J Pers Med. 2021 Mar 16;11(3):210. doi: 10.3390/jpm11030210.

ABSTRACT

With the tremendous advancements in genome sequencing technology in the field of pharmacogenomics, data have to be made accessible to be more efficiently utilized by broader clinical disciplines. Physicians who require the drug-genome interactome information, have been challenged by the complicated pharmacogenomic star-based classification system. We present here an end-to-end web-based pharmacogenomics tool, PharmaKU, which has a comprehensive easy-to-use interface. PharmaKU can help to overcome several hurdles posed by previous pharmacogenomics tools, including input in hg38 format only, while hg19/GRCh37 is now the most popular reference genome assembly among clinicians and geneticists, as well as the lack of clinical recommendations and other pertinent dosage-related information. This tool extracts genetic variants from nine well-annotated pharmacogenes (for which diplotype to phenotype information is available) from whole genome variant files and uses Stargazer software to assign diplotypes and apply prescribing recommendations from pharmacogenomic resources. The tool is wrapped with a user-friendly web interface, which allows for choosing hg19 or hg38 as the reference genome version and reports results as a comprehensive PDF document. PharmaKU is anticipated to enable bench to bedside implementation of pharmacogenomics knowledge by bringing precision medicine closer to a clinical reality.

PMID:33809530 | DOI:10.3390/jpm11030210

J Pers Med. 2021 Mar 30;11(4):252. doi: 10.3390/jpm11040252.

ABSTRACT

Personalised medicine is potentially useful to delay the progression of chronic kidney disease (CKD). The aim of this study was to determine the effects of CYP3A5 polymorphism in rapid CKD progression. This multicentre, observational, prospective cohort study was performed among adult CKD patients (≥18 years) with estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2, who had ≥4 outpatient, non-emergency eGFR values during the three-year study period. The blood samples collected were analysed for CYP3A5*3 polymorphism. Rapid CKD progression was defined as eGFR decline of >5 mL/min/1.73 m2/year. Multiple logistic regression was then performed to identify the factors associated with rapid CKD progression. A total of 124 subjects consented to participate. The distribution of the genotypes adhered to the Hardy-Weinberg equilibrium (X2 = 0.237, p = 0.626). After adjusting for potential confounding factors via multiple logistic regression, the factors associated with rapid CKD progression were CYP3A5*3/*3 polymorphism (adjusted Odds Ratio [aOR] 4.190, 95% confidence interval [CI]: 1.268, 13.852), adjustments to antihypertensives, young age, dyslipidaemia, smoking and use of traditional/complementary medicine. CKD patients should be monitored closely for possible factors associated with rapid CKD progression to optimise clinical outcomes. The CYP3A5*3/*3 genotype could potentially be screened among CKD patients to offer more individualised management among these patients.

PMID:33808503 | DOI:10.3390/jpm11040252

J Pers Med. 2021 Mar 5;11(3):181. doi: 10.3390/jpm11030181.

ABSTRACT

BACKGROUND: Antipsychotic-induced metabolic syndrome (MetS) is a multifactorial disease with a genetic predisposition. Serotonin and its receptors are involved in antipsychotic-drug-induced metabolic disorders. The present study investigated the association of nine polymorphisms in the four 5-hydroxytryptamine receptor (HTR) genes HTR1A, HTR2A, HTR3A, and HTR2C and the gene encoding for the serotonin transporter SLC6A4 with MetS in patients with schizophrenia.

METHODS: A set of nine single-nucleotide polymorphisms of genes of the serotonergic system was investigated in a population of 475 patients from several Siberian regions (Russia) with a clinical diagnosis of schizophrenia. Genotyping was performed and the results were analyzed using chi-square tests.

RESULTS: Polymorphic variant rs521018 (HTR2C) was associated with higher body mass index in patients receiving long-term antipsychotic therapy, but not with drug-induced metabolic syndrome. Rs1150226 (HTR3A) was also associated but did not meet Hardy-Weinberg equilibrium.

