Discovery Category Highlights

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

The Heat Shock Response: Its Role in Pathogenesis of Type 2 Diabetes and Its Complications, and Implications for Therapeutic Intervention

Abstract: The heat shock response (HSR) is an evolutionarily conserved mechanism that cells and organisms utilize to protect themselves from the damaging effects of stress. Induction of HSR involves a complex multi-step process in which heat shock factor-1 (HSF-1), the key modulator of HSR, is activated, leading to the induction of a variety of heat shock genes. There is evidence that the HSR is defective in diabetes, which makes the tissues vulnerable to stress-induced pathological changes. Consistent with this observation, induction of HSR by either non-pharmacological methods such as hyperthermia or by pharmacological inducers has beneficial effects in managing insulin resistance and hyperglycemia, as well as secondary complications of diabetes, such as cardiovascular disease, nephropathy, neuropathy, and retinopathy as well as wound healing. This review summarizes what is currently known about the role of the HSR in diabetes and therapeutic implications of enhancing HSR in the management of diabetes and its associated complications, focusing on small molecule mediated therapeutics. ... Read more

The Role of Ubiquitin-Proteasome in the Metabolism of Amyloid Precursor Protein (APP): Implications for Novel Therapeutic Strategies for Alzheimer's Disease

Abstract: The proteasome serves as a major protein quality control system inside the cell. Dysfunction of this system has been associated with Alzheimer's disease (AD) pathogenesis. Amyloid β accumulation is considered as the central molecular event in the development of AD. This accumulation can result from dysregulated proteolysis of its precursor, APP. Here, we will review the evidence that links proteasome dysfunction to altered APP metabolism, and summarize recent progress in identifying the regulators of APP ubiquitination. Pinpointing UPS components that are APP-specific could lead new pharmaceutical strategies to combat AD. ... Read more

Interplay Between microRNAs, Toll-like Receptors, and HIV-1: Potential Implications in HIV-1 Replication and Chronic Immune Activation

Abstract: MicroRNAs (miRNAs) are important cellular, small non-coding RNAs that regulate host gene expression and have well-characterized roles in inflammation and infectious diseases. It has become apparent as well that cellular miRNAs can play crucial roles in controlling HIV-1 infection and replication. Whether HIV-1 encodes and is able to express viral miRNAs in infected cells remains controversial. HIV-1 can manipulate the biogenesis of miRNAs as well as the expression profiles of cellular miRNAs. Toll-Like receptors (TLRs) are important pathogen recognition receptors that sense invading pathogens orchestrating innate and adaptive immune responses. Innate immune recognition of HIV-1 infection leads to activation of TLR7/8. Recent evidence has shown that certain miRNAs can also be recognized by TLR7/8 leading to immune activation. However, the potential TLR7/8-mediated recognition of HIV-1 encoded miRNAs and/or cellular miRNAs modulated in HIV-1 infected cells has not been experimentally explored. In this review, we summarize the current literature on HIV-1 infection and miRNAs. Furthermore, we underscore the need for future research on potential miRNA-induced activation of TLR7/8, which might contribute to the chronic immune activation observed in HIV-1 infected patients. ... Read more

Novel Methods of Type 1 Diabetes Treatment

Abstract: Type 1 diabetes is an autoimmune disease characterized by the cell-mediated destruction of insulin-producing β-cells, leading to impaired glucose homeostasis, insulin insufficiency, and other complications. Although classic genetic studies have linked numerous genes to the susceptibility of developing diabetes, the mechanisms by which they influence the disease course remain poorly understood. Epigenetics, inheritable changes in gene expression that occur without accompanying genetic mutation, can both serve as a link between the environment and genetic causes of disease and help explain some of the observed vagaries of diabetes. Elucidation of the epigenetic landscape as it relates to putative treatment modalities is highly warranted. Drugs with histone deacetylase activity are in clinical trials for cancer and certain inflammatory diseases with high safety profiles and they hold similar promise for amelioration of type 1 diabetes with diminished secondary complications. Full-fledged studies on the epigenetics of type 1 diabetes are highly likely to provide novel tools for the manipulation of the disease in the years to come. In this review, epigenetic regulation mediated by small molecular inhibitors of histone deacetylases and their potential for preventing diabetes are discussed. Insights into the nature of the genetic mechanisms unraveled by these studies are also highlighted. ... Read more

