Discovery Category Highlights

State-Of-The-Art Human Gene Therapy: Part II. Gene Therapy Strategies and Clinical Applications

Abstract: In Part I of this Review (Wang and Gao, 2014), we introduced recent advances in gene delivery technologies and explained how they have powered some of the current human gene therapy applications. In Part II, we expand the discussion on gene therapy applications, focusing on some of the most exciting clinical uses. To help readers to grasp the essence and to better organize the diverse applications, we categorize them under four gene therapy strategies: (1) gene replacement therapy for monogenic diseases, (2) gene addition for complex disorders and infectious diseases, (3) gene expression alteration targeting RNA, and (4) gene editing to introduce targeted changes in host genome. Human gene therapy started with the simple idea that replacing a faulty gene with a functional copy can cure a disease. It has been a long and bumpy road to finally translate this seemingly straightforward concept into reality. As many disease mechanisms unraveled, gene therapists have employed a gene addition strategy backed by a deep knowledge of what goes wrong in diseases and how to harness host cellular machinery to battle against diseases. Breakthroughs in other biotechnologies, such as RNA interference and genome editing by chimeric nucleases, have the potential to be integrated into gene therapy. Although clinical trials utilizing these new technologies are currently sparse, these innovations are expected to greatly broaden the scope of gene therapy in the near future. ... Read more

Advances in the Etiology and Mechanisms of Type 1 Diabetes

Abstract: Type 1 diabetes (T1D) is an insulin-dependent form of diabetes resulting from the autoimmune destruction of pancreatic beta cells. The past few decades have seen tremendous progress in our understanding of the molecular basis of the disease, with the identification of susceptibility genes and autoantigens, the demonstration of several abnormalities affecting various cell types and functions, and the development of improved assays to detect and monitor autoimmunity and beta cell function. New findings about the disease pathology and pathogenesis are emerging from extensive studies of organ donors with T1D promoted by the JDRF nPOD (Network for the Pancreatic Organ Donor with Diabetes). Furthermore, the establishment of extensive collaborative projects including longitudinal follow-up studies in relatives and clinical trials are setting the stage for a greater understanding of the role of environmental factors, the natural history of the disease, and the discovery of novel biomarkers for improved prediction, which will positively impact future clinical trials. Recent studies have highlighted the chronicity of islet autoimmunity and the persistence of some beta cell function for years after diagnosis, which could be exploited to expand therapeutic options and the time window during which a clinical benefit can be achieved. ... Read more

Recent Advances in the Treatment of Sarcomas in Gynecology

Abstract: Uterine sarcomas are a heterologous group of rare malignancies accounting for 8-10% of all uterine malignancies, but are significantly more aggressive and have worse prognoses. Management of uterine sarcomas including leiomyosarcoma and endometrial stromal sarcoma are reviewed here, with additional discussions regarding high-grade undifferentiated sarcoma and adenosarcoma. Uterine carcinosarcomas are currently staged and treated similar to high-grade epithelial endometrial carcinomas, thus will not be discussed in this review. Gemcitabine/docetaxel with adriamycin holds promise for the treatment of leiomyosarcoma, but currently, limited advancements have been made in discovering targeted therapies to these tumors. Continued translational research in both medical oncology and gynecologic oncology is necessary to forward the development of novel and targeted therapeutic agents in the treatment of sarcoma. Enrollment of these patients in clinical trials is encouraged, and will allow for the development of safer and more effective therapies. ... Read more

Current siRNA Targets in the Prevention and Treatment of Intimal Hyperplasia

Abstract: Intimal hyperplasia (IH) is the leading cause of late vein and prosthetic bypass graft failure. Injury at the time of graft implantation leading to the activation of endothelial cells and dedifferentiation of vascular smooth muscle cells to a synthetic phenotype are known causes of IH. Prior attempts to develop therapy to mitigate these cellular changes to prevent IH and graft failure have failed. Small interfering RNA (siRNA) mediated targeted gene silencing is a promising tool to prevent IH. Several studies have been performed in this direction to target genes that are involved in IH. In this review we discuss siRNA targets that are being investigated for prevention and treatment of IH. ... Read more

Bimodal Plasma Metabolomics Strategy Identifies Novel Inflammatory Metabolites in Inflammatory Bowel Diseases

Abstract: Introduction: Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) characterized by variable phenotypes. Metabolites are signatures of biochemical activity that can reveal unknown pathogenic pathways. We employed untargeted mass spectrometry (MS) based metabolomics to identify novel inflammatory mechanisms in IBD and a targeted assay to quantify metabolites of the auto-immunomodulating kynurenine pathway (KP) in IBDs and health. Materials and Methods: Metabolome analysis of CD, UC, and control plasmas was performed on a Liquid Chromatography (LC)-MS/MS system. KP metabolites quinolinic acid (QA) and picolinic acid (PA) were quantified by gas chromatography/MS. Results: Nineteen UC, 25 CD, and 9 control plasmas were analyzed: 34 metabolites exhibited abundance profiles associated with CD by global metabolome analysis (P≤0.05, false discovery rate q≤0.01). Notably, inflammatory-implicated metabolites angiotensin IV (P=0.049, q<0.001), diphthamide (P=0.018, q<0.001), and GM3 gangliosides (P<0.001, q<0.001) were increased in CD. By targeted kynurenine metabolites assay, QA (73.53 ng/mL ± 23.40 SD) and combined kynurenine metabolites (CKM) were increased in CD (120.19 ± 39.71) compared to controls (QA  50.14 ± 15.04; P<0.01; CKM 92.73 ± 26.30; P<0.01). CD QA positively correlated with CDAI (r=0.85; P<0.01), CRP (r=0.46; P=0.01), and ESR (r=0.42; P=0.03), while CKMs correlated with CDAI (r=0.615; P<0.01) and CRP (r=0.615; P=0.02). Conclusions: Associations of angiotensin IV, diphthamide, and GM3 gangliosides with CD implicate novel pathways in activating a Th1/Th17 inflammatory profile. Increased QA concentrations in CD may indicate a defective auto-immunomodulation mechanism. ... Read more

