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Characterization of Plasma Proteomic Profile in Fabry Disease: Potential gender- and clinical phenotype-specific Biomarkers

ABSTRACT: Fabry disease (FD) is a rare metabolic disorder of X-linked lysosomal storage caused by mutations of the GLA gene that induce a deficiency in the activity of the enzyme α-galactosidase A (α-GalA). This deficiency leads to the lysosomal accumulation of globotriaosylsphingosine (lyso-GB3), resulting in multisystem involvement. Clinical heterogeneity, frequent inconclusive results in biochemical and genetic tests, and the lack of compensation between these markers and clinical evolution often represent a significant challenge in early diagnosis and in the evolutionary prediction of the disease. For this reason, we propose as the study's main objective the identification of new biomarkers of FD that help to understand in depth the disease’s pathophysiology and biomarkers that help to predict the clinical phenotype of the disease. For this purpose, we compared the plasma from 50 patients with FD and 50 healthy controls, matched by sex and age, by a quantitative mass spectrometry study (SWATH-MS). This study has managed to identify more than 30 proteins significantly differentially expressed between patients with FD and healthy controls, also stratifying the results according to sex. Furthermore, the comparative analysis between the predominant clinical phenotypes identifies differential proteomic profiles between the clinical manifestations. These results will help to deepen and discuss the presence of potential biomarkers that will increase the pathophysiological knowledge of FD and the heterogeneity in the presentation of clinical manifestations.

INSTRUMENT(S): TripleTOF 6600

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Plasma

DISEASE(S): Fabry Disease

SUBMITTER: Susana Bravo

LAB HEAD: Susana Belén

PROVIDER: PXD045528 | Pride | 2024-04-23

REPOSITORIES: Pride

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Project description:TNF antagonists are routinely used in severe rheumatoid arthritis (RA) patients who failed conventional DMARD therapy. According to large clinical trials, the three available drugs (adalimumab, infliximab and etanercept) display similar effects in terms of efficacy, tolerability and side effects. These studies also indicate that about 25% of RA patients treated with TNF-antagonists do not display any significant clinical improvement. The aim of this study was to investigate global molecular patterns in synovial biopsies from RA patients obtained 12 weeks after initiation of adalimumab therapy. All patients had rheumatoid arthritis (RA), according to the American College of rheumatology criteria for the diagnosis of RA. They had active disease at the time of initiation of adalimumab therapy and were resistant to conventional therapy. They all had erosive changes imaged on conventional x-rays of the hands and/or feet. All patients were treated with disease-modifying antirheumatic drugs (DMARD’s), 23 with methotrexate (median dose 15 mg/week, range 7.5 – 20 mg/week), and 2 with leflunomide (20 mg/day); 18 of them were treated with low-dose steroids (prednisolone ≤ 7.5 mg/day). Six patients had been included in double-blind clinical trials before inclusion in the present study (1 in a Golimumab versus placebo trial, 3 in a MapKinase inhibitor versus placebo trial and 2 in a TACE-inhibitor versus placebo trial). These trials were stopped at least 3 months prior to initiation of TNF-blocking therapy. All drug dosages were stable from at least 3 months prior to initiation of TNF blocking therapy until completion of the study. No steroid injections were allowed during the duration of the study. Adalimumab therapy was initiated at a dosage of 40 mg subcutaneously every other week. Disease activity at baseline and 12 weeks after initiation of therapy (T12) was evaluated using DAS(28)-CRP (3- and 4-variables) scores, and response to therapy was assessed according to the EULAR response criteria that categorize patients in responders (good- or moderate-) and non- (or poor-) responders based on changes in DAS activity between T0 and T12 and absolute DAS values at T12. Synovial biopsies were obtained by needle-arthroscopy of knee of the patients at T12. The aim of the study was to compare gene expression profiles in synovial tissue of RA patients who responded versus not responded to adalimumab therapy.

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Characterization of Plasma Proteomic Profile in Fabry Disease: Potential gender- and clinical phenotype-specific Biomarkers

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