Current Gene Therapy - Volume 23, Issue 1, 2023

The gene therapy is alluring not only for CNS disorders but also for other pathological conditions. Gene therapy employs the insertion of a healthy gene into the identified genome to replace or replenish genes responsible for pathological disorder or damage due to trauma. The last decade has seen a drastic change in the understanding of vital aspects of gene therapy. Despite the complexity of traumatic brain injury (TBI), the advent of gene therapy in various neurodegenerative disorders has reinforced the ongoing efforts of alleviating TBI-related outcomes with gene therapy. The review highlights the genes modulated in response to TBI and evaluates their impact on the severity and duration of the injury. We have reviewed strategies that pinpointed the most relevant gene targets to restrict debilitating events of brain trauma and utilize vector of choice to deliver the gene of interest at the appropriate site. We have made an attempt to summarize the long-term neurobehavioral consequences of TBI due to numerous pathometabolic perturbations associated with a plethora of genes. Herein, we shed light on the basic pathological mechanisms of brain injury, genetic polymorphism in individuals susceptible to severe outcomes, modulation of gene expression due to TBI, and identification of genes for their possible use in gene therapy. The review also provides insights on the use of vectors and challenges in translations of this gene therapy to clinical practices.

Neurological and neuropsychiatric disorders are the main risks for the health care system, exhibiting a huge socioeconomic load. The available range of pharmacotherapeutics mostly provides palliative consequences and fails to treat such conditions. The molecular etiology of various neurological and neuropsychiatric disorders is mostly associated with a change in genetic background, which can be inherited/triggered by other environmental factors. To address such conditions, gene therapy is considered a potential approach claiming a permanent cure of the disease primarily by deletion, silencing, or edition of faulty genes and by insertion of healthier genes. In gene therapy, vectors (viral/nonvial) play an important role in delivering the desired gene to a specific region of the brain. Targeted gene therapy has unraveled opportunities for the treatment of many neurological and neuropsychiatric disorders. For improved gene delivery, the current techniques mainly focus on designing a precise viral vector, plasmid transfection, nanotechnology, microRNA, and in vivo clustered regulatory interspaced short palindromic repeats (CRISPR)-based therapy. These latest techniques have great benefits in treating predominant neurological and neurodevelopmental disorders, including Parkinson's disease, Alzheimer's disease, and autism spectrum disorder, as well as rarer diseases. Nevertheless, all these delivery methods have their limitations, including immunogenic reactions, off-target effects, and a deficiency of effective biomarkers to appreciate the effectiveness of therapy. In this review, we present a summary of the current methods in targeted gene delivery, followed by the limitations and future direction of gene therapy for the cure of neurological and neuropsychiatric disorders.

Cancer stem cells (CSCs) are cancer-initiating cells found in most tumors and hematological cancers. CSCs are involved in cells progression, recurrence of tumors, and drug resistance. Current therapies have been focused on treating the mass of tumor cells and cannot eradicate the CSCs. CSCs drug-specific targeting is considered as an approach to precisely target these cells. Clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) gene-editing systems are making progress and showing promise in the cancer research field. One of the attractive applications of CRISPR/Cas9 as one approach of gene therapy is targeting the critical genes involved in drug resistance and maintenance of CSCs. The synergistic effects of gene editing as a novel gene therapy approach and traditional therapeutic methods, including chemotherapy, can resolve drug resistance challenges and regression of the cancers. This review article considers different aspects of CRISPR/Cas9 ability in the study and targeting of CSCs with the intention to investigate their application in drug resistance.

As one of the main characteristics of neoplasia, metabolic reprogramming provides nutrition and energy to enhance cell proliferation and maintain environment homeostasis. Glycolysis is one of the most important components of cancer metabolism and the Warburg effect contributes to the competitive advantages of cancer cells in the threatened microenvironment. Studies show strong links between N⁶-methyladenosine (m⁶A) modification and metabolic recombination of cancer cells. As the most abundant modification in eukaryotic RNA, m⁶A methylation plays important roles in regulating RNA processing, including splicing, stability, transportation, translation and degradation. The aberration of m⁶A modification can be observed in a variety of diseases such as diabetes, neurological diseases and cancers. This review describes the mechanisms of m⁶A on cancer glycolysis and their applications in cancer therapy and prognosis evaluation, aiming to emphasize the importance of targeting m⁶A in modulating cancer metabolism.

