The Experts below are selected from a list of 357 Experts worldwide ranked by ideXlab platform
John J Rossi - One of the best experts on this subject based on the ideXlab platform.
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nanoparticle based delivery of RNAi Therapeutics progress and challenges
Pharmaceuticals, 2013Co-Authors: Jiehua Zhou, Ka To Shum, John C Burnett, John J RossiAbstract:RNA interference (RNAi) is an evolutionarily conserved, endogenous process for post-transcriptional regulation of gene expression. Although RNAi Therapeutics have recently progressed through the pipeline toward clinical trials, the application of these as ideal, clinical Therapeutics requires the development of safe and effective delivery systems. Inspired by the immense progress with nanotechnology in drug delivery, efforts have been dedicated to the development of nanoparticle-based RNAi delivery systems. For example, a precisely engineered, multifunctional nanocarrier with combined passive and active targeting capabilities may address the delivery challenges for the widespread use of RNAi as a therapy. Therefore, in this review, we introduce the major hurdles in achieving efficient RNAi delivery and discuss the current advances in applying nanotechnology-based delivery systems to overcome the delivery hurdles of RNAi Therapeutics. In particular, some representative examples of nanoparticle-based delivery formulations for targeted RNAi Therapeutics are highlighted.
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RNAi based Therapeutics current status challenges and prospects
Embo Molecular Medicine, 2009Co-Authors: Katrin Tiemann, John J RossiAbstract:RNA interference (RNAi) is a collection of small RNA directed mechanisms that result in sequence specific inhibition of gene expression. The notion that RNAi could lead to a new class of Therapeutics caught the attention of many investigators soon after its discovery. The field of applied RNAi Therapeutics has moved very quickly from lab to bedside. The RNAi approach has been widely used for drug development and several phase I and II clinical trials are under way. However, there are still some concerns and challenges to overcome for therapeutic applications. These include the potential for off-target effects, triggering innate immune responses and most importantly obtaining specific delivery into the cytoplasm of target cells. This review focuses on the current status of RNAi-based Therapeutics, the challenges it faces and how to overcome them.
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RNAi Therapeutics principles prospects and challenges
Advanced Drug Delivery Reviews, 2007Co-Authors: Lars Aagaard, John J RossiAbstract:RNA interference (RNAi) was discovered less than a decade ago and already there are human clinical trials in progress or planned. A major advantage of RNAi versus other antisense based approaches for therapeutic applications is that it utilizes cellular machinery that efficiently allows targeting of complementary transcripts, often resulting in highly potent down-regulation of gene expression. Despite the excitement about this remarkable biological process for sequence specific gene regulation, there are a number of hurdles and concerns that must be overcome prior to making RNAi a real therapeutic modality, which include off-target effects, triggering of type I interferon responses, and effective delivery in vivo. This review discusses mechanistic aspects of RNAi, the potential problem areas and solutions and therapeutic applications. It is anticipated that RNAi will be a major therapeutic modality within the next several years, and clearly warrants intense investigation to fully understand the mechanisms involved.
Caitriona M Odriscoll - One of the best experts on this subject based on the ideXlab platform.
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RNAi Therapeutics for brain cancer current advancements in RNAi delivery strategies
Molecular BioSystems, 2015Co-Authors: Meenakshi Malhotra, Andre Toulouse, Bruno M D C Godinho, David John Mc Carthy, John F Cryan, Caitriona M OdriscollAbstract:Malignant primary brain tumors are aggressive cancerous cells that invade the surrounding tissues of the central nervous system. The current treatment options for malignant brain tumors are limited due to the inability to cross the blood–brain barrier. The advancements in current research has identified and characterized certain molecular markers that are essential for tumor survival, progression, metastasis and angiogenesis. These molecular markers have served as therapeutic targets for the RNAi based therapies, which enable site-specific silencing of the gene responsible for tumor proliferation. However, to bring about therapeutic success, an efficient delivery carrier that can cross the blood–brain barrier and reach the targeted site is essential. The current review focuses on the potential of targeted, non-viral and viral particles containing RNAi therapeutic molecules as delivery strategies specifically for brain tumors.
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delivering RNAi Therapeutics with non viral technology a promising strategy for prostate cancer
Trends in Molecular Medicine, 2013Co-Authors: Jianfeng Guo, James C Evans, Caitriona M OdriscollAbstract:Prostate cancer is the most prevalent cancer in men of the United States and Europe, and although current treatments have efficacy in treating primary prostate cancer, they are associated with a decreased quality of life and are ineffective in treating the metastatic disease. The identification of oncogenes associated with the formation, proliferation, and metastasis of prostate cancer has presented promising targets for RNA interference (RNAi)-based gene therapy. However, the potential of RNAi as a successful therapeutic depends on effective delivery. In this review, we discuss the potential of targeting oncogenes implicated in prostate cancer with RNAi-based Therapeutics using non-viral bioresponsive ‘smart' delivery systems that work in harmony with the physiological and biochemical environments of prostate tumours.