CONCLUSIONS: Our results indicate that allelic variants of HTR2C genes may have consequences on metabolic parameters. MetS may have too complex a mechanistic background to be studied without dissecting the syndrome into its individual (causal) components.

PMID:33807811 | DOI:10.3390/jpm11030181

Viruses. 2021 Mar 5;13(3):413. doi: 10.3390/v13030413.

ABSTRACT

The treatment of coronavirus disease 2019 (COVID-19) has been a challenge. The efficacy of several drugs has been evaluated and variability in drug response has been observed. Pharmacogenetics could explain this variation and improve patients' outcomes with this complex disease; nevertheless, several disease-related issues must be carefully reviewed in the pharmacogenetic study of COVID-19 treatment. We aimed to describe the pharmacogenetic variants reported for drugs used for COVID-19 treatment (remdesivir, oseltamivir, lopinavir, ritonavir, azithromycin, chloroquine, hydroxychloroquine, ivermectin, and dexamethasone). In addition, other factors relevant to the design of pharmacogenetic studies were mentioned. Variants in CYP3A4, CYP3A5, CYP2C8, CY2D6, ABCB1, ABCC2, and SLCO1B1, among other variants, could be included in pharmacogenetic studies of COVID-19 treatment. Besides, nongenetic factors such as drug-drug interactions and inflammation should be considered in the search for personalized therapy of COVID-19.

PMID:33807592 | DOI:10.3390/v13030413

J Pers Med. 2021 Mar 4;11(3):179. doi: 10.3390/jpm11030179.

ABSTRACT

Pharmacogenomics (PGx) is a key subset of precision medicine that relates genomic variation to individual response to pharmacotherapy. We assessed longitudinal trends in US FDA approval of new drugs labeled with PGx information. Drug labels containing PGx information were obtained from Drugs@FDA and guidelines from PharmGKB were used to compare the actionability of PGx information in drug labels across therapeutic areas. The annual proportion of new drug approvals with PGx labeling has increased by nearly threefold from 10.3% (n = 3) in 2000 to 28.2% (n = 11) in 2020. Inclusion of PGx information in drug labels has increased for all clinical areas over the last two decades but most prominently for cancer therapies, which comprise the largest proportion (75.5%) of biomarker-drug pairs for which PGx testing is required. Clinically actionable information was more frequently observed in biomarker-drug pairs associated with cancer drugs compared to those for other therapeutic areas (n = 92 (59.7%) vs. n = 62 (40.3%), p < 0.0051). These results suggest that further evidence is needed to support the clinical adoption of pharmacogenomics in non-cancer therapeutic areas.

PMID:33806453 | DOI:10.3390/jpm11030179

J Pers Med. 2021 Mar 25;11(4):240. doi: 10.3390/jpm11040240.

ABSTRACT

There is an acute need for advances in pharmacologic therapies and a better understanding of novel drug targets for severe asthma. Imatinib, a tyrosine kinase inhibitor, has been shown to improve forced expiratory volume in 1 s (FEV1) in a clinical trial of patients with severe asthma. In a pilot study, we applied systems biology approaches to epithelium gene expression from these clinical trial patients treated with imatinib to better understand lung function response with imatinib treatment. Bronchial brushings from ten imatinib-treated patient samples and 14 placebo-treated patient samples were analyzed. We used personalized perturbation profiles (PEEPs) to characterize gene expression patterns at the individual patient level. We found that strong responders-patients with greater than 20% increase in FEV1-uniquely shared multiple downregulated mitochondrial-related pathways. In comparison, weak responders (5-10% FEV1 increase), and non-responders to imatinib shared none of these pathways. The use of PEEP highlights its potential for application as a systems biology tool to develop individual-level approaches to predicting disease phenotypes and response to treatment in populations needing innovative therapies. These results support a role for mitochondrial pathways in airflow limitation in severe asthma and as potential therapeutic targets in larger clinical trials.