Advances in the Diagnosis and Treatment of Uterine Sarcomas

Abstract: Uterine sarcomas account for less than 10% of all uterine neoplasms (Tropé et al., 2012). The most common include uterine leiomyosarcoma and the endometrial stromal neoplasms. The diagnosis requires pathologic review of the uterus in order to characterize extent of myometrial invasion. However, molecular diagnosis has aided the classification of endometrial stromal neoplasms, especially in helping to discriminate between endometrial stromal and undifferentiated endometrial sarcoma. The prognosis of these tumors following surgery varies, with endometrial stromal sarcoma associated with a better prognosis compared to leiomyosarcoma or undifferentiated endometrial sarcoma. For aggressive sarcomas, there is interest in adjuvant treatment, which has focused on the evaluation of systemic agents. However, the rarity of these tumors makes the conduct of prospective trials difficult and no consensus adjuvant regimen has emerged. In the absence of Level I data, the use of chemotherapy is based on institutional preferences. Ongoing clinical trials will help inform the standard treatment approach for these tumors, and we encourage patients with uterine sarcoma to participate in well-designed clinical trials. ... Read more

Advances in the Pharmacotherapy of Patients with Acromegaly

Abstract: Acromegaly is a disease characterized by growth hormone (GH) excess originating, in approximately 95% of cases, from a somatotroph pituitary adenoma. Symptomatology and clinical features are due to GH and insulin-like growth factor 1 excess; unfortunately, for most patients diagnosis is delayed by several years. Acromegaly patients' morbidity and mortality are higher than those of the normal population. However, with adequate biochemical control mortality rates can be restored to normal. Tumor size and location, symptoms, comorbidities, and lastly, but not least, patient preference, are all important aspects in treatment decision making, and treatment approach should be individualized. Current therapy includes medical, surgical, and radiation. This review focuses on recent significant developments in medical therapy. There are three major therapeutic drug classes: somatostatin receptor ligands (SRLs), which represent the mainstay of medical therapy, GH receptor blockers, and dopamine agonists. Multi-ligand receptor SRLs such as pasireotide, should increase therapeutic choices for acromegaly patients currently uncontrolled on available SRLs. Furthermore, significant research has been focused in the development of novel delivery modalities (e.g., oral and long acting subcutaneous administration). ... Read more

Gene Therapy for Obesity: Progress and Prospects

Abstract: Advances in understanding the molecular basis of obesity and obesity-associated diseases have made gene therapy a vital approach in coping with this world-wide epidemic. Gene therapy for obesity aims to increase or decrease gene product in favor of lipolysis and energy expenditure, leading toward fat reduction and loss of body weight. It involves successful delivery and expression of therapeutic genes in appropriate cells. The ultimate goal of gene therapy is to restore and maintain energy homeostasis. Here we summarize progress made in recent years in identifying genes responsible for obesity and present examples where the gene therapy approach has been applied to treating or preventing obesity. Discussion on advantages and limitations of gene therapy strategies employed is provided. The intent of this review is to inspire further studies toward the development of new strategies for successful treatment of obesity and obesity-associated diseases. ... Read more

The Impact of New Genomic Technologies in Reproductive Medicine

Abstract: Recent advances in the clinical application of genomic technologies have significantly impacted the field of prenatal diagnosis. Central to these advances has been the implementation of chromosomal microarray analysis (CMA). Microdeletions and microduplications, undetectable by traditional karyotyping, have recently been confirmed to play a role in altered neurocognitive development. CMA is now recommended for fetuses with structural anomalies. However, CMA comes with an increased need and role for genetic counseling, because the potential genomic information available is exponentially increased. CMA also can be performed on a small number of preimplantation embryonic cells for assessment of the embryo's reproductive potential. Implementation of these new genomic techniques in an in vitro fertilization setting has already demonstrated significant improvements in reproductive outcome. Techniques are now being developed to eliminate the necessity for invasive prenatal diagnosis procedures. Currently in its infancy, noninvasive prenatal testing using cell-free fetal DNA from maternal blood has already improved the sensitivity for detection of the common aneuploidies and current efforts are focused on identifying select microdeletions. The explosion of new genomic technologies continues to offer great benefits. However, each needs critical assessment prior to adoption in a clinical setting. ... Read more

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