Identification of Repurpose Drugs by Computational Analysis of Disease-Gene-Drug Associations.

Repurposing of marketed drugs to find new indications has become an alternative to circumvent the risk of traditional drug development by its productivity quality. Despite many approaches, computational analysis has great potential to fuel the development of all-rounder drugs to find new classes of medicine for neglected and rare disease. The genes that can explain variations in drug response associated to disease are more important and significant in drug therapeutics necessitate elucidating the relationships of a gene, drug, and disease. The proposed computational analysis facilitates the discovery of knowledge on both target and disease-based relationships from large sources of biomedical literature spread over different platforms. It uses the utility of text mining for automatic extraction of valuable aggregated biomedical entities (disease, gene, and drug) from PubMed to serves as an input to the analysis of association prediction. The top-ranked associations considered for identification of repurposing drugs and also the hidden associations identified using concurrence principle to extrapolate the new relationships. Such findings are reported as novel and contribute to the knowledge base for pharmacogenomics, would immensely support the discovery and progress of novel therapeutic pathways and patient segment biomarkers.

Chemogenomics and bioinformatics approaches for prioritizing kinases as drug targets for neglected tropical diseases.

Neglected tropical diseases (NTDs) are a group of twenty-one diseases classified by the World Health Organization that prevail in regions with tropical and subtropical climate and affect more than one billion people. There is an urgent need to develop new and safer drugs for these diseases. Protein kinases are a potential class of targets for developing new drugs against NTDs, since they play crucial role in many biological processes, such as signaling pathways, regulating cellular communication, division, metabolism and death. Bioinformatics is a field that aims to organize large amounts of biological data as well as develop and use tools for understanding and analyze them in order to produce meaningful information in a biological manner. In combination with chemogenomics, which analyzes chemical-biological interactions to screen ligands against selected targets families, these approaches can be used to stablish a rational strategy for prioritizing new drug targets for NTDs. Here, we describe how bioinformatics and chemogenomics tools can help to identify protein kinases and their potential inhibitors for the development of new drugs for NTDs. We present a review of bioinformatics tools and techniques that can be used to define an organisms kinome for drug prioritization, drug and target repurposing, multi-quinase inhibition approachs and selectivity profiling. We also present some successful examples of the application of such approaches in recent case studies.

Yeast-based high-throughput screens for discovery of kinase inhibitors for neglected diseases.

The discovery and development of a new drug is a complex, time consuming and costly process that typically takes over 10 years and costs around 1 billion dollars from bench to market. This scenario makes the discovery of novel drugs targeting neglected tropical diseases (NTDs), which afflict in particular people in low-income countries, prohibitive. Despite the intensive use of High-Throughput Screening (HTS) in the past decades, the speed with which new drugs come to the market has remained constant, generating doubts about the efficacy of this approach. Here we review a few of the yeast-based high-throughput approaches that can work synergistically with parasite-based, in vitro, or in silico methods to identify and optimize novel antiparasitic compounds. These yeast-based methods range from HTP screens to identify novel hits against promising parasite kinase targets to the identification of potential antiparasitic kinase inhibitors extracted from databases of yeast chemical genetic screens.

Polymorphism in the catalytic subunit of the PI3Kγ gene is associated with Trypanosoma cruzi-induced chronic chagasic cardiomyopathy.

Chagas disease is caused by the protozoan parasite Trypanosoma cruzi. During the chronic phase of disease, while most infected people do not present symptoms, characterizing the asymptomatic form, some patients develop the cardiac form or chronic chagasic cardiomyopathy, which is considered the most severe manifestation of this disease. Considering that the activation of the PI3Kγ signaling pathway is essential for an efficient immune response against T. cruzi infection, we evaluated the PIK3CG C > T (rs1129293) polymorphism in exon 3 of this gene, which encodes the catalytic subunit of PI3Kγ. The PIK3CG CT and TT genotypes were found to be associated with an increased risk of developing the cardiac form of the disease rather than the asymptomatic or digestive forms. In conclusion, the presence of the T allele at single or double doses may differentiate the cardiac from other clinical manifestations of Chagas disease. This finding should help in further studies to evaluate the mechanisms underlying the differential association of PIK3CG in Chagas disease.

Neglected Tropical Diseases: The Potential Application of microRNAs for Monitoring NTDs in the Real World.