PMID:33805900 | DOI:10.3390/jpm11040240

Pharmaceutics. 2021 Mar 13;13(3):387. doi: 10.3390/pharmaceutics13030387.

ABSTRACT

This theoretical study seeks to critically review the use of excipients in the paediatric population. This study is based on the rules and recommendations of European and American drug regulatory agencies. On the one hand, this review describes the most frequent excipients used in paediatric medicine formulations, identifying the compounds that scientific literature has marked as potentially harmful regarding the side effects generated after exposure. On the other hand, this review also highlights the importance of carrying out safety -checks on the excipients, which, in most cases, are linked to toxicity studies. An excipient in the compilation of paediatric population databases is expected to target safety and toxicity, as in the STEP database. Finally, a promising pharmaceutical form for child population, ODT (Orally Disintegrating Tablets), will be studied.

PMID:33805830 | DOI:10.3390/pharmaceutics13030387

J Pers Med. 2021 Mar 13;11(3):204. doi: 10.3390/jpm11030204.

ABSTRACT

Atorvastatin, prescribed for the treatment of hypercholesterolemia, demonstrated overwhelming benefits in reducing cardiovascular morbidity and mortality. However, many patients discontinue therapy due to adverse reactions, especially myopathy. The Dutch Pharmacogenetics Working Group (DPWG) recommends an alternative agent to atorvastatin and simvastatin or a dose adjustment depending on other risk factors for statin-induced myopathy in SLCO1B1 rs4149056 CC or TC carriers. In contrast, the Clinical Pharmacogenetics Implementation Consortium (CPIC) published their guideline on simvastatin, but not on atorvastatin. In this work, we aimed to demonstrate the effect of SLCO1B1 phenotype and other variants (e.g., in CYP3A4/5, UGT enzymes or SLC transporters) on atorvastatin pharmacokinetics. For this purpose, a candidate-gene pharmacogenetic study was proposed. The study population comprised 156 healthy volunteers enrolled in atorvastatin bioequivalence clinical trials. The genotyping strategy comprised a total of 60 variants in 15 genes. Women showed higher exposure to atorvastatin compared to men (p = 0.001), however this difference disappeared after dose/weight (DW) correction. The most relevant pharmacogenetic differences were the following: AUC/DW and Cmax /DW based on (a) SLCO1B1 phenotype (p < 0.001 for both) and (b) CYP3A5*3 (p = 0.004 and 0.018, respectively). As secondary findings: SLC22A1 *2/*2 genotype was related to higher Cmax/DW (ANOVA p = 0.030) and SLC22A1 *1/*5 genotype was associated with higher Vd/F (ANOVA p = 0.032) compared to SLC22A1 *1/*1, respectively. Finally, UGT2B7 rs7439366 *1/*1 genotype was associated with higher tmax as compared with the *1/*3 genotype (ANOVA p = 0.024). Based on our results, we suggest that SLCO1B1 is the best predictor for atorvastatin pharmacokinetic variability and that prescription should be adjusted based on it. We suggest that the CPIC should include atorvastatin in their statin-SLCO1B1 guidelines. Interesting and novel results were observed based on CYP3A5 genotype, which should be confirmed with further studies.

PMID:33805706 | DOI:10.3390/jpm11030204

J Pers Med. 2021 Mar 13;11(3):201. doi: 10.3390/jpm11030201.