Protective Factors in Diabetic Retinopathy: Focus on Blood-Retinal Barrier

Abstract: The earliest and most significant change in diabetic retinopathy (DR) is blood-retinal barrier (BRB) dysfunction, followed by two main pathologies that may cause severe visual impairment: Diabetic Macular Edema (DME) and Proliferative Diabetic Retinopathy (PDR). The pathological hallmarks of BRB dysfunction include loss of tight junction integrity, VEGF- and AGE-induced damage, oxidative stress, and inflammatory changes. Recently, several BRB protective factors have been reported. Our aim is to give a review of those protective factors and discuss new potential therapeutic targets for DR. ... Read more

Targeting VEGF/VEGFR in the Treatment of Psoriasis

Abstract: Psoriasis is a common chronic skin disorder characterized by cutaneous inflammation and keratinocyte hyperproliferation. In the past decade, a number of novel effective biological agents have been developed to treat moderate-to-severe psoriasis. However, these drugs have potential serious side effects, particularly the development of infectious diseases. Therefore there is still a need for new therapies with better efficacy and less adverse effects. Angiogenesis is implicated in various pathological conditions including psoriasis. Direct targeting of angiogenesis becomes a new therapeutic strategy for the treatment of psoriasis. Vascular endothelial growth factor (VEGF), the most critical angiogenic factor, is thought to play important roles during the pathogenesis of psoriasis and may be a promising target for treating psoriasis. Therefore, we proposed that targeting VEGF/VEGFRs could lead to new treatments for psoriasis. ... Read more

Axonal Pathology and Demyelination in Viral Models of Multiple Sclerosis

Abstract: Multiple sclerosis (MS) is an immune-mediated inflammatory demyelinating disease of the central nervous system (CNS). Monozygotic twin studies suggest that while there is a genetic contribution, genetics alone cannot be the sole determining factor in the development of MS. As the rates of MS are increasing, particularly among women, environmental factors such as viral infections are coming to the foreground as potential agents in triggering disease in genetically susceptible individuals. This review highlights pathological aspects related to two pre-clinical viral models for MS; data are consistent between these two models as experimental infection of susceptible mice can induce axonal degeneration associated with demyelination. These data are consistent with observations in MS that axonal damage or Wallerian degeneration is occurring within the CNS contributing to the disability and disease severity. Such early damage, where axonal damage is primary to secondary demyelination, could set the stage for more extensive immune mediated demyelination arising later. ... Read more

State-Of-The-Art Human Gene Therapy: Part I. Gene Delivery Technologies

Abstract: Safe and effective gene delivery is a prerequisite for successful gene therapy. In the early age of human gene therapy, setbacks due to problematic gene delivery vehicles plagued the exciting therapeutic outcome. However, gene delivery technologies rapidly evolved ever since. With the advancement of gene delivery techniques, gene therapy clinical trials surged during the past decade. As the first gene therapy product (Glybera) has obtained regulatory approval and reached clinic, human gene therapy finally realized the promise that genes can be medicines. The diverse gene delivery techniques available today have laid the foundation for gene therapy applications in treating a wide range of human diseases. Some of the most urgent unmet medical needs, such as cancer and pandemic infectious diseases, have been tackled by gene therapy strategies with promising results. Furthermore, combining gene transfer with other breakthroughs in biomedical research and novel biotechnologies opened new avenues for gene therapy. Such innovative therapeutic strategies are unthinkable until now, and are expected to be revolutionary. In part I of this review, we introduced recent development of non-viral and viral gene delivery technology platforms. As cell-based gene therapy blossomed, we also summarized the diverse types of cells and vectors employed in ex vivo gene transfer. Finally, challenges in current gene delivery technologies for human use were discussed. ... Read more

Next Generation Sequencing and the Management of Diffuse Large B-cell Lymphoma: From Whole Exome Analysis to Targeted Therapy

Abstract: Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma, accounting for 30-40% of newly diagnosed non-Hodgkin lymphomas. Historically, DLBCL has been thought to involve recurrent translocations of the IGH gene and the deregulation of rearranged oncogenes. Recent advances in next generation sequencing (NGS) have provided a vast and comprehensive catalogue of cancer genes involved in DLBCL pathogenesis. Whole exome sequencing (WES) of more than two hundred DLBCLs has completely redefined the genetic landscape of the disease by identifying recurrent single nucleotide variants and providing new therapeutic opportunities for the germinal center B-cell like (GCB), activated B-cell like (ABC), or primary mediastinal B-cell (PMBL) molecular subtypes. Some of these somatic mutations target genes that play a crucial role in B-cell function (BCR signaling, NF-κB pathway, NOTCH signaling, Toll-like receptor signaling, and the PI3K pathway), immunity, cell cycle/apoptosis, or chromatin modification. In this review, we present an overview of the mutations recently discovered by NGS in DLBCL and discuss their biological relevance and possible impacts on clinical management. ... Read more

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