Background: Breast cancer (BRCA) is the most common type of cancer among women worldwide. MiR-1260b has been widely demonstrated to participate in multiple crucial biological functions of cancer tumorigenesis, but its functional effect and mechanism in human breast cancer have not been fully understood. Methods: qRT-PCR was used to detect miR-1260b expression in 29 pairs of breast cancer tissues and normal adjacent tissues. Besides, the expression level of miR-1260b in BRCA cells was also further validated by qRT-PCR. miR-1260b played its role in the prognostic process by using Kaplan-Meier curves. In addition, miR-1260b knockdown and target gene CCDC134 overexpression model was constructed in cell line MDA-MB-231. Transwell migration and invasion assay was performed to analyze the effect of miR-1260b and CCDC134 on the biological function of BRCA cells. TargetScan and miRNAWalk were used to find possible target mRNAs. The relationship between CCDC134 and immune cell surface markers was analyzed using TIMER and database and the XIANTAO platform. GSEA analysis was used to identify possible CCDC134-associated molecular mechanisms and pathways. Results: In the present study, miR-1260b expression was significantly upregulated in human breast cancer tissue and a panel of human breast cancer cell lines, while the secretory protein coiled-coil domain containing 134 (CCDC134) exhibited lower mRNA expression. High expression of miR-1260b was associated with poor overall survival among the patients by KM plot. Knockdown of miR-1260b significantly suppressed breast cancer cell migration and invasion and yielded the opposite result. In addition, overexpression of CCDC134 could inhibit breast cancer migration and invasion, and knockdown yielded the opposite result. There were significant positive correlations of CCDC134 with CD25 (IL2RA), CD80 and CD86. GSEA showed that miR-1260b could function through the MAPK pathway by downregulating CCDC134. Conclusion: Collectively, these results suggested that miR-1260b might be an oncogene of breast cancer and might promote the migration and invasion of BRCA cells by down-regulating its target gene CCDC134 and activating MAPK signaling pathway as well as inhibiting immune function and causing immune escape in human breast cancer.

Background: The fatality rate of acute lung injury (ALI) is as high as 40% to 60%. Although various factors, such as sepsis, trauma, pneumonia, burns, blood transfusion, cardiopulmonary bypass, and pancreatitis, can induce ALI, patients with these risk factors will eventually develop ALI. The rate of developing ALI is not high, and the outcomes of ALI patients vary, indicating that it is related to genetic differences between individuals. In a previous study, we found multiple functions of cavin-2 in lung function. In addition, many other studies have revealed that CAV1 is a critical regulator of lung injury. Due to the strong relationship between cavin-2 and CAV1, we suspect that cavin-2 is also associated with ALI. Furthermore, we are curious about the role of the CAV family and cavin family genes in ALI. Methods: To reveal the mechanism of CAV and CAVIN family genes in ALI, we propose DeepGENE to predict whether CAV and CAVIN family genes are associated with ALI. This method constructs a gene interaction network and extracts gene expression in 84 tissues. We divided these features into two groups and used two network encoders to encode and learn the features. Results: Compared with DNN, GBDT, RF and KNN, the AUC of DeepGENE increased by 7.89%, 16.84%, 20.19% and 32.01%, respectively. The AUPR scores increased by 8.05%, 15.58%, 22.56% and 23.34%. DeepGENE shows that CAVIN-1, CAVIN-2, CAVIN-3 and CAV2 are related to ALI. Conclusion: DeepGENE is a reliable method for identifying acute lung injury-related genes. Multiple CAV and CAVIN family genes are associated with acute lung injury-related genes through multiple pathways and gene functions.