ABSTRACT

Tamoxifen is an endocrine treatment for hormone receptor positive breast cancer. The effectiveness of tamoxifen may be compromised in patients with metabolic resistance, who have insufficient metabolic generation of the active metabolites endoxifen and 4-hydroxy-tamoxifen. This has been challenging to validate due to the lack of measured metabolite concentrations in tamoxifen clinical trials. CYP2D6 activity is the primary determinant of endoxifen concentration. Inconclusive results from studies investigating whether CYP2D6 genotype is associated with tamoxifen efficacy may be due to the imprecision in using CYP2D6 genotype as a surrogate of endoxifen concentration without incorporating the influence of other genetic and clinical variables. This review summarizes the evidence that active metabolite concentrations determine tamoxifen efficacy. We then introduce a novel approach to validate this relationship by generating a precision endoxifen prediction algorithm and comprehensively review the factors that must be incorporated into the algorithm, including genetics of CYP2D6 and other pharmacogenes. A precision endoxifen algorithm could be used to validate metabolic resistance in existing tamoxifen clinical trial cohorts and could then be used to select personalized tamoxifen doses to ensure all patients achieve adequate endoxifen concentrations and maximum benefit from tamoxifen treatment.

PMID:33805613 | DOI:10.3390/jpm11030201

Cancers (Basel). 2021 Mar 29;13(7):1566. doi: 10.3390/cancers13071566.

ABSTRACT

Multi-gene assays often include UGT1A1 and, in certain instances, may report associated toxicity risks for irinotecan, belinostat, pazopanib, and nilotinib. However, guidance for incorporating UGT1A1 results into therapeutic decision-making is mostly lacking for these anticancer drugs. We summarized meta-analyses, genome-wide association studies, clinical trials, drug labels, and guidelines relating to the impact of UGT1A1 polymorphisms on irinotecan, belinostat, pazopanib, or nilotinib toxicities. For irinotecan, UGT1A1*28 was significantly associated with neutropenia and diarrhea, particularly with doses ≥ 180 mg/m2, supporting the use of UGT1A1 to guide irinotecan prescribing. The drug label for belinostat recommends a reduced starting dose of 750 mg/m2 for UGT1A1*28 homozygotes, though published studies supporting this recommendation are sparse. There was a correlation between UGT1A1 polymorphisms and pazopanib-induced hepatotoxicity, though further studies are needed to elucidate the role of UGT1A1-guided pazopanib dose adjustments. Limited studies have investigated the association between UGT1A1 polymorphisms and nilotinib-induced hepatotoxicity, with data currently insufficient for UGT1A1-guided nilotinib dose adjustments.

PMID:33805415 | DOI:10.3390/cancers13071566

Cancers (Basel). 2021 Mar 24;13(7):1497. doi: 10.3390/cancers13071497.

ABSTRACT

Efficacy of 5-Fluorouracil (5-FU)-based chemotherapy is limited by significant toxicity. Tests based upon variants in the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines with high level evidence of a link to dihydropyrimidine dehydrogenase (DPD) phenotype and 5-FU toxicity are available to identify patients at high risk of severe adverse events (AEs). We previously reported associations between rs1213215, rs2612091, and NM_000110.3:c.1906-14763G>A (rs12022243) and capecitabine induced toxicity in clinical trial QUASAR 2. We also identified patients with DPD deficiency alleles NM_000110.3: c.1905+1G>A, NM_000110.3: c.2846C>T, NM_000110.3:c.1679T>G and NM_000110.3:c.1651G>A. We have now assessed the frequency of thirteen additional DPYD deficiency variants in 888 patients from the QUASAR 2 clinical trial. We also compared the area under the curve (AUC)-a measure of diagnostic accuracy-of the high-level evidence variants from the CPIC guidelines plus and minus additional DPYD deficiency variants and or common variants associated with 5-FU toxicity. Including additional DPYD deficiency variants retained good diagnostic accuracy for serious adverse events (AEs) and improved sensitivity for predicting grade 4 haematological toxicities (sensitivity 0.75, specificity 0.94) but the improvement in AUC for this toxicity was not significant. Larger datasets will be required to determine the benefit of including additional DPYD deficiency variants not observed here. Genotyping two common alleles statistically significantly improves AUC for prediction of risk of HFS and may be clinically useful (AUC difference 0.177, sensitivity 0.84, specificity 0.31).

