RNA interference (RNAi) holds considerable promise as a therapeutic approach to silence disease-causing genes, particularly those that encode so-called 'non-druggable' targets that are not amenable to conventional therapeutics such as small molecules, proteins, or monoclonal antibodies. The main obstacle to achieving in vivo gene silencing by RNAi technologies is delivery. Here we show that chemically modified short interfering RNAs (siRNAs) can silence an endogenous gene encoding apolipoprotein B (apoB) after intravenous injection in mice. Administration of chemically modified siRNAs resulted in silencing of the apoB messenger RNA in liver and jejunum, decreased plasma levels of apoB protein, and reduced total cholesterol. We also show that these siRNAs can silence human apoB in a transgenic mouse model. In our in vivo study, the mechanism of action for the siRNAs was proven to occur through RNAi-mediated mRNA degradation, and we determined that cleavage of the apoB mRNA occurred specifically at the predicted site. These findings demonstrate the therapeutic potential of siRNAs for the treatment of disease.

Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs

The discovery that gene expression can be controlled by the Watson–Crick base-pairing of small RNAs with messenger RNAs containing complementary sequence — a process known as RNA interference — has markedly advanced our understanding of eukaryotic gene regulation and function. The ability of short RNA sequences to modulate gene expression has provided a powerful tool with which to study gene function and is set to revolutionize the treatment of disease. Remarkably, despite being just one decade from its discovery, the phenomenon is already being used therapeutically in human clinical trials, and biotechnology companies that focus on RNA-interference-based therapeutics are already publicly traded.

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The promises and pitfalls of RNA-interference-based therapeutics

Technologies that mediate targeted delivery of small interfering RNAs (siRNAs) are needed to improve their therapeutic efficacy and safety. Therefore, we have developed aptamer-siRNA chimeric RNAs capable of cell type-specific binding and delivery of functional siRNAs into cells. The aptamer portion of the chimeras mediates binding to PSMA, a cell-surface receptor overexpressed in prostate cancer cells and tumor vascular endothelium, whereas the siRNA portion targets the expression of survival genes. When applied to cells expressing PSMA, these RNAs are internalized and processed by Dicer, resulting in depletion of the siRNA target proteins and cell death. In contrast, the chimeras do not bind to or function in cells that do not express PSMA. These reagents also specifically inhibit tumor growth and mediate tumor regression in a xenograft model of prostate cancer. These studies demonstrate an approach for targeted delivery of siRNAs with numerous potential applications, including cancer therapeutics.

Cell type-specific delivery of siRNAs with aptamer-siRNA chimeras.

Oligonucleotides can be used to modulate gene expression via a range of processes including RNAi, target degradation by RNase H-mediated cleavage, splicing modulation, non-coding RNA inhibition, gene activation and programmed gene editing. As such, these molecules have potential therapeutic applications for myriad indications, with several oligonucleotide drugs recently gaining approval. However, despite recent technological advances, achieving efficient oligonucleotide delivery, particularly to extrahepatic tissues, remains a major translational limitation. Here, we provide an overview of oligonucleotide-based drug platforms, focusing on key approaches - including chemical modification, bioconjugation and the use of nanocarriers - which aim to address the delivery challenge.

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Advances in oligonucleotide drug delivery

Progress Toward In Vivo Use of siRNAs-II

Steroid and lipid conjugates of siRNAs to enhance cellular uptake and gene silencing in liver cells.

The present invention relates to a double-stranded ribonucleic acid (dsRNA) having improved efficiency of inhibition of gene expression, methods of making the dsRNA, and pharmaceutical compositions comprising the dsRNA. The dsRNA comprises an RNA strand (complementary RNA strand) having a region which is complementary to an RNA transcript of at least a part of a target gene, and at least one covalently linked lipophilic group. The dsRNA are useful for inhibiting the expression of a target gene, as well as for treating diseases caused by expression of the target gene. The invention also relates to methods for inhibiting the expression of a target gene, as well as methods for treating diseases caused by the expression of the gene.

Lipophilic derivatives of double-stranded ribonucleic acid

Double-stranded RNA (I) having a strand (S1) that is complementary, at least in parts, to a target gene (TG) and, the new feature, linked to at least one lipophilic group (A) is new. An Independent claim is also included for a method for producing (I) by solid-phase synthesis, in the 3' to 5' direction, of S1 and/or S2, that uses in the last synthesis cycle a lipophilic molecule that contains a phosphoramidite group.

New double-stranded interfering RNA, useful for inhibiting hepatitis C virus, has one strand linked to a lipophilic group to improve activity and eliminate the need for transfection auxiliaries

La presente invention se rapporte a l'acide ribonucleique a double brin (ARNdb) qui a une meilleure efficacite d'inhibition de l'expression genique, a des procedes de fabrication de l'ARNdb, et a des compositions pharmaceutiques comprenant l'ARNdb. L'ARNdb comprend un brin d'ARN (un brin d'ARN complementaire) possedant une region qui est complementaire au transcrit d'ARN d'au moins une partie du gene cible, et au moins un groupe lipophile lie par covalence. Les ARNdb sont utiles pour inhiber l'expression d'un gene cible ainsi que pour traiter les maladies causees par l'expression du gene cible. L'invention se rapporte a des procedes pour inhiber l'expression d'un gene cible ainsi que des procedes pour traiter les maladies provoquees par l'expression du gene.

Derives lipophiles d'acide ribonucleique a double brin

Die vordere glenohumerale Instabilität ist die häufigste Form der Schulterinstabilität. Oft ist diese mit labralen und ossären Verletzungen sowie rezidivierender Instabilität verbunden. Für die optimale Behandlung sind die detaillierte Anamnese, körperliche Untersuchung und gezielte bildgebende Untersuchung erforderlich, um mögliche pathologische Weichteilveränderungen sowie knöcherne Läsionen des Glenoids und Humeruskopfes beurteilen zu können. Eine frühzeitige operative Versorgung kann das Rezidivrisiko, insbesondere bei jungen, aktiven Sportlern, reduzieren und Sekundärschäden vermeiden. Schulterluxationen bei älteren Patienten erfordern ebenfalls eine sorgfältige Beurteilung und Behandlungswahl, da aufgrund von Rotatorenmanschettenläsionen und Nervenverletzungen persistierende Schmerzen und Bewegungseinschränkungen auftreten können. Ziel dieses Beitrags ist es, einen Überblick über die aktuelle Evidenz und Ergebnisse in Bezug auf diagnostische Erwägungen und die konservative vs. operative Therapie bei der primären, anterioren Schulterluxation zu geben. 

Christina Lorenz

Papers

Steroid and lipid conjugates of siRNAs to enhance cellular uptake and gene silencing in liver cells.

Lipophilic derivatives of double-stranded ribonucleic acid

New double-stranded interfering RNA, useful for inhibiting hepatitis C virus, has one strand linked to a lipophilic group to improve activity and eliminate the need for transfection auxiliaries

Derives lipophiles d'acide ribonucleique a double brin

Therapiestrategien bei traumatischer ventraler Schultererstluxation