Klaus Charisse - One of the best experts on this subject based on the ideXlab platform.
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sirna conjugates carrying sequentially assembled trivalent n acetylgalactosamine linked through nucleosides elicit robust gene silencing in vivo in hepatocytes
ACS Chemical Biology, 2015Co-Authors: Shigeo Matsuda, Klaus Charisse, Kristofer Keiser, Jayaprakash K Nair, Rajar M Manoharan, Philip Kretschmer, Chang G Peng, Alexander V Kelin, Pachamuthu Kandasamy, Jennifer L S WilloughbyAbstract:Asialoglycoprotein receptor (ASGPR) mediated delivery of triantennary N-acetylgalactosamine (GalNAc) conjugated short interfering RNAs (siRNAs) to hepatocytes is a promising paradigm for RNAi Therapeutics. Robust and durable gene silencing upon subcutaneous administration at therapeutically acceptable dose levels resulted in the advancement of GalNAc-conjugated oligonucleotide-based drugs into preclinical and clinical developments. To systematically evaluate the effect of display and positioning of the GalNAc moiety within the siRNA duplex on ASGPR binding and RNAi activity, nucleotides carrying monovalent GalNAc were designed. Evaluation of clustered and dispersed incorporation of GalNAc units to the sense (S) strand indicated that sugar proximity is critical for ASGPR recognition, and location of the clustered ligand impacts the intrinsic potency of the siRNA. An array of nucleosidic GalNAc monomers resembling a trivalent ligand at or near the 3′ end of the S strand retained in vitro and in vivo siRNA a...
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abstract 11936 development of monthly to quarterly subcutaneous administration of RNAi Therapeutics targeting the metabolic diseases genes pcsk9 apoc3 and angptl3
Circulation, 2014Co-Authors: Anna Borodovsky, William Querbes, Stuart Milstein, Klaus Charisse, Renta Hutabarat, Satya Kuchimanchi, Jessica E Sutherland, Kristina Yucius, Rajeev Kuchimanchi, Abigail LiebowAbstract:Introduction: Cardiovascular disease remains the top cause of mortality in the United States. We have developed, and validated in human trials, a platform for reducing the synthesis of genes expressed in the liver. The platform utilizes a GalNAc sugar ligand attached to the 3’end of the sense strand of an RNAi molecule to enable delivery specifically to the liver. Here we present data from this platform on multiple targets of interest in cardiovascular disease, including PCSK9, ANGPLT3 and ApoC3. Hypothesis: RNAi Therapeutics targeting liver genes of interest (such as PCSK9, ApoC3 and Angptl3) will allow for control of lipid levels and reduce the risk of cardiovascular disease. Methods: Chemically modified siRNAs were designed using bioinformatic algorithms and were screened for potency in vitro . pM active siRNA molecules were developed targeting PCSK9, ANGPLT3 and ApoC3. Results: ALN-PCSsc: In NHPs a single dose of ALN-PCSsc at ≥ 6 mg/kg reduced circulating PCSK9 levels up to 97% and LDL-C up to 67%. Moreover the nadir effect ( where LDL-C is clamped) lasted ~90 days suggesting that once monthly to quarterly dosing could be supported. Multidose studies in NHP at 2 mg/kg reduced circulating PCSK9 levels up to 94% with a subsequent lowering of LDL-C up to 67%. Safety studies in rat and NHP at doses up to 300 mg/kg (multi-dose) showed that ALN-PCSsc was safe demonstrating potential for a very wide therapeutic index. ALN-PCSsc was selected as a development candidate and is being advanced towards an IND for the treatment of hypercholesterolemia. ALN-ANGsc: Was tested in two models of hyperlipidemia, the OB/OB mouse and the hCETP-ApoB mouse. In the Ob/Ob model, treatment with ALN-ANGsc at 3mg/kg resulted in a significant lowering ANGPLT3 protein (>95%), cholesterol (>60%) and triglycerides (>85%). ALN-ApoC3: Was tested in the db/db mouse model of hyperlipidemia. A robust lowering of plasma ApoC3 (>90%) lead to a >50% lowering of triglycerides. Screening for both programs is underway for a development candidates. Conclusions: We have developed a modular, robust and reliable platform for the delivery of RNAi Therapeutics to the liver with a large therapeutic index. This small volume, subcutaneous, platform has a remarkable duration of effect.