Neglected Tropical Diseases (NTDs) are a common health problem and require an efficient campaign to be eradicated from tropical countries. Almost a million people die of NTDs every year in the world, and almost forty percent of the patients are under 20 years. Mass Drug Administration (MDA) is an effective tool for eradication of this health condition. However, a monitoring system is required to evaluate treatment-response and early detection of the re-emerging NTD. The relevance of current tests depends on good quality of the specimen. Thus, new molecular methods with high sensitivity and specificity are required. In this review, we focus on microRNAs (miRNAs) as biomarkers of NTDs through a narrative review on human research. We searched for reliable search engines using a systematical literature review algorithm and included studies that fit the criterion. Five NTDs (lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminthiases, and trachoma) were set as our target diseases. Later on, the data were extracted and classified as monitoring response and early detection. Four miRNAs were studied in filariasis as a monitoring response. There were 12 miRNAs related to onchocerciasis infection, and 6 miRNAs with schistosomiasis infection. Six miRNAs showed a link to soil-transmitted helminths. Only 3 miRNAs correlated with trachoma infection. In conclusion, circulating miR is a less invasive and promising approach to evaluate NTDs. Further field study may translate those candidate miRs to clinical application of the prevention and control of NTDs.

Association between IL1 gene polymorphism and human African trypanosomiasis in populations of sleeping sickness foci of southern Cameroon.

BACKGROUND: Human African Trypanosomiasis (HAT) is a neglected tropical disease caused by infections due to Trypanosoma brucei subspecies. In addition to the well-established environmental and behavioural risks of becoming infected, there is evidence for a genetic component to the response to trypanosome infection. We undertook a candidate gene case-control study to investigate genetic associations further. METHODOLOGY: We genotyped one polymorphism in each of seven genes (IL1A, IL1RN, IL4RN, IL6, HP, HPR, and HLA-G) in 73 cases and 250 controls collected from 19 ethno-linguistic subgroups stratified into three major ethno-linguistic groups, 2 pooled ethno-linguistic groups and 11 ethno-linguistic subgroups from three Cameroonian HAT foci. The seven polymorphic loci tested consisted of three SNPs, three variable numbers of tandem repeat (VNTR) and one INDEL. RESULTS: We found that the genotype (TT) and minor allele (T) of IL1A gene as well as the genotype 1A3A of IL1RN were associated with an increased risk of getting Trypanosoma brucei gambiense and develop HAT when all data were analysed together and also when stratified by the three major ethno-linguistic groups, 2 pooled ethno-linguistic subgroups and 11 ethno-linguistic subgroups. CONCLUSION: This study revealed that one SNP rs1800794 of IL1A and one VNTR rs2234663 of IL1RN were associated with the increased risk to be infected by Trypanosoma brucei gambiense and develop sleeping sickness in southern Cameroon. The minor allele T and the genotype TT of SNP rs1800794 in IL1A as well as the genotype 1A3A of IL1RN rs2234663 VNTR seem to increase the risk of getting Trypanosoma brucei gambiense infections and develop sleeping sickness in southern Cameroon.

mutTCPdb: a comprehensive database for genomic variants of a tropical country neglected disease-tropical calcific pancreatitis.

Tropical calcific pancreatitis (TCP) is a juvenile, non-alcoholic form of chronic pancreatitis with its exclusive presence in tropical regions associated with the low economic status. TCP initiates in the childhood itself and then proliferates silently. mutTCPdb is a manually curated and comprehensive disease specific single nucleotide variant (SNV) database. Extensive search strategies were employed to create a repository while SNV information was collected from published articles. Several existing databases such as the dbSNP, Uniprot, miRTarBase2.0, HGNC, PFAM, KEGG, PROSITE, MINT, BIOGRID 3.4 and Ensemble Genome Browser 87 were queried to collect information specific to the gene. mutTCPdb is running on the XAMPP web server with MYSQL database in the backend for data storage and management. Currently, the mutTCPdb enlists 100 variants of all 11 genes identified in TCP, out of which 45 are non-synonymous (missense, nonsense, deletions and insertions), 46 are present in non-coding regions (UTRs, promoter region and introns) and 9 are synonymous variants. The database is highly curated for disease-specific gene variants and provides complete information on function, transcript information, pathways, interactions, miRNAs and PubMed references along with remarks. It is an informative portal for clinicians and researchers for a better understanding of the disease, as it may help in identifying novel targets and diagnostic markers, hence, can be a source to improve the strategies for TCP management.Database URL: http://lms.snu.edu.in/mutTCPDB/index.php.

Clock Gene Period in the Chagas Disease Vector Triatoma infestans (Hemiptera: Reduviidae).

