Podcasts about rna sirna

  Lipoprotein(a) [Lp(a)] is a genetically determined risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis. Traditional lipid-lowering therapies have minimal impact on Lp(a), necessitating novel treatments. Zerlasiran, a small-interfering RNA (siRNA), significantly reduces Lp(a) (~85%) by inhibiting hepatic apolipoprotein(a) synthesis via subcutaneous injection. Muvalaplin, an oral small-molecule inhibitor, prevents Lp(a) particle formation, reducing levels by up to 85.8%. Both drugs were well-tolerated in Phase 2 trials, with further studies needed to evaluate cardiovascular event reduction.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.12.548547v1?rss=1 Authors: Prislusky, M. I. A., Lam, J. G., Ruiz Contreras, V., Ng, M., Chamberlain, M., Fields, M., Zhang, X., Amer, A., Seveau, S. M. Abstract: Mammalian cells are frequently exposed to mechanical and biochemical stresses resulting in plasma membrane injuries. Repair mechanisms rapidly reseal the plasma membrane to restore homeostasis and prevent cell death. In the present work, a silencing RNA (siRNA) screen was performed to uncover the plasma membrane repair mechanisms of cells injured by the bacterial pore-forming toxin listeriolysin O (LLO). The screen identified a novel role for the septin cytoskeleton in mediating plasma membrane repair. Upon cell injury, the septin cytoskeleton partially dissociates from actin stress fibers and remodels with cortical F-actin and myosin-II to form loop (and ring)-like domains that protrude from the cell surface. These domains strictly colocalize with the calcium-dependent phospholipid-binding protein, annexin A2 (ANXA2). Importantly, formation of the SEPT/F-actin/ANXA2 domains are dependent on SEPT7 expression and is functionally correlated with the plasma membrane repair efficiency. Our studies open new research avenues by identifying a novel role for the septin cytoskeleton in remodeling the plasma membrane for its repair. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.14.511731v1?rss=1 Authors: Gurler, G., Uruk, G., Sever-Bahcekapili, M., Belder, N., Beker, M. C., Kilic, E., Yemisci, M. Abstract: The inner blood-retina barrier (BRB) resembles the blood-brain barrier (BBB) and is comprised of a single layer endothelium sealed with tight junctions whose abluminal surface is ensheathed by pericytes. The inner BRB is essential for providing a constant and controlled flow of nutrients and molecules to meet metabolic needs. Accordingly, the inner BRB harbors numerous carriers providing the exchange of molecules between blood and retina. One of these carriers is Reduced Folate Carrier 1 (RFC1), which functions as a folate transporter, and has been one of the most consistently detected genes in cerebral pericytes in a recent meta-analysis. The presence of RFC1 protein and its functions in retinal pericytes and microvessels have been overlooked so far despite the similarities between retinal and cerebral microcirculation. In this report, our purposes were to assess the presence of RFC1 protein in retinal microvessels and surrounding pericytes, and modify to increase or decrease RFC1 levels to explore its roles in healthy and ischemic retinal microvessels. Our analyses on whole mount retinas, and trypsin digest preparations from adult Swiss albino mice with concomitant pericyte and endothelial cell markers have shown the presence of RFC1 protein in the inner BRB and colocalization with pericytes. In vivo modifications of RFC1 expression levels were accomplished by intravitreal delivery of genetic and pharmacological agents. Knocking down RFC1 expression via custom-designed short interfering RNA (siRNA) resulted in microvascular dysfunction which was presented by the disintegration of tight junction proteins and the main basal membrane protein collagen-4. This was accompanied by extensive endogenous IgG extravasation suggesting impairment in the barrier functions. On the other hand, delivering RFC1 expressing lentiviral vector to overexpress RFC1 in the retina induced immunosignal increase in tight junction proteins and collagen-4 confirming the role of RFC1 in the inner BRB functions. Administration of methotrexate (MTX), the pharmacological competitive inhibitor of folate, resulted in increased levels of RFC1. In retinal ischemia models, one-hour retinal ischemia increased RFC1 levels and decreased collagen-4 and occludin levels. These effects could be partially reversed with pre-treatment by RFC1 expressing lentiviral vector. All these indicate the importance of RFC1 levels in the pathophysiology of retinal ischemia, a prevalent cause of blindness worldwide. In conclusion, our study clarifies the presence of RFC1 in inner BRB and offers a novel perspective on RFC1, other than being a folate carrier, as a regulator of inner BRB in healthy and ischemic retinas. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Top 5 Most Read RNS's on Vox Markets for Tuesday 4th October 2022 5. N4 Pharma PLC #N4P - Double siRNA Testing Update Announce successful in vitro testing of Nuvec® loaded with two small interfering RNA (siRNA) probes. 4. Poolbeg Pharma PLC #POLB - POLB 001 US Patent update The US Patent and Trademarks Office, after reviewing a patent application that is directed to the use of POLB 001 and its homologues for the treatment of hypercytokinemia (or "cytokine storm"), has indicated to the Company that the main claim is allowable. 3. Union Jack Oil PLC #UJO - US$10m Net Revenues Landmark Reached at Wressle Announce that material landmark net revenues of US$10,000,000 have been achieved from the Wressle hydrocarbon development, located within licences PEDL180 and PEDL182 in North Lincolnshire on the western margin of the Humber Basin. Union Jack holds a 40% economic interest in this development. 2. Deepverge PLC #DVRG - Labskin contract Labskin contract to develop revolutionary new approach to testing for radiation exposure. Collaboration with team of experts to develop new standards to protect military and civilians working or living near radiation sources. In a 3-year project worth $810k to the Company. 1. Synairgen plc #SNG - Data from the US NIH-led ACTIV-2 Phase 2 trial Synairgen announces positive data from the US NIH-led ACTIV-2 Phase 2 trial for SNG001 in home-based participants with COVID-19

