A Double-Blind, Randomized, Placebo-Controlled Clinical Study of Trofinetide in the Treatment of Rett Syndrome

Glaze, Daniel G.; Neul, Jeffrey L.; Percy, Alan K.; Feyma, Tim; Beisang, Arthur; Yaroshinsky, Alex; Stoms, George; Zuchero, David; Horrigan, Joseph P.; Glass, Larry; Jones, Nicholas E.

doi:10.1016/j.pediatrneurol.2017.07.002

Cited by 74 publications

(86 citation statements)

References 17 publications

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“…Currently approaches to therapies are symptomatic, however work in mouse models provides hope that targeted therapies hold promise of significantly modifying or even reversing the disease (Guy et al, 2007). Recently, promising clinical trials in RTT have been completed (Glaze et al, 2017(Glaze et al, , 2019 or are being initiated, that could alter the treatment options in this disease.…”

Section: Introductionmentioning

confidence: 99%

Metabolic Signatures Differentiate Rett Syndrome From Unaffected Siblings

Neul

Skinner

Annese

et al. 2020

Front. Integr. Neurosci.

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Rett syndrome (RTT, OMIM 312750), a severe neurodevelopmental disorder characterized by regression with loss of spoken language and hand skills, development of characteristic hand stereotypies, and gait dysfunction, is primarily caused by de novo mutations in the X-linked gene Methyl-CpG-binding protein 2 (MECP2). Currently, treatment options are limited to symptomatic management, however, reversal of disease phenotype is possible in mouse models by restoration of normal MECP2 gene expression. A significant challenge is the lack of biomarkers of disease state, disease severity, or treatment response. Using a non-targeted metabolomic approach we evaluated metabolite profiles in plasma from thirty-four people with RTT compared to thirty-seven unaffected age-and gender-matched siblings. We identified sixty-six significantly altered metabolites that cluster broadly into amino acid, nitrogen handling, and exogenous substance pathways. RTT disease metabolite and metabolic pathways abnormalities point to evidence of oxidative stress, mitochondrial dysfunction, and alterations in gut microflora. These observed changes provide insight into underlying pathological mechanisms and the foundation for biomarker discovery of disease severity biomarkers.

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Section: Introductionmentioning

confidence: 99%

Metabolic Signatures Differentiate Rett Syndrome From Unaffected Siblings

Neul

Skinner

Annese

et al. 2020

Front. Integr. Neurosci.

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“…Currently, a chemically modified form of GPE, called Trofinetide, makes the peptide suitable for oral administration, with a longer half-life in plasma and an easy passage to the brain. These are the reasons why Trofinetide is being used in clinical trials in human patients with RTT with significantly promising results [34]. Trofinetide is safe and well tolerated, and the highest dose used (70 mg/kg/day, twice a day, for 14 or 28 days) improved the main characteristics of this syndrome (communication and speech, behavior, respiratory abnormalities, hand stereotypies and muscle dysfunction) compared with placebo, despite the advanced age of the patients and the short time of administration of the peptide [34].…”

Section: Discussionmentioning

confidence: 99%

“…Another clinical trial, carried out in 56 adolescent and adult females with RTT, used a chemically modified form of the naturally formed N-terminal IGF-I tripeptide Gly-Pro-Glu (GPE), called Trofinetide, with significant promising results [34], but this peptide is not yet available for medical use, at least in Spain.…”

Section: Introductionmentioning

confidence: 99%

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

Devesa¹,

Devesa²,

Carrillo³

et al. 2018

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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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“…IGF1 treatment increased glutamatergic synapse number, thus rescuing the disease phenotype (de Souza et al, 2017;Tang et al, 2013). A phase 2 trial has recently been conducted using Trofinetide, a small molecule analog of IGF1 (Glaze et al, 2017). Treatment with Trofinetide resulted in an improvement in several outcome measures which represented clinically meaningful improvement in disease symptoms.…”

Section: Testing Candidate Drugsmentioning

confidence: 99%

Using stem cell–derived neurons in drug screening for neurological diseases

Little

Ketteler

Gissen

et al. 2019

Neurobiology of Aging

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Induced pluripotent stem cells (iPSCs) and their derivatives have become an important tool for researching disease mechanisms. It is hoped that they could be used to discover new therapies by providing the most reliable and relevant human in vitro disease models for drug discovery. This review will summarise recent efforts to use stem cell-derived neurons for drug screening. We also explain the current hurdles to using these cells for high throughput pharmaceutical screening and developments that may help overcome these hurdles. Finally, we critically discuss whether iPSC-derived neurons will come to fruition as a model that is regularly used to screen for drugs to treat neurological diseases.

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A Double-Blind, Randomized, Placebo-Controlled Clinical Study of Trofinetide in the Treatment of Rett Syndrome

Cited by 74 publications

References 17 publications

Metabolic Signatures Differentiate Rett Syndrome From Unaffected Siblings

Metabolic Signatures Differentiate Rett Syndrome From Unaffected Siblings

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

Using stem cell–derived neurons in drug screening for neurological diseases

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