Review

Abstract

RNA interference provides a potent and specific method for controlling gene expression in human cells. To translate this potential into a broad new family of therapeutics, it is necessary to optimize the efficacy of the RNA-based drugs. As discussed in this Review, it might be possible to achieve this optimization using chemical modifications that improve their in vivo stability, cellular delivery, biodistribution, pharmacokinetics, potency, and specificity.

Authors

David R. Corey

×

Abstract

Sequence-specific gene silencing using small interfering RNA (siRNA) is a Nobel prize–winning technology that is now being evaluated in clinical trials as a potentially novel therapeutic strategy. This article provides an overview of the major pharmaceutical challenges facing siRNA therapeutics, focusing on the delivery strategies for synthetic siRNA duplexes in vivo, as this remains one of the most important issues to be resolved. This article also highlights the importance of understanding the genocompatibility/toxicogenomics of siRNA delivery reagents in terms of their impact on gene-silencing activity and specificity. Collectively, this information is essential for the selection of optimally acting siRNA delivery system combinations for the many proposed applications of RNA interference.

Authors

Saghir Akhtar , Ibrahim F. Benter

×

Abstract

With unprecedented speed, RNA interference (RNAi) has advanced from its basic discovery in lower organisms to becoming a powerful genetic tool and perhaps our single most promising biotherapeutic for a wide array of diseases. Numerous studies document RNAi efficacy in laboratory animals, and the first clinical trials are underway and thus far suggest that RNAi is safe to use in humans. Yet substantial hurdles have also surfaced and must be surmounted before therapeutic RNAi applications can become a standard therapy. Here we review the most critical roadblocks and concerns for clinical RNAi transition, delivery, and safety. We highlight emerging solutions and concurrently discuss novel therapeutic RNAi-based concepts. The current rapid advances create realistic optimism that the establishment of RNAi as a new and potent clinical modality in humans is near.

Authors

Dirk Grimm, Mark A. Kay

×

Abstract

Small molecules and antibodies have revolutionized the treatment of malignant diseases and appear promising for the treatment of many others. Nonetheless, there are many candidate therapeutic targets that are not amenable to attack by the current generation of targeted therapies, and in a small but growing number of patients, resistance to initially successful treatments evolves. This Review Series on the medicinal promise of posttranscriptional gene silencing with small interfering RNA and other molecules capable of inducing RNA interference (RNAi) is motivated by the hypothesis that effectors of RNAi can be developed into effective drugs for treating malignancies as well as many other types of disease. As this Review Series points out, there is still much to do, but many in the field now hope that the time has finally arrived when “antisense” therapies will finally come of age and fulfill their promise as the magic bullets of the 21st century.

Authors

Alan M. Gewirtz

×

Abstract

In striking contrast to HIV infection, natural SIV infection of African nonhuman primates is asymptomatic and usually does not induce significant CD4+ T cell depletion despite high levels of virus replication. Recently, significant progress has been made in understanding the mechanisms underlying the remarkable difference in infection outcome between natural and nonnatural HIV/SIV hosts. These advances include the identification of limited immune activation as a key factor protecting natural SIV hosts from AIDS and the discovery of low CC chemokine receptor 5 expression on CD4+ T cells as a specific and consistent immunologic feature in these animals. Further elucidation of the pathways by which the differences in immune activation between natural and nonnatural hosts are manifest holds promise for the design of novel therapeutic approaches to HIV infection.

Authors

Guido Silvestri, Mirko Paiardini, Ivona Pandrea, Michael M. Lederman, Donald L. Sodora

×

Abstract

Breast cancer is not a single disease, but rather is composed of distinct subtypes associated with different clinical outcomes. Understanding this heterogeneity is key for the development of targeted cancer-preventative and -therapeutic interventions. Current models explaining inter- and intratumoral diversity are the cancer stem cell and the clonal evolution hypotheses. Although tumor initiation and progression are predominantly driven by acquired genetic alterations, recent data implicate a role for microenvironmental and epigenetic changes as well. Comprehensive unbiased studies of tumors and patient populations have significantly advanced our molecular understanding of breast cancer, but translating these findings into clinical practice remains a challenge.

Authors

Kornelia Polyak

×

Abstract

Lung cancer is the leading cause of cancer death worldwide. The disease is particularly difficult to detect, and patients often present at an advanced stage. Current treatments have limited effectiveness, and unfortunately, the prognosis remains poor. Recent insights into the molecular pathogenesis and biologic behavior of lung cancer have led to the development of rationally designed methods of early detection, prevention, and treatment of this disease. This article will review the important clinical implications of these advances, with a focus on new molecularly targeted therapies currently in development.

Authors

Sophie Sun, Joan H. Schiller, Monica Spinola, John D. Minna

×

Abstract

Since the effectiveness of androgen deprivation for treatment of advanced prostate cancer was first demonstrated, prevention strategies and medical therapies for prostate cancer have been based on understanding the biologic underpinnings of the disease. Prostate cancer treatment is one of the best examples of a systematic therapeutic approach to target not only the cancer cells themselves, but the microenvironment in which they are proliferating. As the population ages and prostate cancer prevalence increases, challenges remain in the diagnosis of clinically relevant prostate cancer as well as the management of the metastatic and androgen-independent metastatic disease states.

Authors

Russel S. Taichman, Robert D. Loberg, Rohit Mehra, Kenneth J. Pienta

×

Abstract

Substantial evidence shows that neoplastic and nonneoplastic tissue growth is dependent on angiogenesis. Neovascularization and adipogenesis are temporally and spatially coupled processes during prenatal life and they continue to reciprocally interact via paracrine signaling systems throughout adult life. Activated adipocytes produce multiple angiogenic factors including leptin, angiopoietins, HGF, GM-CSF, VEGF, FGF-2, and TGF-β, which either alone or collectively stimulate neovascularization during fat mass expansion. Thus antiangiogenic agents provide a novel therapeutic option for prevention and treatment of human obesity and its related disorders.

Authors

Yihai Cao

×

Abstract

MicroRNAs act as negative regulators of gene expression by inhibiting the translation or promoting the degradation of target mRNAs. Recent studies have revealed key roles of microRNAs as regulators of the growth, development, function, and stress responsiveness of the heart, providing glimpses of undiscovered regulatory mechanisms and potential therapeutic targets for the treatment of heart disease.

Authors

Eva van Rooij, Eric N. Olson

×

No posts were found with this tag.