of Wnt6 Increases the Promoter Activity And Ementioning

confidence: 99%

Restoring Wnt6 signaling ameliorates behavioral deficits in MeCP2 T158A mouse model of Rett syndrome

Hsu

Liu

et al. 2020

Sci Rep

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The methyl-CpG-binding protein 2 gene, MECP2, is an X chromosome-linked gene encoding the MeCP2 protein, and mutations of MECP2 cause Rett syndrome (RTT). Previous study has shown that reexpression of SUMO-modified MeCP2 in Mecp2-null neurons rescues synaptic and behavioral deficits in Mecp2 conditional knockout mice, whereas about 12-fold decrease in Wnt6 mRNA level was found in MeCP2K412R sumo-mutant mice. Here, we examined the role of Wnt6 in MeCP2 T158A mouse model of RTT. Results show that lentiviral delivery of Wnt6 to the amygdala ameliorates locomotor impairment and social behavioral deficits in these animals. MeCP2 T158A mice show decreased level of GSK-3β phosphorylation and increased level of β-catenin phosphorylation. They also show reduced level of MeCP2 SUMOylation. These alterations were also restored by lenti-Wnt6 transduction. Further, both BDNF and IGF-1 expressions are decreased in MeCP2 T158A mice. Overexpression of Wnt6 increases Bdnf and Igf-1 promoter activity in HEK293T cells in a dose-dependent manner. Lenti-Wnt6 transduction to the amygdala similarly increases the mRNA level and protein expression of BDNF and IGF-1 in MeCP2 T158A mice. Moreover, environmental enrichment (EE) similarly ameliorates the locomotor and social behavioral deficits in MeCP2 T158A mice. One of the mechanisms underlying EE is mediated through enhanced MeCP2 SUMOylation and increased Wnt6 expression in these animals by EE. Methyl-CpG-binding protein 2 (MECP2) is an X chromosome-linked gene that encodes the MeCP2 protein. MeCP2 contains two major domains, the methyl-DNA binding domain and the transcriptional repression domain, which are both structurally conserved 1. MeCP2 was first found to function as a transcriptional repressor. It binds to the CpG island of methylated DNA and recruits co-repressors, such as the histone deacetylase (HDAC) complex, for transcriptional repression 2. But a later study has indicated that MeCP2 could also function as a transcriptional activator 3. MeCP2 plays an important role in a few neuro-developmental disorders, and one of them is the Rett syndrome (RTT) 1,4,5. RTT is a rare neurological and developmental disorder and it shares some common features with autism spectrum disorder 6. The RTT patients usually develop normally at their infant stage, but regression develops afterwards. The abnormal behaviors usually include motor function deficits, cognitive impairment and other symptoms associated with mental retardation 1,7. RTT is caused by mutations of the MECP2 gene. So far, more than 200 mutations have been identified that are associated with RTT 8. Some of these mutations are rare, but there are several most commonly seen mutations including T158M, R168X (X represents a premature stop codon), R133C, R106W, P152A, R306C and P376R, and the first three mutations account for approximately 32% of total RTT patients 9,10. Our previous study reveals that six out of these seven MECP2 mutations, except MECP2R168X as it lacks the C-terminal domain, show significantly decreased MeCP2 SUMOyl...

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“…As expected form the studies with the Mecp2 knockout mouse model, IGF-1 treatment was able to restore proper numbers of glutamatergic synapses, as measured by quantifying VGLUT positive synaptic punctae 30 . In terms of translation, on-going clinical studies in Rett syndrome subjects described by Pini et al indicate IGF-1 administrations is safe and well tolerated 34 . In an open label study in a single patient with repeated treatment, modest improvement in Rett symptoms (cognitive, social, and autonomic); however, the apparent benefits were short term since they did not persist between the two cycles of treatment.…”

Section: Phenotypic Assays In Human Ipsc Models Of Neuropsychiatrimentioning

confidence: 99%

Advancing drug discovery for neuropsychiatric disorders using patient-specific stem cell models

Haggarty

Silva

Cross

et al. 2016

Molecular and Cellular Neuroscience

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Compelling clinical, social, and economic reasons exist to innovate in the process of drug discovery for neuropsychiatric disorders. The use of patient-specific, induced pluripotent stem cells (iPSCs) now affords the ability to generate neuronal cell-based models that recapitulate key aspects of human disease. In the context of neuropsychiatric disorders, where access to physiologically active and relevant cell types of the central nervous system for research is extremely limiting, iPSC-derived in vitro culture of human neurons and glial cells is transformative. Potential applications relevant to early stage drug discovery, include support of quantitative biochemistry, functional genomics, proteomics, and perhaps most notably, high-throughput and high-content chemical screening. While many phenotypes in human iPSC-derived culture systems may prove adaptable to screening formats, addressing the question of which in vitro phenotypes are ultimately relevant to disease pathophysiology and therefore more likely to yield effective pharmacological agents that are disease-modifying treatments requires careful consideration. Here, we review recent examples of studies of neuropsychiatric disorders using human stem cell models where cellular phenotypes linked to disease and functional assays have been reported. We also highlight technical advances using genome-editing technologies in iPSCs to support drug discovery efforts, including the interpretation of the functional significance of rare genetic variants of unknown significance and for the purpose of creating cell type- and pathway-selective functional reporter assays. Additionally, we evaluate the potential of in vitro stem cell models to investigate early events of disease pathogenesis, in an effort to understand the underlying molecular mechanism, including the basis of selective cell-type vulnerability, and the potential to create new cell-based diagnostics to aid in the classification of patients and subsequent selection for clinical trials. A number of key challenges remain, including the scaling of iPSC models to larger cohorts and integration with rich clinicopathological information and translation of phenotypes. Still, the overall use of iPSC-based human cell models with functional cellular and biochemical assays holds promise for supporting the discovery of next-generation neuropharmacological agents for the treatment and ultimately prevention of a range of severe mental illnesses.

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Repeated Insulin-Like Growth Factor 1 Treatment in a Patient with Rett Syndrome: A Single Case Study

Cited by 29 publications

References 14 publications

Rett Syndrome: Treatment with IGF-I, Melatonin, Blackcurrant Extracts, and Rehabilitation

Rett Syndrome: Treatment with IGF-I, Melatonin, Blackcurrant Extracts, and Rehabilitation

Restoring Wnt6 signaling ameliorates behavioral deficits in MeCP2 T158A mouse model of Rett syndrome

Advancing drug discovery for neuropsychiatric disorders using patient-specific stem cell models

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