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abstract 666 RNAi Therapeutics targeting human angiotensinogen hagt ameliorate preeclamptic sequelae in an established transgenic rodent model for preeclampsia
Hypertension, 2014Co-Authors: Nadine Haase, Stuart Milstein, Klaus Charisse, Don Foster, Satya Kuchimanchi, Julia Bercher, Michaela Golic, Julianna Rugor, Lukasz Przybyl, Brian BettencourtAbstract:Preeclampsia, a disorder with the hallmark features of new-onset hypertension and proteinuria beginning after 20 weeks of gestation, affects 5% of pregnancies in industrialized nations. It is a major cause of fetal and maternal morbidity/mortality. Several studies have demonstrated that angiotensinogen is involved in the pathogenesis of the disease; however, treatment with ACE Inhibitor or AT1 Receptor blocker is contraindicated due to fetal toxicity. RNAi Therapeutics are highly potent mediators of gene-specific silencing. We tested a human angiotensinogen (hAGT)-specifc siRNA, conjugated to triantennary GalNAc, for the ability to ameliorate symptoms of preeclampsia in an established rat model, without affecting the fetus. Transgenic rats expressing hAGT and human renin (hREN) were crossed to produce a model of preeclampsia (PE rat) in the dams. Beginning on day 3 of gestation, transgenic hAGT dams were dosed subcutaneously with 10 mg/kg siRNA every third day through gestation day 15. Mean blood pressure was continuously recorded by radiotelemetry and 24 hour urine samples were collected in metabolic cages at day 18 of gestation. Rats were euthanized at day 21 of gestation. Treatment with the GalNAc-conjugated siRNA reduced the spike in blood pressure seen on gestation day 13 and lasted through study termination (MAP on day 16 of gestation: 155.1 ± 1.4 mmHg untreated vs. 138.4 ± 1.8 mmHg treated). Proteinuria was ameliorated (21.7 ± 3.1 mg/d untreated vs. 2.7 ± 0.6 mg/d treated) and levels of agonistic autoantibodies against the angiotensin receptor AT1 were reduced below the limit of detection. Fetal and uteroplacental unit weights increased with RNAi therapy, demonstrating a reduction in intra-uterine growth restriction (brain to liver ratio (0.95 ± 0.04 untreated vs. 0.73 ± 0.02 treated). mRNA levels of hAGT were reduced to background levels in the liver, but were not affected in the placenta, which is of fetal origin. Our data show that an RNAi therapeutic targeting hAGT ameliorates the clinical sequelae of preeclampsia in a transgenic rat model and improves the outcome of the fetus.
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850c RNAi Therapeutics ameliorate liver disease associated with alpha 1 antitrypsin deficiency
Gastroenterology, 2014Co-Authors: Alfica Sehgal, Stuart Milstein, Brian Bettencourt, Scott Barros, James Butler, Shannon Fishman, Keith Blomenkamp, Kun Qian, Satya Kuchimanch, Klaus CharisseAbstract:The segmentation motor pattern of the intestine, the most dominant pattern in response to eating, designed to optimally absorb nutrients, was described in the late 19th century. How the intestine switches from propulsion to segmentation was revealed recently by us in Nature Communications (in press). Fatty acids induce a low frequency transient rhythmic pacemaker in a network of interstitial cells of Cajal (ICC) associated with the deepmuscular neural plexus (ICC-DMP; 1-4 cycles/min), second to the dominant omnipresent slow wave pacemaker that is generated by ICC associated with the myenteric plexus (ICC-MP; 30-40 cycles/min) in both mouse and rat colon. The introduction of the second pacemaker is associated with slow wave activity changing into a waxing and waning electrical pattern. Not unlike the interaction of waves caused by two stones dropped in water, the pacemaker activities interact with each other, changing a propulsive motor pattern into a non-propagating rhythmic pattern of short-lasting contractions. Our aim of the present study was to understand the mechanism of initiation and control of this trigger for segmentation, and the switch that can change segmentation into propulsion and vice versa. Using intracellular electrical recordings (n=21), we found that the ICC-DMP pacemaker is under tonic inhibitory control by enteric nitrergic nerves and can be evoked by substance P acting on NK1 receptors of ICCDMP at 3.6 ± 0.6 cycles/min. Furthermore, the switch can be activated by medium chain fatty acids through the blood stream at 2.8 ± 0.5 cycles/min, and by short chain fatty acids via the lumen. To further understand the nature of the interaction between the two pacemakers we have developed a model based on the electrophysiological characteristics of the electrical pacemaker activities and based on phase-amplitude coupling of the electrical activities. The motor patterns of the musculature develop because both pacemaker activities propagate into the musculature from opposite sides. The segmentation activity develops when the propagation velocities of the two pacemakers are significantly different from each other. When the propagation velocities are similar, the two pacemakers strengthen each other to create strong low frequency propulsive activity. Hence, the ICC-DMP play a critical role in initiation and the regulation of the nature of the motor pattern of the intestine. It is likely therefore that abnormalities in the ICC-DMP pacemaker activity or its neural or nutrient control may give rise to either the propulsive or segmentation motor pattern becoming too dominant resulting in diarrhea or constipation. The ICC-DMP pacemaker will therefore become a target for rectifying abnormal motor patterns.