In this third episode of a three-episode podcast series, COR2ED and ASBMR have partnered with patient advocates Inês Alves (European Rare Bone Forum) and Tracy Hart (Osteogenesis Imperfecta Foundation) to provide rare bone disease highlights from the ASBMR 2022 Annual Meeting, focusing on the patient perspective. The experts opened the podcast with the importance of engaging diverse patient communities. Independent of geography, patients should be educated about their condition and prepared for clinical trial participation; advocacy groups play a central role in this engagement. The experts then discussed outcomes of the IMPACT survey in OI (osteogenesis imperfecta), whose extensive database (66 countries, >2000 participants) offers meaningful insights into the clinical, humanistic and economic challenges faced by OI patients around the world. Looking to advances in pre-clinical research, the experts reviewed data on nanoparticle-mediated delivery of small interfering RNA (siRNA) to targeted mutation sites, tested in an animal model of autosomal dominant osteopetrosis. As the experts note, patient communities struggle with lengthy research and development timelines for novel therapies; therefore, it’s important for advocates to keep communities informed about ongoing efforts.

Arthur T. Suckow, PhD, became CEO of DTx Pharma through a path that taught him what he needed for this position, but before taking the title he had to prove to himself that he was ready. A recently completed series B financing of $100M and a growing team of executives, are solid evidence that he in fact was. In this episode Dr. Suckow tells host Firas Rahhal, MD, how his time spent working at Johnson & Johnson, AstraZeneca, and Regulus Therapeutics gave him the inspiration, and the different pieces of the puzzle that he needed, to focus his attention on the challenge of drug delivery, specifically using fatty acids. He explains the work DTx is doing with small interfering RNA (siRNA) on the delivery of RNA therapeutics, and explains that fatty acids can bind to albumin, which can be used as an “Uber” to maintain exposure of drugs over prolonged periods of time.DTx is first developing a treatment for retinitis pigmentosa, but Dr. Suckow said, “I’ve been a drug hunter my whole career,” and the company will be looking to develop products for other indications both in and outside of the eye.Click play to hear Dr. Suckow talk about all this and much more!

