Illness Severity, Social and Cognitive Ability, and EEG Analysis of Ten Patients with Rett Syndrome Treated with Mecasermin (Recombinant Human IGF-1)

Pini, Giorgio; Congiu, L; Benincasa, Alberto; DiMarco, Pietro; Bigoni, Stefania; Dyer, Adam H.; Mortimer, Niall; Della-Chiesa, Andrea; O’Leary, Seán; McNamara, Rachel; Mitchell, Kevin J.; Gill, Michael; Tropea, Daniela

doi:10.1155/2016/5073078

Cited by 46 publications

(40 citation statements)

References 29 publications

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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%

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%

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

Devesa¹,

Devesa²,

Carrillo³

et al. 2018

Reports

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“…Pini and colleagues also showed significant decreases in mean amplitude difference of delta power between electrodes C4 and T4 in participants treated with a maximum open-label rhIGF-1 dose of 100 lg/kg for 20-24 weeks compared to untreated age-matched controls. 37 A follow-up study will focus on data analysis, including intermediate visits, to determine whether some rhIGF-1 effects are shorter term or could lead to carry forward.…”

Section: Discussionmentioning

confidence: 99%

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

O’Leary

Kaufmann

Barnes

et al. 2018

Ann Clin Transl Neurol

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ObjectiveTo measure the efficacy of mecasermin (recombinant human insulin‐like growth factor 1, rhIGF‐1), for treating symptoms of Rett syndrome (RTT) in a pediatric population using a double‐blind crossover study design.MethodsThirty girls with classic RTT in postregression stage were randomly assigned to placebo or rhIGF‐1 in treatment period 1 and crossed over to the opposite assignment for period 2 (both 20 weeks), separated by a 28‐week washout period. The primary endpoints were as follows: Anxiety Depression and Mood Scale (ADAMS) Social Avoidance subscale, Rett Syndrome Behaviour Questionnaire (RSBQ) Fear/Anxiety subscale, Parent Target Symptom Visual Analog Scale (PTSVAS) top three concerns, Clinical Global Impression (CGI), Parent Global Impression (PGI), and the Kerr severity scale. Cardiorespiratory‐ and electroencephalography (EEG)‐based biomarkers were also analyzed.ResultsThere were no significant differences between randomization groups. The majority of AEs were mild to moderate, although 12 episodes of serious AEs occurred. The Kerr severity scale, ADAMS Depressed Mood subscale, Visual Analog Scale Hyperventilation, and delta average power change scores significantly increased, implying worsening of symptoms. Electroencephalography (EEG) parameters also deteriorated. A secondary analysis of subjects who were not involved in a placebo recall confirmed most of these findings. However, it also revealed improvements on a measure of stereotypic behavior and another of social communication.InterpretationAs in the phase 1 trial, rhIGF‐1 was safe; however, the drug did not reveal significant improvement, and some parameters worsened.

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“…A variety of EEG parameters, frequently spike counts, have been used as endpoints since the pre- MECP2 era [25,83,122]. More recently, other biomarkers have been employed.…”

Section: Outcome Measures and Biomarkers In Rtt Trialsmentioning

confidence: 99%

Neurobiologically-based treatments in Rett syndrome: opportunities and challenges

Kaufmann

Stallworth

Everman

et al. 2016

Expert Opinion on Orphan Drugs

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Introduction: Rett syndrome (RTT) is an X-linked neurodevelopmental disorder that primarily affects females, typically resulting in a period of developmental regression in early childhood followed by stabilization and severe chronic cognitive, behavioral, and physical disability. No known treatment exists beyond symptomatic management, and while insights into the genetic cause, pathophysiology, neurobiology, and natural history of RTT have been gained, many challenges remain. Areas covered: Based on a comprehensive survey of the primary literature on RTT, this article describes and comments upon the general and unique features of the disorder, genetic and neurobiological bases of drug development, and the history of clinical trials in RTT, with an emphasis on drug trial design, outcome measures, and implementation. Expert opinion: Neurobiologically based drug trials are the ultimate goal in RTT, and due to the complexity and global nature of the disorder, drugs targeting both general mechanisms (e.g., growth factors) and specific systems (e.g., glutamate modulators) could be effective. Trial design should optimize data on safety and efficacy, but selection of outcome measures with adequate measurement properties, as well as innovative strategies, such as those enhancing synaptic plasticity and use of biomarkers, are essential for progress in RTT and other neurodevelopmental disorders.

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Illness Severity, Social and Cognitive Ability, and EEG Analysis of Ten Patients with Rett Syndrome Treated with Mecasermin (Recombinant Human IGF-1)

Cited by 46 publications

References 29 publications

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

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

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

Neurobiologically-based treatments in Rett syndrome: opportunities and challenges

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