PMID:33805100 | DOI:10.3390/cancers13071497

Pharmaceuticals (Basel). 2021 Mar 24;14(4):287. doi: 10.3390/ph14040287.

ABSTRACT

Despite being the most widely studied mood stabilizer, researchers have not confirmed a mechanism for lithium's therapeutic efficacy in Bipolar Disorder (BD). Pharmacogenomic applications may be clinically useful in the future for identifying lithium-responsive patients and facilitating personalized treatment. Six genome-wide association studies (GWAS) reviewed here present evidence of genetic variations related to lithium responsivity and side effect expression. Variants were found on genes regulating the glutamate system, including GAD-like gene 1 (GADL1) and GRIA2 gene, a mutually-regulated target of lithium. In addition, single nucleotide polymorphisms (SNPs) discovered on SESTD1 may account for lithium's exceptional ability to permeate cell membranes and mediate autoimmune and renal effects. Studies also corroborated the importance of epigenetics and stress regulation on lithium response, finding variants on long, non-coding RNA genes and associations between response and genetic loading for psychiatric comorbidities. Overall, the precision medicine model of stratifying patients based on phenotype seems to derive genotypic support of a separate clinical subtype of lithium-responsive BD. Results have yet to be expounded upon and should therefore be interpreted with caution.

PMID:33804842 | DOI:10.3390/ph14040287

Pharmaceuticals (Basel). 2021 Mar 1;14(3):204. doi: 10.3390/ph14030204.

ABSTRACT

Pharmacogenomics can identify polymorphisms in genes involved in drug pharmacokinetics and pharmacodynamics determining differences in efficacy and safety and causing inter-individual variability in drug response. Therefore, pharmacogenomics can help clinicians in optimizing therapy based on patient's genotype, also in psychiatric and neurological settings. However, pharmacogenetic screenings for psychotropic drugs are not routinely employed in diagnosis and monitoring of patients treated with mood stabilizers, such as carbamazepine and valproate, because their benefit in clinical practice is still controversial. In this review, we summarize the current knowledge on pharmacogenetic biomarkers of these anticonvulsant drugs.

PMID:33804537 | DOI:10.3390/ph14030204

Children (Basel). 2021 Mar 1;8(3):186. doi: 10.3390/children8030186.

ABSTRACT

BACKGROUND: The prevalence of pediatric metabolic syndrome is usually closely linked to overweight and obesity; however, this condition has also been described in children with disabilities. We performed a multivariate pattern analysis of metabolic profiles in neurologically impaired children and adolescents in order to reveal patterns and crucial biomarkers among highly interrelated variables.

PATIENTS AND METHODS: We retrospectively reviewed 44 cases of patients (25M/19F, mean age 12.9 ± 8.0) with severe disabilities. Clinical and anthropometric parameters, body composition, blood pressure, and metabolic and endocrinological assessment (fasting blood glucose, insulin, total cholesterol, high-density lipoprotein cholesterol, triglycerides, glutamic oxaloacetic transaminase, glutamate pyruvate transaminase, gamma-glutamyl transpeptidase) were recorded in all patients. As a control group, we evaluated 120 healthy children and adolescents (61M/59F, mean age 12.9 ± 2.7).

RESULTS: In the univariate analysis, the children-with-disabilities group showed a more dispersed distribution, thus with higher variability of the features related to glucose metabolism and insulin resistance (IR) compared to the healthy controls. The principal component (PC1), which emerged from the PC analysis conducted on the merged dataset and characterized by these variables, was crucial in describing the differences between the children-with-disabilities group and controls.

CONCLUSION: Children and adolescents with disabilities displayed a different metabolic profile compared to controls. Metabolic syndrome (MetS), particularly glucose metabolism and IR, is a crucial point to consider in the treatment and care of this fragile pediatric population. Early detection of the interrelated variables and intervention on these modifiable risk factors for metabolic disturbances play a central role in pediatric health and life expectancy in patients with a severe disability.

