Fourth our findings could impact the most widely used

Fourth, our findings could impact the most widely used pharmacokinetic models of maturation as commonly recommended by regulatory authorities (European Medicines Agency, 2007). Several methods are used to examine the effect of maturation on pharmacokinetic parameters, with the two most common being allometric scaling based on the ¾ fractal geometry law and physiologically-based pharmacokinetic modeling (Hope et al., 2007). These methods use specific drug clearance rates derived in adults to estimate drug clearances in children, with ontogeny effects scaled based on dry tissue weight of the organ clearing the drug. The central assumption is that xenobiotic metabolism enzyme reaction rates are the same between adults and children, and that what varies is the quantity of the saha inhibitor Supplier proportional to organ weight and size. It is recognized in some cases, as for example sirolimus, that there could be different fetal isoform enzymes that get replaced by others after birth, thereby leading to altered clearance (Emoto et al., 2015); nevertheless the reaction kinetic constants of each of the different isoforms are assumed fixed. Moreover, the development of clearance with maturation is described by a single mathematical function. Our data suggests that non-linear functions and analyses, with no a priori assumptions, could be more accurate.
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Author Contributions
Conception and design: T. Gumbo, B.M., J. Pasipanodya, P. Jeena, W. Bishai.
Development of methodology: Z. Rogers, H. Hiruy, J. G. Pasipanodya, J. Adamson, P. Jeena, W. Bishai, T. Gumbo
Acquisition of data: Z. Rogers, H. Hiruy, C. Mbowane, J. Adamson, L. Ngotho, F. Karim, P. Jeena, W. Bishai
Analysis and interpretation of data: Z. Rogers, J. Pasipanodya, P. Jeena, W. Bishai, T. Gumbo
Writing, review and/or revision of the manuscript: Z. Rogers, H. Hiruy, J. Pasipanodya, P. Jeena, W. Bishai, T. Gumbo
Study supervision: P. Jeena, W. Bishai

Conflict of Interest

The support of the Howard Hughes Medical Institute and NIH grants AI37856, AI36973, 97138, R56AI111985 is gratefully acknowledged.

Gaucher disease (GD), a common lysosomal storage disease (LSD), is caused by mutations in GBA1 with resultant defective glucocerebrosidase (GCase) function and the consequent accumulation of its substrate glucosylceramide (β-GlcCer) in macrophages and other cell types (Platt, 2014). There are three types of GD based on its neurological complications (type 1 is non-neuropathic, type 2 is acute neuropathic and type 3 is chronic neuropathic). Extra-neurologic systematic features include hepatosplenomegaly, pancytopenia, and osteoporosis as a consequence of Gaucher cell infiltration in target organs. GD has been regarded as wholly attributable to GBA1 mutations. However, clinical manifestations may have huge variations among patients carrying the same GBA1 mutations, ranging from very early disease onset to very mild clinical presentations (Biegstraaten et al., 2011; Elstein et al., 2010). It has therefore been speculated that additional disease modifiers exist in GD patients.
Progranulin (PGRN), also known as granulin epithelin precursor (GEP), is recognized for its roles in a variety of physiologic and disease processes, including immunomodulation (Jian et al., 2013a), cell growth, wound healing (He and Bateman, 2003), host defense (Park et al., 2011) and inflammation (Park et al., 2011; Tang et al., 2011; He et al., 2003). PGRN acts as an anti-inflammation molecule by direct binding to TNF receptors (Tang et al., 2011; Jian et al., 2013b). PGRN also functions as an important neurotrophic factor and mutations of the GRN gene (coding PGRN) are directly linked to frontotemporal dementia (Baker et al., 2006; Cruts et al., 2006), as well as considered contributory to other neurological diseases (Mateo et al., 2013; Perry et al., 2013). PGRN has been shown to play an important role in lysosomes, and homozygous mutation of the GRN gene results in neuronal ceroid lipofuscinosis (Smith et al., 2012; Gotzl et al., 2014). In this study we reported PGRN as a novel disease modifier in GD. In addition, recombinant PGRN is therapeutic against GD in various preclinical models.