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D'Avanzo, Francesca (2013) Analysis of Hunter Syndrome by RNA-Sequencing. [Tesi di dottorato]

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Abstract (inglese)

Hunter Syndrome (Mucopolysaccharidosis type II, MPS II) is a rare inherited metabolic disease due to an extremely reduced or total absent activity of the lysosomal enzyme iduronate 2-sulfatase (IDS), involved in the degradation of the mucopolysaccharides heparan- and dermatan-sulphate. This causes a progressive pathologic accumulation of the two macromolecules within cell lysosomes and in the extracellular matrix of most tissues and organs, leading to their general malfunctioning and finally to death. In fact, due to the housekeeping nature of IDS, most of the organ systems are involved in the pathology, including the central nervous system in the severe forms of the disease.
MPS II belongs to the group of Mucopolysaccharidoses (MPSs), a cluster of pathologies characterized by accumulation of mucopolysaccahrides (or glycosaminoglycans, GAG). They, in turn, represent a subgroup of the wider class of the Lysosmal Storage Disorders (LSDs), about fifty pathological conditions characterized by the progressive endo- and extra-cellular overstorage of several types of undegraded macromolecules.
LSDs, for long time poorly considered by the medical-scientific community, have received in the past few years an increasing attention due to their elevated overall incidence, up to 1:1500-1:7000 live newborns, dependently on the population analyzed. Although the enzyme or protein defect underlying each of these pathologies is known, almost unknown remains the complexity of the biochemical pathways involved or altered in the lysosomal storage in general, or in specific type of storage. Studies conducted in the last decade have separately highlighted alterations of signalling proteins, intracellular calcium homeostasis, oxidative stress, autophagy, intracellular trafficking, lipid biosynthesis and iron metabolism. However, no systematic and complete studies have been so far conducted for the analysis of the whole pathologic scenario. This would help to acquire a general overview of the lysosomal storage and would also help in defining new, potential therapeutic targets and/or biomarkers useful in the diagnosis, prognosis, progression of LSDs as well as in the evaluation of efficacy of the therapeutic strategies applied. Moreover, since LSDs share several pathological signs and symptoms, it appears evident that a deep analysis of some of them could be of great help in the understanding of others.
For the first time, this project evaluated, by an high throughput technology, the whole transcriptome profile of LSD cells by comparing skin fibroblasts obtained from Hunter patients and healthy controls, thus allowing a deep analysis of MPS II pathogenesis. The study, conducted by total RNA sequencing, was performed by using the SOLiD technology. Results have shown alterations in: 1) basic cellular processes as cell cycle, apoptosis, intercellular communication; 2) metabolic processes as proteoglycan metabolism, synthesis of lipids, aminoacids and nucleotides; 3) response to stimuli as oxidative stress, insulin, cytokines; 4) alteration of the developmental processes.
From the therapeutic point of view, as for MPS II the major treatment strategy used in the last 5-6 years is represented by the Enzyme Replacement Therapy (ERT), consisting in the weekly systemic administration of the active form of the enzyme, which is missing in the patients. Clinical monitoring of the patients under treatment, organized since 2005 by Shire HGT, has shown, among other results, an important subjectivity in the efficacy of ERT, as expected for a pathology presenting several degrees of severity and a high number of different mutations. Despite this, ERT is administered to all patients following the same therapeutic protocol. Therefore, it becomes necessary to perform a deep clinical and molecular evaluation to identify potential candidate biomarkers of efficacy allowing an adequate follow-up of the patients under ERT; this would allow the set up of a personalized therapeutic protocol.
Starting from these considerations, in this project an in vitro evaluation of ERT has been performed in Hunter primary fibroblasts treated with the therapeutic IDS enzyme and collected 24 and 144 h post-treatment. Their transcriptional profile has been studied to characterize the early cellular response to the enzyme supply. Such analysis allowed to highlight 20 candidate biomarkers of therapeutic efficacy. Some of these have been afterwards evaluated by using Real Time PCR, in blood samples obtained from Hunter patients under ERT. Finally, a correlation analysis was performed between clinical parameter obtained by the follow-up of the Hunter population and the gene expression profile of each gene. Such analysis has shown a good correlation for 8 pairs of gene/parameter evaluated. In particular, correlations were found for hearing impairment, seizures, hepatomegaly, splenomegaly, and other clinical parameters, with at least one gene. The analysis of the other candidate genes isolated from transcriptome analysis might indentify other potential biomarkers

Abstract (italiano)