PMID:33804501 | DOI:10.3390/children8030186

Cancers (Basel). 2021 Mar 18;13(6):1375. doi: 10.3390/cancers13061375.

ABSTRACT

The early detection of cancer can reduce cancer-related mortality. There is no clinically useful noninvasive biomarker for early detection of breast cancer. The aim of this study was to develop accurate and precise early detection biomarkers and a dynamic monitoring system following treatment. We analyzed a genome-wide methylation array in Taiwanese and The Cancer Genome Atlas (TCGA) breast cancer (BC) patients. Most breast cancer-specific circulating methylated CCDC181, GCM2 and ITPRIPL1 biomarkers were found in the plasma. An automatic analysis process of methylated ccfDNA was established. A combined analysis of CCDC181, GCM2 and ITPRIPL1 (CGIm) was performed in R using Recursive Partitioning and Regression Trees to establish a new prediction model. Combined analysis of CCDC181, GCM2 and ITPRIPL1 (CGIm) was found to have a sensitivity level of 97% and an area under the curve (AUC) of 0.955 in the training set, and a sensitivity level of 100% and an AUC of 0.961 in the test set. The circulating methylated CCDC181, GCM2 and ITPRIPL1 was also significantly decreased after surgery (all p < 0.001). The aberrant methylation patterns of the CCDC181, GCM2 and ITPRIPL1 genes means that they are potential biomarkers for the detection of early BC and can be combined with breast imaging data to achieve higher accuracy, sensitivity and specificity, facilitating breast cancer detection. They may also be applied to monitor the surgical treatment response.

PMID:33803633 | DOI:10.3390/cancers13061375

J Clin Med. 2021 Mar 9;10(5):1148. doi: 10.3390/jcm10051148.

ABSTRACT

Oxidative stress and neuroinflammation are involved in the pathogenesis and progression of glaucoma. Our aim was to evaluate the impact of selected single-nucleotide polymorphisms in inflammation and oxidative stress genes on the risk of glaucoma, the patients' clinical characteristics and the glaucoma phenotype. In total, 307 patients with primary open-angle glaucoma or ocular hypertension were enrolled. The control group included 339 healthy Slovenian blood donors. DNA was isolated from peripheral blood. Genotyping was performed for SOD2 rs4880, CAT rs1001179, GPX1 rs1050450, GSTP1 rs1695, GSTM1 gene deletion, GSTT1 gene deletion, IL1B rs1143623, IL1B rs16944, IL6 rs1800795 and TNF rs1800629. We found a nominally significant association of GSTM1 gene deletion with decreased risk of ocular hypertension and a protective role of IL1B rs16944 and IL6 rs1800629 in the risk of glaucoma. The CT and TT genotypes of GPX1 rs1050450 were significantly associated with advanced disease, lower intraocular pressure and a larger vertical cup-disc ratio. In conclusion, genetic variability in IL1B and IL6 may be associated with glaucoma risk, while GPX and TNF may be associated with the glaucoma phenotype. In the future, improved knowledge of these pathways has the potential for new strategies and personalised treatment of glaucoma.

PMID:33803434 | DOI:10.3390/jcm10051148

J Pers Med. 2021 Mar 17;11(3):215. doi: 10.3390/jpm11030215.

ABSTRACT

Unhealthy lifestyle, as sedentary, unbalanced diet, smoking, and body composition change are often observed in non-Hodgkin's lymphoma (NHL) survivors, and could be determinant for the onset of cancer treatment-induced metabolic syndrome (CTIMetS), including abdominal obesity, sarcopenia, and insulin resistance. The aim of this study was to assess whether changes in body composition, unhealthy lifestyles and types of anti-cancer treatment could increase the risk of metabolic syndrome (MetSyn) and sarcopenia in long-term NHL survivors. We enrolled 60 consecutive NHL patients in continuous remission for at least 3 years. Nutritional status was assessed by anthropometry-plicometry, and a questionnaire concerning lifestyles and eating habits was administered. More than 60% of survivors exhibited weight gain and a change in body composition, with an increased risk of MetSyn. Univariate analysis showed a significantly higher risk of metabolic disorder in patients treated with steroids, and in patients with unhealthy lifestyles. These data suggest that a nutritional intervention, associated with adequate physical activity and a healthier lifestyle, should be indicated early during the follow-up of lymphoma patients, in order to decrease the risk of MetSyn's onset and correlated diseases in the long term.