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abstract 15574 a subcutaneous platform for RNAi Therapeutics targeting angptl3
Circulation, 2013Co-Authors: William Querbes, Stuart Milstein, Klaus Charisse, Renta Hutabarat, Scott Barros, Rajeev G Kallanthottathil, Satya Kuchimanchi, Rachel Myers, Muthiah Manoharan, Martin MaierAbstract:RNAi Therapeutics have gone from an idea in 2002 to positive clinical trial results in phase 1 and 2 by 2013, remarkable progress for a novel technology. Our initial clinical delivery systems consisted of siRNA formulated in lipid nanoparticles (LNPs) dosed via an intravenous route. Utilizing this system we were able to demonstrate proof of concept in humans with ALN-PCS, an RNAi therapeutic targeting PCSK9, which reduced both plasma PCSK9 as well as the clinically validated endpoint of LDL-C. For many metabolic diseases, however, a subcutaneous route of administration is much preferred. We have recently demonstrated that subcutaneous delivery of siRNA conjugated to a triantennary N -acetylgalactosamine ligand enables robust and sustained target silencing with siRNA uptake mediated by the hepatocyte-specific asiologlycoprotein receptor (ASGPR). Angiopoietin-like 3 (ANGPTL3) was recently implicated via human genetic studies in the regulation of lipoprotein levels. We have identified active siRNA molecules targeting ANGPTL3 and have demonstrated their ability to lower circulating ANGPTL3 protein, resulting in the reduction of Total-cholesterol, Low Density Lipoprotein Cholesterol and Triglycerides in various animal models of metabolic disease. In addition, we have identified several potent siRNA-GalNAc conjugates capable of lowering ANGPLT3 via subcutaneous dosing. Results from pre-clinical studies on ANGPTL3 and the application of a subcutaneous platform for RNAi Therapeutics targeting genes implicated in metabolic disease will be presented
John M. Maraganore - One of the best experts on this subject based on the ideXlab platform.
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A status report on RNAi Therapeutics
Silence, 2010Co-Authors: Akshay Vaishnaw, Jared Gollob, Christina Gamba-vitalo, Renta Hutabarat, Rachel Meyers, Dinah Sah, Tony De Fougerolles, John M. MaraganoreAbstract:Fire and Mello initiated the current explosion of interest in RNA interference (RNAi) biology with their seminal work in Caenorhabditis elegans . These observations were closely followed by the demonstration of RNAi in Drosophila melanogaster . However, the full potential of these new discoveries only became clear when Tuschl and colleagues showed that 21-22 bp RNA duplexes with 3" overhangs, termed small interfering (si)RNAs, could reliably execute RNAi in a range of mammalian cells. Soon afterwards, it became clear that many different human cell types had endogenous machinery, the RNA-induced silencing complex (RISC), which could be harnessed to silence any gene in the genome. Beyond the availability of a novel way to dissect biology, an important target validation tool was now available. More importantly, two key properties of the RNAi pathway - sequence-mediated specificity and potency - suggested that RNAi might be the most important pharmacological advance since the advent of protein Therapeutics. The implications were profound. One could now envisage selecting disease-associated targets at will and expect to suppress proteins that had remained intractable to inhibition by conventional methods, such as small molecules. This review attempts to summarize the current understanding on siRNA lead discovery, the delivery of RNAi Therapeutics, typical in vivo pharmacological profiles, preclinical safety evaluation and an overview of the 14 programs that have already entered clinical practice.
