CAR-NK Cells for Cancer Therapy: Molecular Redesign of the Innate Antineoplastic Response

: The Chimeric Antigen Receptor (CAR) has arisen as a powerful synthetic biology-based technology with demonstrated versatility for implementation in T and NK cells. Despite CAR T cell successes in clinical trials, several challenges remain to be addressed regarding adverse events and long-term efficacy. NK cells present an attractive alternative with intrinsic advantages over T cells for treating solid and liquid tumors. Early preclinical and clinical trials suggest at least two major advantages: improved safety and an off-the-shelf application in patients due to its HLA independence. Due to the early stages of CAR NK translation to clinical trials, limited data is currently available. By analyzing these results, it seems that CAR NK cells could offer a reduced probability of Cytokine Release Syndrome (CRS) or Graft versus Host Disease (GvHD) in cancer patients, reducing safety concerns. Furthermore, NK cell therapy approaches may be boosted by combining it with immunological checkpoint inhibitors and by implementing genetic circuits to direct CAR-bearing cell behavior. This review provides a description of the CAR technology for modifying NK cells and the translation from preclinical studies to early clinical trials in this new field of immunotherapy.

CircRNAs in lung adenocarcinoma: diagnosis and therapy

: Lung adenocarcinoma (LUAD) is the common histological subtype of non-small-cell lung carcinoma (NSCLC). Circular RNAs (circRNAs) represent a new class of non-coding RNAs (ncRNAs) involved in the development of cancer. Accumulating evidence indicated that a large number of circular RNAs were found to be involved in many biological processes, including tumor initiation, proliferation and progression. These circRNAs present great potentials as new biomarkers and vital targets for disease diagnosis and prognosis. In this review, we mainly focus on the differentially expressed circRNAs and their functions in the pathogenesis of LUAD, which makes it possible for the utility of circRNAs as novel biomarkers for early diagnosis and therapy. Especially, it is helpful to develop circRNAs as crucial therapeutic targets, thus providing a promising biomedical application in the field of cancer gene therapy.

Roles of M6A Regulators in Hepatocellular Carcinoma: Promotion or Suppression

: Hepatocellular carcinoma (HCC) is the sixth globally diagnosed cancer with a poor prognosis. Although the pathological factors of hepatocellular carcinoma are well elucidated, the underlying molecular mechanisms remain unclear. N6-methyladenosine (m6A) is an adenosine methylation occurring at the N6 site, which is the most prevalent modification of eukaryotic mRNA. Recent studies have shown that m6A can regulate gene expression, thus modulating the processes of cell self-renewal, differentiation, and apoptosis. The methyls in m6A are installed by methyltransferases (“writers”), removed by demethylases (“erasers”) and recognized by m6A-binding proteins (“readers”). In this review, we discuss the roles of above regulators in the progression and prognosis of HCC, and summarize the clinical association between m6A modification and hepatocellular carcinoma, so as to provide more valuable information for clinical treatment.

Gene therapy for chronic traumatic brain injury: Challenges to resolve long-term consequences of brain damage

: The promise of 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 sea 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 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 attempted 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 provided insights on the use of vectors and challenges in translations of this gene therapy to clinical practices.

Cancer treatment evolution from traditional methods to stem cells and gene therapy

Background: Cancer, a malignant tumor, is caused by the failure of the mechanism that controls cell growth and proliferation. Late clinical symptoms often manifest as lumps, pain, ulcers, and bleeding. Systemic symptoms include weight loss, fatigue, and loss of appetite. It is a major disease that threatens human life and health. How to treat cancer is a long-standing problem that needs to be overcome in the history of medicine. Discussion: In the text, we systematically review the cancer treatment evolution from traditional methods to novel approaches that include immunotherapy, nanotherapy, stem cell theapy, and gene therapy. We provide the latest review of the application status, clinical trials and development prospects of mesenchymal stem cells and gene therapy for cancer, as well as their integration in cancer treatment. Mesenchymal stem cells are effective carriers carrying genes and provide new clinical ideas for tumor treatment. Conclusion: This review focuses on the current status, application prospects and challenges of mesenchymal stem cell combined gene therapy for cancer, and provides new ideas for clinical research.

The effects of human umbilical cord mesenchymal stem cell transplantation on female fertility restoration in mice

Background: Female fertility refers to the capacity to produce oocytes and achieve fertilization and pregnancy, and it is impaired by age, disease, environment and social pressure. However, no effective therapy that restores female reproductive ability has been established. Mesenchymal stromal cells (MSCs) exhibit multilineage differentiation potential and have attracted considerable attention as a tool for restoring female fertility. Methods: This study used human umbilical cord-MSCs (Huc-MSCs) to restore fertility in aging female mice and mice with chemotherapy-induced damage through the rescue of ovarian function and reconstruction of the fallopian tubes and uterus. In our study, two mouse models were generated: aging mice (35 weeks of age) and mice with chemotherapy-induced damage. Results: The effect of MSCs on the ovaries, fallopian tubes and uterus was evaluated by analyzing gonadal hormone levels and by performing morphological and statistical analyses. The levels of estradiol (E2) and follicle-stimulating hormone (FSH) exhibited significant recovery after Huc-MSC transplantation in both aging mice and chemotherapy-treated mice. Huc-MSC treatment also increased the number of primordial, developing and preovulatory follicles in the ovaries of mice. Moreover, MSCs were shown to rescue the morphology of the fallopian tubes and uterus through mechanisms such as cilia regeneration in the fallopian tubes and reformation of glands and endometrial tissue in the uterus. Conclusion: Huc-MSCs may represent an effective treatment for restoring female fertility through recovery from chemotherapy-induced damage and rescue of female reproductive organs from the effects of aging.

CRISPR Systems Suitable for Single AAV Vector Delivery

: CRISPR (clustered regularly interspaced short palindromic repeats)/Cas gene editing is a revolutionary technology that can enable the correction of genetic mutations in vivo, providing great promise as a therapeutic intervention for inherited diseases. Adeno-associated viral (AAV) vectors are a potential vehicle for delivering CRISPR/Cas. However, they are restricted by their limited packaging capacity. Identifying smaller Cas orthologs that can be packaged, along with the required guide RNA elements, into a single AAV would be an important optimization for CRISPR/Cas gene editing. Expanding the options of Cas proteins that can be delivered by a single AAV not only increases translational application but also expands the genetic sites that can be targeted for editing. This review considers the benefits and current scope of small Cas protein orthologs that are suitable for gene editing approaches using single AAV vector delivery.

Reduced Immunogenicity of Intraparenchymal Delivery of Adeno-Associated Virus Serotype 2 Vectors: Brief Overview

: Preexisting immunity to adeno-associated virus (AAV) poses a concern in AAV vector–mediated gene therapy. Localized administration of low doses of carefully chosen AAV serotypes can mitigate the risk of an immune response. This article will illustrate the low risk of immune response to AAV serotype 2 vector–mediated gene therapy to the brain with support from clinical trial data in aromatic L-amino acid decarboxylase deficiency and Parkinson disease.