5B). and Droxinostat late ERT outcomes. MPS I mice were treated with 1.2mg/kg of laronidase intravenously every two weeks for the indicated periods.(DOCX) pone.0117271.s003.docx (18K) GUID:?25AF2FDA-2B75-444E-9BC1-50881EFCC86E Data Availability StatementAll relevant data are within the paper and its Supporting Information files. Abstract Mucopolysaccharidosis type I (MPS I) is usually a progressive disorder caused by deficiency of -L-iduronidase (IDUA), which leads to storage of heparan and dermatan sulphate. It is Droxinostat suggested that early enzyme replacement therapy (ERT) leads to better outcomes, although many patients are diagnosed late and dont receive immediate treatment. This study aims to evaluate the effects of late onset ERT in a MPS I murine model. MPS I mice received treatment from 6 to 8 8 months of age (ERT 6C8mo) with 1.2mg laronidase/kg every 2 weeks and were compared to 8 months-old wild-type (Normal) and untreated animals (MPS I). ERT was effective in reducing urinary and visceral GAG to normal levels. Heart GAG levels and left ventricular (LV) shortening fraction were normalized but cardiac function was not completely improved. While no significant improvements were found on aortic wall width, treatment was able to significantly reduce heart valves thickening. High variability was found in behavior tests, with treated animals presenting intermediate results between normal and affected mice, without correlation with cerebral cortex GAG levels. Cathepsin D activity BTD in cerebral cortex also did not correlate with behavior heterogeneity. All treated animals developed anti-laronidase antibodies but no correlation was found with any parameters analyzed. However, intermediary results from locomotion parameters analyzed are in accordance with intermediary levels of heart function, cathepsin D, activated glia and reduction of TNF- expression in the cerebral cortex. In conclusion, even if started late, ERT can have beneficial effects on many aspects of the disease and should be considered whenever possible. Introduction Mucopolysaccharidosis type I (MPS I) is usually a rare autosomal recessive disorder caused by deficiency of lysosomal hydrolase alpha-L-iduronidase (IDUA, EC 3.2.1.76), involved in the degradation of glycosaminoglycans (GAG) heparan sulphate (HS) and dermatan sulphate (DS). Its deficiency leads to progressive accumulation of undegraded or partially degraded substrate within lysosomes, with subsequent multiorgan dysfunction and damage [1]. There is a considerable clinical variability in the age of onset and rate of disease progression [2]. However, three classical phenotypes are Droxinostat usually considered: severe Hurler (OMIM #67014), intermediary Hurler Scheie (OMIM #607015) and the attenuated Scheie syndrome (OMIM # 67016) [3]. The Hurler form corresponds to 50C80% of known cases [2]. It shares many systemic manifestations that are found in the attenuated forms, such as growth retardation hepatosplenomegaly, joint stiffness, heart disease and respiratory insufficiency. However, it is rapidly progressive, presents progressive neurodegeneration and death usually occurs during the first decade of life [1,4,5]. Two treatment options are available for MPS I: hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT). HSCT is the treatment Droxinostat of choice for Hurler patients and when performed before cognitive impairment begins, it can significantly preserve intellectual development [2,6,7]. ERT with laronidase (Aldurazyme, Genzyme Corporation) has been approved for human Droxinostat use since 2003/2005 (USA and Europe/Brazil). It is indicated for treatment of the non-neurological symptoms of MPS I [2,6,8C10]. The most constant results from laronidase clinical trials are decrease of urinary GAG excretion, and reduction of hepatosplenomegaly and apnea/hypopnea episodes, regardless of the patients clinical form. Moreover, improvements in 6-Minute Walk Test [4,11], increase in height and weight growth rate [12], increase in shoulder and/or elbow range of flexion [4,12], and stabilization or improvement in forced vital capacity [4, 11] were also observed. There is a consensus in the literature that, being a progressive disorder, early treatment leads to a better outcome of MPS I patients, reducing or avoiding irreversible harm [2,4,6,9,13C16]. Nevertheless, world-wide many patients are diagnosed in life and don’t receive immediate treatment later on. Therefore, the purpose of this research was to judge the consequences of ERT when began later in existence for the reversibility of founded disease manifestations inside a murine style of MPS I. Strategies and Materials Experimental Organizations em Idua /em -/- mice.