To contribute to a better understanding of the molecular bases of the circadian biological rhythms in Chagas disease vectors, in this work we identified functional domains in the sequences of the clock protein PERIOD (PER) in Rhodnius prolixus and Triatoma infestans and analyzed the expression of the PER gene at mRNA level in T. infestans. The PER protein sequences comparison among these species and those from other insects revealed that the most similar regions are the PAS domains and the most variable is the COOH-terminal. On the other hand, the per gene expression in nervous tissue of adult T. infestans varies with a daily canonical rhythm in groups of individuals maintained under photoperiod (light/dark, LD) and constant dark (DD), showing a significant peak of expression at sunset. The pattern of expression detected in LD persists under the DD condition. As expected, in the group maintained in constant light (LL), no daily increase was detected in per transcript level. Besides, the presence of per transcript in different tissues of adult individuals and in nervous tissue of nymphs evidenced activity of peripheral clocks in adults and activity of the central clock in nymphs of T. infestans.

A polymorphism in the haptoglobin, haptoglobin related protein locus is associated with risk of human sleeping sickness within Cameroonian populations.

BACKGROUND: Human African Trypanosomiasis (HAT) is a neglected disease targeted for elimination as a public health problem by 2020. Elimination requires a better understanding of the epidemiology and clinical evolution of HAT. In addition to the classical clinical evolution of HAT, asymptomatic carriers and spontaneous cure have been reported in West Africa. A genetic component to human susceptibility to HAT has been suggested to explain these newly observed responses to infection. In order to test for genetic associations with infection response, genetic polymorphism in 17 genes were tested (APOL1, IL1B, IL4, IL4R, IL6, IL8, IL12B, IL12RB1, IL10, TNFA, INFG, MIF, HLA-G, HLA-A, HP, HPR and CFH). METHODOLOGY: A case-control study was performed on 180 blood samples collected from 56 cases and 124 controls from Cameroon. DNA was extracted from blood samples. After quality control, 25 samples (24 controls and 1 case) were eliminated. The genotyping undertaken on 155 individuals including 55 cases and 100 controls were investigated at 96 loci (88 SNPs and 8 indels) located on 17 genes. Associations between these loci and HAT were estimated via a case-control association test. RESULTS: Analyses of 64 SNPs and 4 indels out of 96 identified in the selected genes reveal that the minor allele (T) of rs8062041 in haptoglobin (HP) appeared to be protective against HAT (p = 0.0002395, OR 0.359 (CI95 [0.204-0.6319])); indicating higher frequency in cases compared to controls. This minor allele with adjusted p value of 0.0163 is associated with a lower risk (protective effect) of developing sleeping sickness. CONCLUSION: The haptoglobin related protein HPR and HP are tightly linked and both are duplicated in some people and may lead to higher activity. This increased production could be responsible of the protection associated with rs8062041 even though this SNP is within HP.

Pauci- and Multibacillary Leprosy: Two Distinct, Genetically Neglected Diseases.

After sustained exposure to Mycobacterium leprae, only a subset of exposed individuals develops clinical leprosy. Moreover, leprosy patients show a wide spectrum of clinical manifestations that extend from the paucibacillary (PB) to the multibacillary (MB) form of the disease. This "polarization" of leprosy has long been a major focus of investigation for immunologists because of the different immune response in these two forms. But while leprosy per se has been shown to be under tight human genetic control, few epidemiological or genetic studies have focused on leprosy subtypes. Using PubMed, we collected available data in English on the epidemiology of leprosy polarization and the possible role of human genetics in its pathophysiology until September 2015. At the genetic level, we assembled a list of 28 genes from the literature that are associated with leprosy subtypes or implicated in the polarization process. Our bibliographical search revealed that improved study designs are needed to identify genes associated with leprosy polarization. Future investigations should not be restricted to a subanalysis of leprosy per se studies but should instead contrast MB to PB individuals. We show the latter approach to be the most powerful design for the identification of genetic polarization determinants. Finally, we bring to light the important resource represented by the nine-banded armadillo model, a unique animal model for leprosy.

Interpretations of education about gene-environment influences on health in rural Ethiopia: the context of a neglected tropical disease.

BACKGROUND: Misunderstandings of the role of genetics in disease development are associated with stigmatizing behaviors and fatalistic attitudes about prevention. This report describes an evaluation of community understanding of an educational module about genetic and environmental influences on the development of podoconiosis, a neglected tropical disease endemic in highland Ethiopia. METHODS: A qualitative process assessment was conducted as part of a large prospective intervention trial in August 2013, in Wolaita Zone, southern Ethiopia. Sixty five participants were purposively selected from 600 households randomized to receive the inherited susceptibility module. The educational module used pictorial representations and oral explanations of the interaction of inherited sensitivity and soil exposure and was delivered by lay health educators in participants' homes. Data were collected using semi-structured individual interviews (IDIs) or focus group discussions (FGDs). RESULTS: Qualitative analyses showed that most participants improved their understanding of inherited soil sensitivity and susceptibility to podoconiosis. Participants linked their new understanding to decreased stigma-related attitudes. The module also corrected misconceptions that the condition was contagious, again diminishing stigmatizing attitudes. Lastly, these improvements in understanding increased the perceived value of foot protection. CONCLUSIONS: Taken together, these improvements support the acceptability, feasibility and potential benefits of implementing gene-environment education in low and middle income countries.