PMID:33802940 | DOI:10.3390/jpm11030215

Genes (Basel). 2021 Mar 3;12(3):361. doi: 10.3390/genes12030361.

ABSTRACT

Direct-to-consumer genetic tests (DTC-GT) have become a bridge between marketing and traditional healthcare services. After earning FDA endorsement for such facilities, several fast-developing companies started to compete in the related area. Pharmacogenomic (PGx) tests have been introduced as potentially one of the main medical services of such companies. Most of the individuals will be interested in finding out about the phenotypic consequences of their genetic variants and molecular risk factors against diverse medicines they take or will take later. Direct-to-consumer pharmacogenomic tests (DTC-PT) is still in its young age, however it is expected to expand rapidly through the industry in the future. The result of PGx tests could be considered as the main road toward the implementation of personalized and precision medicine in the clinic. This narrative critical review study provides a descriptive overview on DTC-GT, then focuses on DTC-PT, and also introduces and suggests the potential approaches for improving the clinical related outcomes of such tests on healthcare systems.

PMID:33802585 | DOI:10.3390/genes12030361

Genes (Basel). 2021 Mar 10;12(3):393. doi: 10.3390/genes12030393.

ABSTRACT

Since the term "pharmacogenetics" was first published in the late 1950s by Friedrich Vogel, the field has evolved into genome-wide association studies identifying novel variants associated with drug response phenotypes, international societies and consortia dedicated to pharmacogenomic research and clinical implementation, clinical practice guidelines, and the increasing availability of pharmacogenomic tests for healthcare providers in both hospital and primary care [...].

PMID:33801919 | DOI:10.3390/genes12030393

Int J Mol Sci. 2021 Mar 27;22(7):3470. doi: 10.3390/ijms22073470.

ABSTRACT

BACKGROUND: In recent years, there has been great interest in developing molecular adjuvants based on antisense oligonucleotides (ASOs) targeting immunosuppressor pathways with inhibitory effects on regulatory T cells (Tregs) to improve immunogenicity and vaccine efficacy. We aim to evaluate the immunostimulating effect of 2'OMe phosphorothioated Foxp3-targeted ASO in an antifungal adjuvanted recombinant vaccine.

METHODS: The uptake kinetics of Foxp3 ASO, its cytotoxicity and its ability to deplete Tregs were evaluated in murine splenocytes in vitro. Groups of mice were vaccinated with recombinant enolase (Eno) of Sporothix schenckii in Montanide Gel 01 adjuvant alone or in combination with either 1 µg or 8 µg of Foxp3 ASO. The titers of antigen-specific antibody in serum samples from vaccinated mice (male C57BL/6) were determined by ELISA (enzyme-linked immunosorbent assay). Cultured splenocytes from each group were activated in vitro with Eno and the levels of IFN-γ and IL-12 were also measured by ELISA. The results showed that the anti-Eno antibody titer was significantly higher upon addition of 8 µM Foxp3 ASO in the vaccine formulation compared to the standard vaccine without ASO. In vitro and in vivo experiments suggest that Foxp3 ASO enhances specific immune responses by means of Treg depletion during vaccination.

CONCLUSION: Foxp3 ASO significantly enhances immune responses against co-delivered adjuvanted recombinant Eno vaccine and it has the potential to improve vaccine immunogenicity.

PMID:33801683 | DOI:10.3390/ijms22073470