Messenger RNA-Based Therapeutics and Vaccines: What's beyond COVID-19?

With the rapid success in the development of mRNA vaccines against COVID-19 and with a number of mRNA-based drugs ahead in the pipelines, mRNA has catapulted to the forefront of drug research, demonstrating its substantial effectiveness against a broad range of diseases. As the recent global pandemic gradually fades, we cannot stop thinking about what the world has gained: the realization and validation of the power of mRNA in modern medicine. A significant amount of research has now been concentrated on developing mRNA drugs and vaccine platforms against infectious and immune diseases, cancer, and other debilitating diseases and has demonstrated encouraging results. Here, based on the CAS Content Collection, we provide a landscape view of the current state, outline trends in the research and development of mRNA therapeutics and vaccines, and highlight some notable patents focusing on mRNA therapeutics, vaccines, and delivery systems. Analysis of diseases disclosed in patents also reveals highly investigated diseases for treatments with these medicines. Finally, we provide information about mRNA therapeutics and vaccines in clinical trials. We hope this Review will be useful for understanding the current knowledge in the field of mRNA medicines and will assist in efforts to solve its remaining challenges and revolutionize the treatment of human diseases.

FBXO2 modulates STAT3 signaling to regulate proliferation and tumorigenicity of osteosarcoma cells.

BACKGROUND: Osteosarcoma (OS) is the most common primary bone malignancy in children and adolescents, and hyperproliferation of cells is a major problem of OS. FBXO2 belongs to the family of F-box proteins, and is a substrate recognition component of the Skp1-Cul1-F-box protein (SCF) E3 ubiquitin ligase complex with specificity for high-mannose glycoproteins. The aim of the present study was to investigate the critical role of FBXO2 in OS cells. METHODS: The protein and mRNA expression levels of FBXO2 in clinic OS patients were measured by quantitative real time-polymerase chain reaction (qRT-PCR), Western blot and Immunohistochemical (IHC) staining assays, respectively. The FBXO2 overexpression model was constructed by retro-virus transfection in OS cells. FBXO2 knockout (KO) cells were generated by Clustered regularly interspaced short palindromic repeat (CRISPR)-CRISPR-associated protein 9 (Cas9) assay. Cell counting and colony formation assays were used to analyze the effect of FBXO2 on the biological function of OS cells. FBXO2 KO cells were injected into nude mice to observe tumor growth in vivo. The interaction between FBXO2 and IL-6 was detected by immunoprecipitation. Luciferase assay was used to determine the transcriptional activity of STAT3. RESULTS: Here, we show that FBXO2 is significantly up-regulated in clinical OS samples compared to adjacent normal tissues. Ectopic expression of FBXO2 leads to increased OS cell proliferation and colony-forming ability, while FBXO2 knockout by CRISPR-Cas9-based gene editing has the opposite effect. In addition, the glycoprotein recognition activity of FBXO2 is required for its biological function in OS. In vivo experiments showed that FBXO2 knockout greatly impaired the tumorigenicity of OS cells in nude mice. At the molecular level, we found that knocking out FBXO2 can significantly inhibit STAT3 phosphorylation and downstream target gene expression through IL-6R stabilization. CONCLUSION: Together, these results indicate that FBXO2 promotes OS development by activating the STAT3 signaling pathway, suggesting that FBXO2 may be a new target for OS treatment.

Characteristics and risk factors for proximal junctional kyphosis in adult spinal deformity after correction surgery: a systematic review and meta-analysis.

There are still controversies on characteristics and risk factors for proximal junctional kyphosis (PJK) in adult spinal deformity (ASD) patients. The objective of this study is to explore the characteristics and risk factors for PJK in ASD. A systematic online search in databases including PubMed, EMBASE, Web of Science, and the Cochrane Library was performed to identify eligible studies. OR and weight mean difference with 95% CI were used to evaluate characteristics and risk factors. A total of 31 studies were finally included. ASD patients with PJK had larger proximal junctional angle (PJA), thoracic kyphosis (TK), pelvic incidence minus lumbar lordosis (PI-LL), and sagittal alignment. Age, female gender, and low BMD/osteoporosis were demographic risk factors for PJK. Using hooks at upper instrumented vertebra (UIV) and the selection of UIV above T8 could reduce the occurrence of PJK, while pelvic fixation was significantly associated with increased occurrence of PJK. Preoperative LL, preoperative pelvic tilt (PT), preoperative LL-TK, preoperative PI-LL, preoperative sagittal vertical axis (SVA), preoperative global spine alignment (GSA), postoperative PJA, change in PJA, postoperative TK, change in LL, change in SVA, and postoperative GSA were identified as risk factors for PJK. In conclusion, PJK patients had larger PJA, larger TK, smaller PI-LL, and larger sagittal alignment. Older female ASD patients with low BMD/osteoporosis are more likely to suffer from PJK. We recommend the following: (1) using hooks at UIV; (2) UIV should be chosen above T8, and pelvic fixation should be avoided if possible; (3) ideal correction of sagittal alignment should be performed to prevent the occurrence of PJK.

Different responses to mechanical injury in neonatal and adult ovine articular cartilage.

BACKGROUND: Articular cartilage injury remains a major challenge in orthopedic surgery. This study aimed to identify differences in gene expression and molecular responses between neonatal and adult articular cartilage during the healing of an injury. METHODS: An established in vitro model was used to compare the transcriptional response to cartilage injury in neonatal and adult sheep by microarray analysis of gene expression. Total RNA was isolated from tissue samples, linearly amplified, and 15,208 ovine probes were applied to cDNA microarray. Validation for selected genes was obtained by real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: We found 1,075 (11.6%) differentially expressed probe sets in adult injured cartilage relative to normal cartilage. A total of 1,016 (11.0%) probe sets were differentially expressed in neonatal injured cartilage relative to normal cartilage. A total of 1,492 (16.1%) probe sets were differentially expressed in adult normal cartilage relative to neonatal normal cartilage. A total of 1,411 (15.3%) probe sets were differentially expressed in adult injured cartilage relative to neonatal injured cartilage. Significant functional clusters included genes associated with wound healing, articular protection, inflammation, and energy metabolism. Selected genes (PPARG, LDH, TOM, HIF1A, SMAD7, and NF-κB) were also found and validated by RT-qPCR. CONCLUSIONS: There are significant differences in gene expression between neonatal and adult ovine articular cartilage following acute injury. They are partly due to intrinsic differences in the process of development, and partly to different biological responses to mechanical trauma between neonatal and adult articular cartilage.