Antioxidant Therapy With N-acetylcysteine for Children With Neurofibromatosis Type 1

Overview

Children with neurofibromatosis type 1 (NF1) commonly suffer from the effects of cognitive, behavioral, and motor impairments. At present, there is no specific treatment for this NF1 complication. In this project, the investigators will assess the safety and clinical benefit of N-acetylcysteine (NAC) as a pharmacological intervention in children with NF1. This drug choice is based on the recent findings from mouse models to study the central nervous system manifestations of NF1 at Cincinnati Children's Hospital Medical Center (CCHMC). These findings revealed a role for myelin-forming oligodendrocytes in the control of nitric oxide synthases (NOS) and their product, nitric oxide (NO), in maintenance of brain structure and function, including regulation of behavior and motor control. Treating these mice with NAC corrected cellular and behavioral abnormalities. This data from animal models of NF1 along with uncontrolled clinical observations in children with NF1 suggest that the antioxidant compound, NAC, may reduce these impairments. Therefore, the investigators propose performing a single center double-blind placebo controlled, prospective, Phase II study to explore safety, tolerability, and efficacy of NAC on motor behavior and/or learning in children with NF1 aged 8 through 16 years old. Participants will be carefully monitored for side effects. Primary and secondary outcome measures will be administered at baseline, follow-up, and post-treatment.

This is a phase II clinical trial with the goal to explore safety, tolerability, and efficacy of NAC on motor behavior in children with NF1 aged 8 through 16 years old. The investigators hypothesize that NAC therapy will improve motor function evaluated by the Physical and Neurological Examination for Soft Signs (PANESS) scale. This is based on studies demonstrating that NAC significantly improved impairments in the animal model of NF1. The investigators will also analyze NAC effects on attention deficit and impulsivity in children with NF1. This study will also help develop novel predictive biomarkers of response to neurocognitive therapies in patients with NF1 which are needed to evaluate treatment outcomes. The investigators will gain information in children with NF1 about possible clinical benefit of anti-oxidant treatment and to develop and evaluate quantitative brain-based and blood biomarkers relating to presence of NF1, symptom severity, and response to antioxidant therapy. Clinically, 50 percent of children with NF1 are underperforming or failing at school. This frequently leads to decreased educational attainment and fewer opportunities as adults. An important first step was preliminary work using the PANESS scale and Transcranial Magnetic Stimulation (TMS)-evoked Short Interval Cortical Inhibition (SICI) in children with NF1. The investigators propose to develop and extend understanding of NF1-related motor and learning behavior in response to antioxidant therapy with NAC. The purpose of the present study is to 1) evaluate tolerability, safety, and clinical benefit of NAC in this double-blind placebo controlled study using the motor function scale (PANESS); 2) to evaluate the effects of NAC on measures of NF1 neurocognitive symptomatology (ADHD/impulsive symptoms, executive function, working memory); and 3) to determine if TMS measurement (SICI) in children with NF1 will correlate with clinical effects of NAC treatment and evaluate utility of advanced brain imaging and spectroscopy measurements in children with NF1, and effects of NAC therapy. The investigators propose to study 58 children with NF1, ages 8-16 years, at baseline and after completion of 8 weeks of treatment with NAC, followed by a washout period of 4 weeks. The investigators believe this work has the potential to lay groundwork for future use of relevant biomarkers for treatment and outcomes research for NF1 as well as other biologically similar conditions, collectively designated the "RASopathies" (due to involvement of a protein first discovered in rat sarcomas (RAS), but not technically an acronym). RAS is family of proteins. This work may ultimately guide development of more effective treatments based on disease pathophysiology. STUDY OBJECTIVE: NAC Trial at Cincinnati Children's Hospital Medical Center (CCHMC) The investigators propose performing a single center randomized double-blind placebo controlled, prospective, Phase II study to explore safety, tolerability, and efficacy of NAC on motor behavior in children with NF1 aged 8 through 16 years old. Hypothesis: The investigators hypothesize that NAC therapy will improve motor function evaluated by the PANESS scale. This is based on studies demonstrating that NAC significantly improved impairments in the animal model of NF1. The investigators will also analyze NAC effects on attention deficit and impulsivity in children with NF1. Specific Aim: The primary outcome of this study is to characterize the effects of NAC treatment on motor function in children and adolescents with NF1 using the PANESS. The investigators hypothesize that motor function scores rated with the PANESS scale will improve after treatment with NAC. Secondary Aims: 1. To evaluate the effects of NAC on measures of NF1 neurocognitive symptomatology (ADHD/impulsive symptoms, executive function, working memory), the investigators will use Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) committee recommended assessments tools ADHD rating scale (ADHD-RS), Behavioral Rating Inventory of Executive Function second edition (BRIEF-2), Wechsler Intelligence Scale for Children, Fifth Edition (WISC-V) subtests, and Test of Variables of Attention (TOVA). 2. To determine if TMS measurement (SICI) in children with NF1 will correlate with clinical effects of NAC treatment. 3. To quantify microstructural properties of brain tissue based on water diffusion, glutathione (GSH) concentrations, and gamma-aminobutyric acid (GABA) concentration using brain magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) in children with NF1. This will allow for regional correlation between imaging, spectroscopy and neuropsychometric outcomes. The investigators will also determine if these magnetic resonance based outcomes correlate with clinical effects of NAC treatment. 4. To evaluate safety and tolerability of NAC in children with NF1.