Neglected tropical diseases in the genomics era: re-evaluating the impact of new drugs and mass drug administration.

Simon Croft answers Genome Biology's questions on ways to approach neglected tropical diseases in the genomics era, including re-evaluating the impact of new drugs and mass drug administration.

Combattre les maladies négligées en ciblant sélectivement leurs enzymes épigénétiques : le cas de la désacétylase 8 (HDAC8) de Schistosoma mansoni.

Chromatin structure in eukaryotes and its modulation by epigenetic mechanisms enable the regulation of the different nuclear processes. Perturbation of epigenetic mechanisms can thus affect the proper functioning of cells, and numerous diseases have been linked to the deregulation of the activity of epigenetic effectors in human. The reversibility of epigenetic mechanisms has allowed the development of "Epigenetic drugs" or "Epidrugs". In a chemical biology approach, we have made use of the importance of eukaryotic epigenetic mechanisms to find drug leads that specifically affect pathogens responsible for neglected diseases. Our work on histone deacetylase 8 from Schistosoma mansoni (smHDAC8) has enabled us to design drug leads that show stronger selectivity for the pathogen enzyme than for its human homologs. Specifically, we have used a structure-based approach to understand the structural specificities of the smHDAC8 enzyme compared to the human enzymes, notably human HDAC8. The structure of smHDAC8 in complex with various pan-HDAC drugs led to the design of inhibitors that make use of all the structural specificities of this enzyme and that can be stabilized in the smHDAC8 catalytic pocket through a pathogen-specific clamp. Collectively, our results provide the proof of concept that epigenetic enzymes from pathogens can be targeted to develop anti-pathogenic epidrugs in the fight against neglected diseases. Our results also provide information that can be used to develop epidrugs to fight human diseases, including cancer.

Neglected Tropical Diseases in the Post-Genomic Era.

Neglected tropical diseases (NTDs) are a group of viral, bacterial, and eukaryotic parasitic diseases that are especially endemic in low-income populations, with a large health and economic impact on both the developing and developed world. The structure and dynamics of the genomes of the organisms causing these diseases, as well as the modes of expression, exchange, and transmission of their genetic information, often deviate from those found in classical, model organism-centric textbooks. We assess the role of basic and applied genetic research in our understanding of key aspects of their biology and evolution, and discuss the impact of novel high-throughput approaches spawned by the post-genomic era on the development of next-generation drugs, vaccines, molecular epidemiology, and/or diagnostic tools for these important pathogens.

Are Salmonella-Induced Gastroenteritis Neglected in Developing Countries? Feedback from Microbiological Investigations in N'Djamena Hospitals, Chad.

Salmonella is considered to be one of the main pathogens causing human gastroenteritis worldwide. Looking for Salmonella in Africa in patients suffering from gastroenteritis is rather unusual, and the use of antibiotics is not subject to any regulation. This study intends for stressing the possible prominent importance of Salmonella in digestive diseases in Africa as well as identifying antimicrobial resistance of Salmonella isolates from faeces samples of human origin. All samples were collected from five N'Djamena hospitals, from patients suffering from diarrhoea. The collecting was undertaken over two periods of six months each: from August 2010 to January 2011 and from September 2011 to February 2012. Salmonella isolates were obtained by standard cultivation and serotyping methods. A total of 43 Salmonella isolates were identified, belonging to 21 different serovars. The most prevalent serovar was Salmonella Stanleyville (n = 7), followed by S. Anatum (n = 4) and S. Kottbus (n = 3). The other serovars were under-represented. The majority of these isolates were susceptible to all antibiotics tested (CLSI Standards), except two S. Enteritidis isolates that exhibited resistance to fluoroquinolones. The different serovars and antibiotic resistance profiles that were observed highlight the substantial diversity of Salmonella in N'Djamena, Chad. Roughly, one out of ten patients who consulted for gastroenteritis was shedding Salmonella spp. and none of them would have been diagnosed outside the context of this research program. This study may encourage local clinicians to explore more often salmonellosis suspicion in their daily practice.

Association of Ficolin-2 Serum Levels and FCN2 Genetic Variants with Indian Visceral Leishmaniasis.

