Epigenetic therapy is a promising tool for the treatment of a wide range of diseases. Several fundamental epigenetic approaches have been proposed. Firstly, the use of small molecules as epigenetic effectors, as the most developed pharmacological method, has contributed to the introduction of a number of drugs into clinical practice. Secondly, various innovative epigenetic approaches based on dCas9 and the use of small non-coding RNAs as therapeutic agents are also under extensive research. In this review, we present the current state of research in the field of epigenetic therapy, considering the prospects for its application and possible limitations.

Anti-SARS-CoV-2 vaccination leads to the production of neutralizing as well as non-neutralizing antibodies. In the current study, we investigated the temporal dynamics of both sides of immunity after vaccination with two doses of Sputnik V against SARS-CoV-2 variants Wuhan-Hu-1 SARS-CoV-2 G614-variant (D614G), B.1.617.2 (Delta), and BA.1 (Omicron). First, we constructed a SARS-CoV-2 pseudovirus assay to assess the neutralization activity of vaccine sera. We show that serum neutralization activity against BA.1 compared to D614G is decreased by 8.16-, 11.05-, and 11.16- fold in 1, 4, and 6 months after vaccination, respectively. Moreover, previous vaccination did not increase serum neutralization activity against BA.1 in recovered patients. Next, we used the ADMP assay to evaluate the Fc-mediated function of vaccine-induced serum antibodies. Our results show that the antibody-dependent phagocytosis triggered by S-proteins of the D614G, B.1.617.2 and BA.1 variants did not differ significantly in vaccinated individuals. Moreover, the ADMP efficacy was retained over up to 6 months in vaccine sera. Our results demonstrate differences in the temporal dynamics of neutralizing and non-neutralizing antibody functions after vaccination with Sputnik V.

Background: HML-2 subgroup mobile genetic elements of the HERV-K family were described to participate in carcinogenesis processes, but their expression and epigenetic regulation in molecular subtypes of colorectal cancer (CRC) remain partly characterized. The present study aimed to evaluate the expression of HML-2 elements using RNA-sequencing data in paired tumor and normal intestinal tissue samples from 63 patients with CRC to identify patterns of the retrotransposons’ activity in different molecular subtypes (CMSs). Methods: RNA-sequencing and DNA methylation data were analyzed for paired CRC and normal tissue samples. HERV-K expression was assessed using three bioinformatics tools: Telescope (version 1.0.3), TEtranscripts (version 2.2.3), GeneTEFlow (version 2020). Molecular tumor subtypes were defined using the CMScaller (version 0.99.2) program. The results of the HML-2 loci expression analysis were supplemented with the HML-2 proteins expression data obtained by quantitative RT-PCR. Results: HML-2 expression assessment by GeneTEFlow (version 2020), TECount (version 2.2.3) and Telescope (version 1.0.3) showed high convergence: the Pearson correlation coefficient for each tool exceeded 0.88. Several HML-2 loci were identified as differentially expressed in CRC samples of different CMS. The PCR results confirmed an increase in HML-2 expression in tumor tissues. For all CMSs, an inverse association was detected between differential methylation of CpG sites and differential expression of HML-2 loci. Associations of HML-2 expressions with differentially expressed genes in which they are located were found, and for a number of such genes an inverse relationship between the expression level and the methylation level of their promoters were demonstrated, and data on the involvement in the pathogenesis of CRC were described: CR1, CD48, TTLL3, ABCC2 and ZNF420. Expression signatures associated with the activity of the RIG-I-like receptor signaling cascade were identified in CMS1–3 CRC samples, which may indicate the possible implementation of viral mimicry against the background of HML-2 activation. Conclusions: Analysis of the expression of HML-2 and its association with CpG methylation contributes to a comprehensive interpretation of the CRC pathogenesis mechanisms.

INTRODUCTION. Developing novel medicines based on non-pathogenic enterovirus strains exhibiting oncotropic and oncolytic properties represents an up-to-date and safe approach to complex cancer treatment and postoperative metastasis prevention. Safety pharmacology studies are a necessary step in the preclinical development of medicinal products. AIM. The study aimed to investigate the single and repeated-dose general toxicity, local tolerance, safety pharmacology, and pyrogenicity of medicinal products based on non-pathogenic LEV4, LEV7, LEV8, LEV14, and Russo enterovirus strains as part of preclinical safety studies. MATERIALS AND METHODS. The study used medicinal products of highly purified group A, B, and C enteroviruses at a titre of 2×107–5×108 CPD ₅₀ /mL (CPD ₅₀ is a cytopathogenic dose of the virus causing 50% cell lysis) and normal saline as a diluent. The viruses were propagated in Vero cells. The safety study used 220 male and female BALB/c mice, 440 male and female Wistar rats, and 18 male Soviet chinchilla rabbits. The study animals received an intravenous dose of 1×105 or 1×106 CPD ₅₀ /animal once (single-dose toxicity) or weekly for 90 days (repeated-dose toxicity). Clinical examination, laboratory testing, and necropsy were performed on Days 45 and 91 of the experiment. Statistical data processing was performed using Prism 8.0 software (GraphPad Software, Inc., USA). RESULTS. Upon single administration of each of the five enterovirus medicinal products to mice and rats, the authors observed complete survival, upward trends in body weight gain, and no gross or histopathological changes in the brain, spleen, liver, kidneys, lungs, or at the injection site. Upon repeated administration at the study doses, the medicinal products caused no functional changes in the organs and systems. All the studied parameters were within the normal physiological ranges for male and female rats. Histopathological examination revealed no pathological changes or specific cytolytic and/or cytopathic effects. No local irritation was observed. None of the investigational medicinal products showed pyrogenicity. CONCLUSIONS. The obtained preclinical results demonstrate the safety of antineoplastic agents based on live non-pathogenic LEV4, LEV7, LEV8, LEV14, and Russo enteroviruses.

Background/Objectives: CTLA4 (Cytotoxic T-Lymphocyte Antigen 4) is a key immune checkpoint that plays a principal part in controlling T-cell activation and maintaining immune homeostasis. CTLA4 haploinsufficiency (CTLA4^+/−) results in severe autoimmune disorders and increased susceptibility to infections, often associated with dysregulated T cell activity. CTLA4^+/− patients experience life-threatening complications and exhibit moderate survival rates that can vary significantly, depending on the treatment of associated autoimmune phenotypes. Current therapeutic approaches primarily use immunosuppressives and monoclonal antibodies to modulate the immune response; however, their effectiveness and specificity are often limited. In this study, we aimed to develop a novel therapy approach for CTLA4 haploinsufficiency utilizing the CRISPR activation system (CRISPRa) to enhance wild-type CTLA4 allele expression. Methods: The CRISPR/Cas9 system has become a widely used method for precise genome editing, allowing for targeted gene regulation. We applied a CRISPRa-based strategy to induce endogenous CTLA4 expression using appropriate cellular models and evaluated transcriptomic changes. Results: CRISPRa-mediated activation enabled increased CTLA4 expression, suggesting the feasibility of restoring physiological expression levels. Conclusions: This approach may provide a basis for developing CRISPRa-based strategies to restore immune regulation and improve clinical outcomes in CTLA4^+/− patients.