Dataset Information

Safety of P28GST, a Protein Derived from a Schistosome Helminth Parasite, in Patients with Crohn's Disease: A Pilot Study (ACROHNEM).

ABSTRACT: Despite the development of novel therapies, inflammatory bowel diseases remain an innovative treatment challenge. Helminth therapy is a new promising approach, and a key issue is the identification of helminth-derived anti-inflammatory mediators. P28 glutathione-S-transferase (P28GST), a protein derived from schistosomes, a trematode parasitic helminth, was shown to reduce intestinal inflammation in experimental colitis by down-regulating the Th1/Th17 response. In this multicenter, open-label, pilot Phase 2a study, we evaluated the safety of P28GST administered to patients with mild Crohn's disease (CD). We enrolled 10 patients with a baseline Crohn's disease activity index (CDAI) value <220. Eight patients received two to three subcutaneous injections of recombinant P28GST with adjuvant. This three-month treatment was followed by a nine-month monitoring period. The primary endpoints were the monthly rate and seriousness of adverse events (AEs). Secondary endpoints were clinical recurrence, assessed with the CDAI as well as the levels of immunologic and inflammatory blood and tissue markers. The most common AEs were local or regional events at the injection site and gastrointestinal disorders. At three months after the first injection, CDAI scores and blood calprotectin levels decreased in parallel. These results indicate that P28GST showed promise as a safe and new therapeutic option for treating CD.

SUBMITTER: Capron M

PROVIDER: S-EPMC7019330 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Safety of P28GST, a Protein Derived from a Schistosome Helminth Parasite, in Patients with Crohn's Disease: A Pilot Study (ACROHNEM).

Capron Monique M Béghin Laurent L Leclercq Céline C Labreuche Julien J Dendooven Arnaud A Standaert Annie A Delbeke Marie M Porcherie Adeline A Nachury Maria M Boruchowicz Arnaud A Dupas Jean-Louis JL Fumery Mathurin M Paupard Thierry T Catteau Sylviane S Deplanque Dominique D Colombel Jean-Frederic JF Desreumaux Pierre P

Journal of clinical medicine 20191224 1

Despite the development of novel therapies, inflammatory bowel diseases remain an innovative treatment challenge. Helminth therapy is a new promising approach, and a key issue is the identification of helminth-derived anti-inflammatory mediators. P28 glutathione-S-transferase (P28GST), a protein derived from schistosomes, a trematode parasitic helminth, was shown to reduce intestinal inflammation in experimental colitis by down-regulating the Th1/Th17 response. In this multicenter, open-label, p ...[more]

PMID: 31878146

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Project description:Schistosomiasis remains an important parasitic disease and a major economic problem in many countries. The Schistosoma mansoni genome and predicted proteome sequences were recently published providing the opportunity to identify new drug candidates. Eukaryotic protein kinases (ePKs) play a central role in mediating signal transduction through complex networks and are considered druggable targets from the medical and chemical viewpoints. Our work aimed at analyzing the S. mansoni predicted proteome in order to identify and classify all ePKs of this parasite through combined computational approaches. Functional annotation was performed mainly to yield insights into the parasite signaling processes relevant to its complex lifestyle and to select some ePKs as potential drug targets.We have identified 252 ePKs, which corresponds to 1.9% of the S. mansoni predicted proteome, through sequence similarity searches using HMMs (Hidden Markov Models). Amino acid sequences corresponding to the conserved catalytic domain of ePKs were aligned by MAFFT and further used in distance-based phylogenetic analysis as implemented in PHYLIP. Our analysis also included the ePK homologs from six other eukaryotes. The results show that S. mansoni has proteins in all ePK groups. Most of them are clearly clustered with known ePKs in other eukaryotes according to the phylogenetic analysis. None of the ePKs are exclusively found in S. mansoni or belong to an expanded family in this parasite. Only 16 S. mansoni ePKs were experimentally studied, 12 proteins are predicted to be catalytically inactive and approximately 2% of the parasite ePKs remain unclassified. Some proteins were mentioned as good target for drug development since they have a predicted essential function for the parasite.Our approach has improved the functional annotation of 40% of S. mansoni ePKs through combined similarity and phylogenetic-based approaches. As we continue this work, we will highlight the biochemical and physiological adaptations of S. mansoni in response to diverse environments during the parasite development, vector interaction, and host infection.

Project description:BackgroundAn accurate understanding of the geographical distributions of both soil-transmitted helminths (STHs; Ascaris lumbricoides, Trichuris trichiura, and the hookworms Necator americanus and Ancylostoma duodenale) and schistosomes (SCH; Schistosoma mansoni and S. haematobium) is pivotal to be able to effectively design and implement mass drug administration (MDA) programmes. The objective of this study was to provide up-to-date data on the distribution of both STH and SCH in Ethiopia to inform the design of the national control program and to be able to efficiently achieve the 75% MDA coverage target set by the WHO.MethodsBetween 2013 and 2015, we assessed the distributions of STH and SCH infections in a nationwide survey covering 153,238 school-aged children (aged 5-15 years), from 625 woredas (districts), representing all nine Regional States and two City Administrations of Ethiopia. Nationwide disease maps were developed at the woreda level to enable recommendations on the design of the national MDA programme.ResultsThe prevalence of any STH infection across the study population was 21.7%, with A. lumbricoides (12.8%) being the most prevalent STH, followed by hookworms (7.6%) and T. trichiura (5.9%). The prevalence for any SCH was 4.0% in areas where both SCH species were evaluated. Schistosoma mansoni was the most prevalent SCH (3.5 vs 0.3%). STHs were more prevalent in southwest Ethiopia, whereas SCH was found mostly in the west and northeast of the country. The prevalence of moderate-to-heavy intensity infections was 2.0% for STHs and 1.6% for SCH. For STH, a total of 251 woredas were classified as moderately (n = 178) or highly endemic (n = 73), and therefore qualify for an annual and biannual MDA program, respectively. For SCH, 67 woredas were classified as endemic and 8 as highly endemic, and hence they require every two years and annual MDA programme, respectively.ConclusionsThe results confirm that Ethiopia is endemic for both STHs and SCH, posing a significant public health problem. Following the WHO recommendations on mass drug administration, 18 and 14 million school-aged children are in need of MDA for STHs and SCH, respectively, based on the number of SACs that live on the eligible geographical areas.

Dataset Information

Safety of P28GST, a Protein Derived from a Schistosome Helminth Parasite, in Patients with Crohn's Disease: A Pilot Study (ACROHNEM).

Publications

Safety of P28GST, a Protein Derived from a Schistosome Helminth Parasite, in Patients with Crohn's Disease: A Pilot Study (ACROHNEM).

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