BACKGROUND: Visceral leishmaniasis (VL), one of the neglected tropical diseases, is endemic in the Indian subcontinent. Ficolins are circulating serum proteins of the lectin complement system and involved in innate immunity. METHODS: We have estimated ficolin-2 serum levels and analyzed the functional variants of the encoding gene FCN2 in 218 cases of VL and in 225 controls from an endemic region of India. RESULTS: Elevated levels of serum ficolin-2 were observed in VL cases compared to the controls (adjusted P<0.0001). The genetic analysis revealed that the FCN2 structural variant +6359 C>T (p.T236M) was associated with VL (OR=2.2, 95% CI=1.23-7.25, P=0.008) and with high ficolin-2 serum levels. We also found that the FCN2*AAAC haplotype occurred more frequently among healthy controls when compared to cases (OR=0.59, 95%CI=0.37-0.94, P=0.023). CONCLUSIONS: Our findings indicate that the FCN2 variant +6359C>T is associated with the occurrence of VL and that ficolin-2 serum levels are elevated in Leishmania infections.

MAPKAP1 rs10118570 polymorphism is associated with anti-infection and anti-hepatic fibrogenesis in schistosomiasis japonica.

Chronic infection with Schistosoma japonicum is an important cause of hepatic fibrosis (HF). Human 9q33.3 is one of the most important loci for stress-related diseases. We examined the potential associations of 43 single-nucleotide polymorphisms (SNPs) with S. japonicum infection and HF in epidemic region in China. We identified a SNP (rs10118570 GG in mitogen-activated protein kinase associated protein 1, MAPKAP1) contributes to anti-infection (adjusted OR = 0.35) and anti-fibrogenesis (adjusted RR = 0.44) in the discovery study. Replicative and combined studies showed consistent protective quality for this genotype (replicative: adjusted OR = 0.37 for anti-infection, and adjusted RR = 0.40 for anti-fibrogenesis; Combined: adjusted OR = 0.45 for anti-infection, and adjusted RR = 0.42 for anti-fibrogenesis). Univariate and multivariate analysis in the discovery, replicative and combined studies, suggested that durations (years), splenomegaly, serum ALB and rs10118570 were independent predictors influencing the fibrogenesis. The analysis of gene-gene interaction showed rs10118570 functions independently. We conclude that MAPKAP1 may represent a novel anti-infection and anti-fibrogenesis genomic locus in chronic schistosomiasis japonica. And rs10118570 may be a potential biomarker and target for the treatment of this life-threatening ancient disease.

“Abordando las Enfermedades Raras desde la consulta de Atención Primaria: si se quiere, se puede" / Tackling rare diseases from the primary healthcare centre: "Where there's a will, there's a way"

Durante los últimos años, la atención a los pacientes con enfermedades raras (ER) comienza a tener cierta relevancia en el día a día de la consulta del médico de familia. Como la formación en estas patologías tan heterogéneas (más de 8.000 ER, más del 80% de origen genético) es escasa en Atención Primaria, y dado que se trata de un colectivo de pacientes crónicos con necesidades especiales, se ha desarrollado una herramienta online para su manejo desde la consulta de Atención Primaria que facilite la tarea del médico de familia a la hora de atender a estos pacientes: el protocolo DICE-APER (AU)

In recent years health care for patients with rare diseases (RD) has started to take on a certain significance in the daily routine of the family doctor’s practice. Since training in such heterogeneous pathologies (more than 8,000 RD, more than 80% of genetic origin) is limited in primary care, and given that a group of chronic patients with special needs is concerned, an online tool has been developed to manage them from the primary healthcare centre to facilitate the the family doctor’s task of caring for these patients: the DICE-APER protocol (AU)

Breast cancer: a neglected disease for the majority of affected women worldwide.

Recent progress with declines in mortality in some high-income countries has obscured the fact that for the majority of women worldwide who are newly diagnosed, breast cancer is a neglected disease in the context of other numerically more frequent health problems. For this growing majority, it is also an orphan disease, in that detailed knowledge about tumor characteristics and relevant host biology necessary to provide even basic care is absent. With the possible exception of nutritional recommendations, current international cancer policy and planning initiatives are irrelevant to breast cancer. The progress that has occurred in high-income countries has come at extraordinary fiscal expense and patient toxicity, which of themselves suggest nonrelevance to women and healthcare practitioners in middle- and low-income countries. The implications of these circumstances appear clear: if the promise of the now 60-year-old Declaration of Human Rights that the fruits of medical science accrue to all mankind is to be realized with respect to breast cancer, a basic and translational global research initiative should be launched.