A major challenge facing the development of therapeutic treatments of many neurological and psychiatric disorders is the general lack of robust biomarkers and outcome measures that are suitable for assessing treatment efficacy across the entire patient population and throughout the patient's lifespan. Patient-based outcome measures commonly used for this purpose, such as rating scales, are far from ideal because they often rely on subjective and imprecise assessments of symptoms with mixed etiology and require considerable administrative and respondent (patient/medical proxy) cooperation. Clinical assessments of symptoms and signs have some of the same shortcomings, with the additional limitation of perhaps not being the most representative sampling of the phenomenon under study. In recognition of this significant and neglected need in the field, the NICHD and NIMH of the National Institutes of Health have issued a funding opportunity announcement PAR-13-213: Outcome Measures for Use in Treatment Trials for Individuals with Intellectual and Developmental Disabilities to encourage R01 grant applications that propose to develop, validate, and/or calibrate informative outcome measures that are essential for therapy and pharmacological treatment development for these patient populations. Among the spectrum of diseases causing intellectual and developmental disabilities is Rett syndrome (RTT), a severe X-linked neurodevelopmental disorder that mainly affects females and is associated with mutations in MECP2, the gene encoding methyl CpG-binding protein 2. In a recent phase 1 trial of Insulin-like Growth Factor 1 (IGF-1 or mecasermin) in RTT, we demonstrated an improvement in apnea using automated cardiorespiratory measures. Such breathing abnormalities are a common and impairing aspect of the RTT phenotype. The present R03 small research grant application intends to further refine the abovementioned apnea index, by providing separate automated measures of central apnea and pathologic breathholding through analyses of data obtained in the completed phase 1 and ongoing phase 2 IGF-1 trials. Towards this goal, a multidisciplinary consortium comprising a respiratory neurobiologist (Dr. Poon, Co-PI) and a neurologist specialized in neurodevelopmental disorders (Dr. Kaufmann, PI) with a unique set of expertise has been established in order to capitalize on this groundbreaking opportunity emergent from the original studies.
Our specific aim i s to perform de novo analysis of the data from our phase 1/phase 2 IGF-1 trials in order to select and refine an optimal apnea index as a biomarker-based outcome measure for IGF-1 treatment of RTT. Our recently reported data support our postulate that these novel breathing measures will allow better assessments of the efficacy of IGF-1 and other treatments of RTT, as well as lay the foundation for developing novel biomarker type outcome measures in neurodevelopmental disorders. The results of this pilot study will provide valuable preliminary data necessary for the design of a ful- scale clinical trial in the future under funding opportunities specifically for this purpose, such s PAR-13-213.

Public Health Relevance

Rett syndrome, a neurodevelopmental disorder, is the second most common cause of severe intellectual disability in females after Down syndrome. Affected individuals suffer expressive language, purposeful hand skills, gait impairment, stereotypic hand movements, growth retardation, seizures, behavioral abnormalities, and life-threatening breathing disturbances. Effective treatment of the disease with promising new drugs such as mecasermin (IGF1) requires the development of suitable biomarkers of the response to treatment. In this project, we will develop one such biomarker for breathing abnormalities, a common and diabling problem in Rett syndrome. 27

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Small Research Grants (R03)
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Pediatrics Subcommittee (CHHD)
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Kau, Alice S
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Children's Hospital Boston
United States
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O'Leary, Heather M; Kaufmann, Walter E; Barnes, Katherine V et al. (2018) Placebo-controlled crossover assessment of mecasermin for the treatment of Rett syndrome. Ann Clin Transl Neurol 5:323-332