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Reviewreport on RNAi Therapeutics
2010Co-Authors: Akshay Vaishnaw, Jared Gollob, Christina Gamba-vitalo, Renta Hutabarat, Dinah W.y. Sah, Rachel Meyers, John M. MaraganoreAbstract:Fire and Mello initiated the current explosion of interest in RNA interference (RNAi) biology with their seminal work in Caenorhabditis elegans. These observations were closely followed by the demonstration of RNAi in Drosophila melanogaster. However, the full potential of these new discoveries only became clear when Tuschl and colleagues showed that 21-22 bp RNA duplexes with 3" overhangs, termed small interfering (si)RNAs, could reliably execute RNAi in a range of mammalian cells. Soon afterwards, it became clear that many different human cell types had endogenous machinery, the RNA-induced silencing complex (RISC), which could be harnessed to silence any gene in the genome. Beyond the availability of a novel way to dissect biology, an important target validation tool was now available. More importantly, two key properties of the RNAi pathway - sequence-mediated specificity and potency - suggested that RNAi might be the most important pharmacological advance since the advent of protein Therapeutics. The implications were profound. One could now envisage selecting disease-associated targets at will and expect to suppress proteins that had remained intractable to inhibition by conventional methods, such as small molecules. This review attempts to summarize the current understanding on siRNA lead discovery, the delivery of RNAi Therapeutics, typical in vivo pharmacological profiles, preclinical safety evaluation and an overview of the 14 programs that have already entered clinical practice.
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interfering with disease a progress report on sirna based Therapeutics
Nature Reviews Drug Discovery, 2007Co-Authors: Antonin De Fougerolles, John M. Maraganore, Hans Peter Vornlocher, Judy LiebermanAbstract:RNA interference (RNAi) quietly crept into biological research in the 1990s when unexpected gene-silencing phenomena in plants and flatworms first perplexed scientists. Following the demonstration of RNAi in mammalian cells in 2001, it was quickly realized that this highly specific mechanism of sequence-specific gene silencing might be harnessed to develop a new class of drugs that interfere with disease-causing or disease-promoting genes. Here we discuss the considerations that go into developing RNAi-based Therapeutics starting from in vitro lead design and identification, to in vivo pre-clinical drug delivery and testing. We conclude by reviewing the latest clinical experience with RNAi Therapeutics.
Beverly L. Davidson - One of the best experts on this subject based on the ideXlab platform.
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RNAi Therapeutics for CNS disorders.
Brain Research, 2010Co-Authors: Ryan L. Boudreau, Beverly L. DavidsonAbstract:RNA interference (RNAi) is a process of sequence-specific gene silencing and serves as a powerful molecular tool to manipulate gene expression in vitro and in vivo. RNAi technologies have been applied to study gene function and validate drug targets. Researchers are investigating RNAi-based compounds as novel Therapeutics to treat a variety of human diseases that are currently lacking sufficient treatment. To date, numerous studies support that RNAi Therapeutics can improve disease phenotypes in various rodent models of human disease. Here, we focus on the development of RNAi-based therapies aimed at treating neurological disorders for which reduction of mutant or toxic gene expression may provide clinical benefit. We review RNAi-based gene-silencing strategies, proof-of-concept studies testing therapeutic RNAi for CNS disorders, and highlight the most recent research aimed at transitioning RNAi-based Therapeutics toward clinical trials.
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nonallele specific silencing of mutant and wild type huntingtin demonstrates therapeutic efficacy in huntington s disease mice
Molecular Therapy, 2009Co-Authors: Ryan L. Boudreau, Jodi L Mcbride, Ines Martins, Shihao Shen, Yi Xing, Barrie J Carter, Beverly L. DavidsonAbstract:Huntington's disease (HD) is a fatal neurodegenerative disease caused by mutant huntingtin (htt) protein, and there are currently no effective treatments. Recently, we and others demonstrated that silencing mutant htt via RNA interference (RNAi) provides therapeutic benefit in HD mice. We have since found that silencing wild-type htt in adult mouse striatum is tolerated for at least 4 months. However, given the role of htt in various cellular processes, it remains unknown whether nonallele-specific silencing of both wild-type and mutant htt is a viable therapeutic strategy for HD. Here, we tested whether cosilencing wild-type and mutant htt provides therapeutic benefit and is tolerable in HD mice. After treatment, HD mice showed significant reductions in wild-type and mutant htt, and demonstrated improved motor coordination and survival. We performed transcriptional profiling to evaluate the effects of reducing wild-type htt in adult mouse striatum. We identified gene expression changes that are concordant with previously described roles for htt in various cellular processes. Also, several abnormally expressed transcripts associated with early-stage HD were differentially expressed in our studies, but intriguingly, those involved in neuronal function changed in opposing directions. Together, these encouraging and surprising findings support further testing of nonallele-specific RNAi Therapeutics for HD.
