Mucopolysaccharidosis type I (MPS-I) is a lysosomal storage disorder due to deficiency in the alpha-L-iduronidase enzyme, resulting in the progressive accumulation of glycosaminoglycans (GAGs) in multiple organs and the consequent multiorgan dysfunction. Hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT) are the currently available therapies for MPS-I patients. Despite their effectiveness in correcting most clinical manifestations, muscoloskeletal abnormalities and neurocognitive defects still impact quality of life of treated patients. It is widely accepted that an early intervention may be crucial to obtain a better outcome. On the basis of these observations, we tested the therapeutic efficacy of HSCT and ERT, alone or in combination, administered at birth, in a MPS-I mouse model. We demonstrated that all three treatments were able to prevent biochemical and pathological manifestations of the disease in visceral organs, and, in particular, the combination therapy had a better outcome in difficult-to-treat organs, such as kidney and heart. Of note, transplant procedure can halt the production of antibodies specific for the recombinant enzyme that could reduce ERT efficacy. Regarding the severe skeletal disease, we observed a differential effect in reduction of bone disease, with a significant better correction in transplanted mice, in the presence of ERT or not. Otherwise in the brain, all the treatments provided a moderate decrease of inflammation without an evident metabolic correction. Our findings demonstrate that most manifestations of MPS-I can be prevented by a neonatal treatment based on a combination of HSCT and ERT, promoting the idea of an early intervention supported by the development of newborn screening programs.

La mucopolisaccaridosi di tipo I (MPS-I) è una malattia da accumulo lisosomiale, dovuta alla carenza dell'enzima alfa-L-iduronidasi, determinando il progressivo accumulo di glicosaminoglicani (GAGs) negli organi. Il trapianto di cellule staminali ematopoietiche (HSCT) e la terapia di sostituzione enzimatica (ERT) sono le terapie attualmente disponibili per i pazienti affetti da MPS-I. Nonostante la loro efficacia nel correggere la maggior parte delle manifestazioni cliniche, le alterazioni muscolo-scheletriche e i difetti neurocognitivi influenzano ancora la qualità della vita dei pazienti anche dopo la terapia. Oggigiorno è ampiamente riconosciuto che un intervento precoce è di cruciale importanza per ottenere un migliore outcome clinico. Sulla base di queste osservazioni abbiamo testato l'efficacia terapeutica di HSCT e ERT, da soli o in combinazione, somministrati alla nascita, in un modello murino di MPS-I. Abbiamo dimostrato che tutti e tre i trattamenti sono in grado migliorare i parametri biochimici, ripristinando l’attività enzimatica e riducendo l’accumulo dei GAGs negli organi e nel plasma; in particolare, la terapia combinata ha dimostrato una maggiore efficacia negli organi più difficili da correggere, come i reni e il cuore. Abbiamo osservato solamente una moderata riduzione dell’infiammazione, senza una evidente correzione metabolica nel cervello. Per quanto riguarda invece il fenotipo scheletrico abbiamo riscontrato un effetto differenziale nella riduzione della patologia ossea, con una migliore correzione nei topi trapiantati. I nostri risultati dimostrano che la maggior parte delle manifestazioni patologiche possono essere prevenute, agendo in epoca neonatale, con un trattamento basato sulla combinazione di HSCT e ERT, promuovendo l'idea di un intervento precoce supportato dallo sviluppo di programmi di screening neonatali.

(2019). Neonatal combination therapy approaches, based on hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT), in a mouse model of Mucopolysaccharidosis type I (MPS-I). (Tesi di dottorato, Università degli Studi di Milano-Bicocca, 2019).

Neonatal combination therapy approaches, based on hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT), in a mouse model of Mucopolysaccharidosis type I (MPS-I)

SANTI, LUDOVICA
2019

Abstract

Mucopolysaccharidosis type I (MPS-I) is a lysosomal storage disorder due to deficiency in the alpha-L-iduronidase enzyme, resulting in the progressive accumulation of glycosaminoglycans (GAGs) in multiple organs and the consequent multiorgan dysfunction. Hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT) are the currently available therapies for MPS-I patients. Despite their effectiveness in correcting most clinical manifestations, muscoloskeletal abnormalities and neurocognitive defects still impact quality of life of treated patients. It is widely accepted that an early intervention may be crucial to obtain a better outcome. On the basis of these observations, we tested the therapeutic efficacy of HSCT and ERT, alone or in combination, administered at birth, in a MPS-I mouse model. We demonstrated that all three treatments were able to prevent biochemical and pathological manifestations of the disease in visceral organs, and, in particular, the combination therapy had a better outcome in difficult-to-treat organs, such as kidney and heart. Of note, transplant procedure can halt the production of antibodies specific for the recombinant enzyme that could reduce ERT efficacy. Regarding the severe skeletal disease, we observed a differential effect in reduction of bone disease, with a significant better correction in transplanted mice, in the presence of ERT or not. Otherwise in the brain, all the treatments provided a moderate decrease of inflammation without an evident metabolic correction. Our findings demonstrate that most manifestations of MPS-I can be prevented by a neonatal treatment based on a combination of HSCT and ERT, promoting the idea of an early intervention supported by the development of newborn screening programs.
SERAFINI, MARTA
MPS-I; Trapianto; Neonatale; ERT; GAGs
MPS-I; Transplantation; Neonatal; ERT; GAGs
MED/38 - PEDIATRIA GENERALE E SPECIALISTICA
English
9-apr-2019
MEDICINA TRASLAZIONALE E MOLECOLARE - DIMET - 76R
31
2017/2018
open
(2019). Neonatal combination therapy approaches, based on hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT), in a mouse model of Mucopolysaccharidosis type I (MPS-I). (Tesi di dottorato, Università degli Studi di Milano-Bicocca, 2019).
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/241341
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