La Sindrome di Hunter (o Mucopolisaccaridosi di tipo II, MPS II) è una malattia metabolica ereditaria rara, causata da un’attività estremamente ridotta o del tutto assente dell’enzima lisosomiale iduronato 2-solfatasi (IDS), deputato alla degradazione dei mucopolisaccaridi eparan- e dermatan-solfato. Tale deficit determina un progressivo accumulo patologico delle due macromolecole sia nei lisosomi cellulari che nella matrice extracellulare di quasi tutti i tessuti ed organi, conducendo progressivamente ad un malfunzionamento generale e, infine, alla morte. Infatti, essendo l’IDS un enzima ubiquitario, quasi tutti i distretti risultano compromessi, compreso il sistema nervoso centrale nelle forme severe della malattia.
La MPS II appartiene al gruppo delle mucopolisaccaridosi (MPSs), un cluster di malattie caratterizzate proprio dall’accumulo di mucopolisaccaridi (o glicosaminoglicani, GAG. Esse rappresentano, a loro volta, un sottogruppo della più ampia classe delle malattie da accumulo lisososmiale (Lysosomal Storage Disorders, LSD), una cinquantina di patologie caratterizzate dall’accumulo endo- ed extra-cellulare di diversi tipi di macromolecole non degradate.
Le LSD, a lungo trascurate dalla comunità medico-scientifica, negli ultimi anni hanno ricevuto una maggiore attenzione a causa della loro elevata incidenza complessiva, fino a 1:1500–1:7000 nati vivi, anche dipendentemente dalla popolazione analizzata. Nonostante il difetto enzimatico o comunque proteico alla base di ciascuna di queste patologie sia ormai noto, per lo più sconosciuta rimane la complessità dei pathways biochimici che risultano coinvolti o alterati nell’accumulo lisosomiale in generale, o in specifici tipi di accumulo. Gli studi condotti nell’ultima decade hanno separatamente evidenziato alterazioni a carico di proteine di segnale, dell’omeostasi del calcio endocellulare, dello stress ossidativo, dell’autofagia, del trafficking intracellulare, della biosintesi dei lipidi e del metabolismo del ferro. Nessuno studio è stato, tuttavia, condotto in modo sistematico e completo per l’analisi dell’intero quadro patologico. Ciò aiuterebbe non solo ad acquisire una visione complessiva del problema dell’accumulo lisosomiale, ma anche alla messa in luce di nuovi, potenziali target terapeutici e/o di biomarcatori utilizzabili nella diagnosi delle patologie, nella definizione della loro prognosi e progressione, nella valutazione di efficacia terapeutica dei trattamenti applicati. Inoltre, poiché le LSD condividono numerosi segni e sintomi patologici, è evidente come lo studio approfondito di alcune potrebbe risultare di grande aiuto anche per la comprensione delle altre.
Per la prima volta questo progetto ha valutato con tecnologia high throughput l’intero trascrittoma di cellule LSD mediante comparazione di fibroblasti cutanei ottenuti da pazienti Hunter e da controlli sani, consentendo uno studio approfondito della patogenesi della MPS II. Lo studio, condotto mediante sequenziamento di tutto l’mRNA cellulare, è stato effettuato utilizzando la tecnologia SOLiD. I risultati hanno evidenziato alterazioni a livello di: 1) processi cellulari di base, quali il ciclo cellulare, l’apopotosi, la comunicazione intercellulare; 2) processi metabolici quali il metabolismo dei proteoglicani, la sintesi dei lipidi, degli aminoacidi e dei nucleotidi; 3) la risposta agli stimoli quali lo stress ossidativo, l’insulina, le citochine; 4) l’alterazione dei processi dello sviluppo.
Dal punto di vista del trattamento, nel caso della MPS II, valutata in questo progetto di studio, la terapia maggiormente applicata negli ultimi 5-6 anni è rappresentata dalla sostituzione enzimatica (Enzyme Replacement Therapy, ERT), che consiste nella somministrazione sistemica settimanale della forma attiva dell’enzima che è deficitario nei pazienti. Il monitoraggio clinico dei pazienti in trattamento, organizzato a partire dal 2005 dalla ditta che distribuisce il farmaco (Shire HGT) ha evidenziato, tra le altre cose, una importante soggettività nell’efficacia della terapia, come atteso per un trattamento effettuato per una patologia con diverse forme di severità, causata da un elevato numero di mutazioni diverse. Tuttavia l'ERT è di norma somministrato a tutti i pazienti con il medesimo protocollo. Da qui la necessità di effettuare uno studio approfondito sia clinico che molecolare allo scopo di individuare dei potenziali candidati a biomarcatori di efficacia che consentano un follow-up adeguato dei pazienti in ERT; ciò permetterebbe la messa a punto di un protocollo terapeutico personalizzato.
A partire da queste considerazioni, in questo progetto è stata effettuata una valutazione dell’ERT in vitro, in fibroblasti primari Hunter trattati con l’enzima IDS terapeutico e raccolti 24 e 144 ore dall’inizio del trattamento. Il loro profilo trascrizionale è stato studiato allo scopo di caratterizzare la risposta cellulare precoce alla somministrazione dell’enzima. Tale analisi ha consentito di evidenziare una ventina di geni candidati a marcatori di efficacia terapeutica. Alcuni di questi sono stati poi valutati, mediante Real Time PCR, in alcuni campioni ematici provenienti da una popolazione di soggetti Hunter in ERT. Infine, è stato effettuato uno studio di correlazione tra l’andamento osservato dei marcatori molecolari e l’andamento di alcuni parametri clinici, provenienti dal follow-up clinico della popolazione Hunter studiata. Tale analisi ha evidenziato una buona correlazione per 8 appaiamenti gene candidato/parametro clinico valutato; in particolare, correlazioni con almeno un gene sono state trovate per la sordità, le crisi epilettiche, l’epatomegalia, la splenomegalia e altri parametri clinici. E’ auspicabile che l’estensione di tale valutazione ai rimanenti geni candidati metta in luce altri potenziali candidati biomarcatori di efficacia terapeutica

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Tipo di EPrint:Tesi di dottorato
Relatore:Scarpa, Maurizio
Correlatore:Tomanin, Rosella
Dottorato (corsi e scuole):Ciclo 25 > Scuole 25 > MEDICINA DELLO SVILUPPO E SCIENZE DELLA PROGRAMMAZIONE > MALATTIE RARE, GENETICA, BIOLOGIA E BIOCHIMICA
Data di deposito della tesi:31 Gennaio 2013
Anno di Pubblicazione:31 Gennaio 2013
Parole chiave (italiano / inglese):Hunter syndrome; Mucopolysaccharidosis II; lysosomal storage disorders; RNA Sequencing
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/11 Biologia molecolare
Area 06 - Scienze mediche > MED/38 Pediatria generale e specialistica
Struttura di riferimento:Dipartimenti > Dipartimento di Salute della Donna e del Bambino
Codice ID:5865
Depositato il:14 Ott 2013 09:32
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