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.30.321596v1?rss=1 Authors: Medeiros, I. G., Khayat, A. S., Stransky, B., dos Santos, S. E. B., Assumpcao, P. P., de Souza, J. E. S. Abstract: Coronavirus disease 2019 (COVID-19) rapidly transformed into a global pandemic, for which a demand for developing antivirals capable of targeting the SARS-CoV-2 RNA genome and blocking the activity of its genes has emerged. In this work, we propose a database of SARS-CoV-2 targets for siRNA approaches, aiming to speed the design process by providing a broad set of possible targets and siRNA sequences. Beyond target sequences, it also displays more than 170 features, including thermodynamic information, base context, target genes and alignment information of sequences against the human genome, and diverse SARS-CoV-2 strains, to assess whether siRNAs targets bind or not off-target sequences. This dataset is available as a set of four tables in a single spreadsheet file, each table corresponding to sequences of 18, 19, 20, and 21 nucleotides length, respectively, aiming to meet the diversity of technology and expertise among labs around the world concerning siRNAs design of varied sizes, more specifically between 18 and 21nt length. We hope that this database helps to speed the development of new target antivirals for SARS-CoV-2, contributing to more rapid and effective responses to the COVID-19 pandemic. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.26.222125v1?rss=1 Authors: Hernandez, G., Poirier, E., Lebied, K., Kouwenhoven, W. M., Levesque, D., Rompre, P.-P. Abstract: Background: Glutamate relays the reward signal from the dorsal raphe (DR) to ventral tegmental area (VTA) dopamine (DA) neurons. However, its role is complex and not clearly understood. We measured NMDA receptors subunits expression in limbic brain areas and studied the effects of VTA down-regulation of GluN2C subunit-containing NMDA receptor on the reward signal that arises from DR electrical stimulation. Methods: Via qPCR, we identified the relative composition of the different GluN2 NMDA receptors subunits in several brain areas. Then we used fluorescent in situ hybridization (FISH) to evaluate the colocalization of Grin2c and Tyrosine hydroxylase (Th) mRNA in VTA neurons. To assess the role of GluN2C in reward pursuit; we downregulated this receptor using small interfering RNA (siRNA) in rats self-stimulating for electrical pulses delivered to the DR. To delineate further the specific role of GluN2C in relaying the reward signal, we pharmacologically altered the function of VTA NMDA receptors by either bilaterally microinjecting the NMDA receptor antagonist PPPA or the glutamate transporter inhibitor (GLT-1), Dhk. Results: We identified that GluN2C is the most abundant NMDA receptor subunit expressed in the VTA. FISH revealed that a substantial number of TH+ neurons colocalize with Grin2C. The siRNA manipulation produced a selective down-regulation of GluN2C and a significant reduction in reward pursuit. Interestingly, PPPA and DHK respectively enhanced and suppressed reward pursuit, but only in rats that received the non-active RNA sequence. Conclusion: The present results suggest that VTA Glutamate neurotransmission relays the reward signal initiated by DR stimulation by acting on GluN2C NMDA receptors. Copy rights belong to original authors. Visit the link for more info

Lipid management continues to be an essential component in the prevention and treatment of atherosclerotic cardiovascular disease (ASCVD).  For the past decade, clinical practice guidelines have gone back and forth about optimal treatment goals but guidelines all agree that statins should be used as the preferred initial therapy. However, there is still a lack of clarity about the optimal add-on therapies. The newest LDL-lowering therapy is inclisiran, a small interfering RNA (siRNA) that targets the PCSK9 pathway. Guest Authors:  Joshua O. Holmes, PharmD, MS and Amanda Schartel, PharmD, BCACP Music by Good Talk

RNA interference (RNAi) is a highly conserved process of gene silencing in which Argonaute family proteins are guided by small RNA molecules to complementary targets. In the fission yeast Schizosaccharomyces pombe, RNAi is required for heterochromatin formation at centromeres. Although it seems counterintuitive, pericentromeric heterochromatin in fission yeast is transcribed. The transcripts are processed by RNAi machinery, which is in turn guided back to the pericentromeric repeats by sequence complementarity of the Argonaute-bound small interfering RNA (siRNA) and the nascent transcript. This generates a positive-feedback loop of siRNA amplification that recruits factors required for the assembly of heterochromatin. Previously, it was suggested that a fission yeast class of Dicer-independent small RNAs called primal small RNAs (priRNAs) initiates the positive-feedback loop of siRNA generation and heterochromatin assembly. However, the biogenesis of priRNAs as well as of Dicer-independent small RNAs from other organisms was not well understood. The results presented here identify Triman, a novel 3’-5’ exonuclease that is involved in the final step of biogenesis of both priRNAs and siRNAs in fission yeast. It was observed that Argonaute binds longer priRNA and siRNA precursors from the total RNA fraction. This is followed by the recruitment of Triman to trim 3’ ends of Argonaute-bound small RNAs to the mature size. The final trimming of priRNAs and siRNAs is required for de novo heterochromatin formation at centromeres and the mating-type locus as well as for the maintenance of facultative heterochromatin islands. Furthermore, it was shown that in cells lacking Rrp6, a nuclease subunit of the exosome, RNAi targets various genes across the yeast genome. This demonstrated that the exosome protects the genome against aberrant RNAi. Spurious RNAi targeting in rrp6∆ cells at majority of loci occurs via accumulation of antisense transcripts that are processed into priRNAs in a Triman-dependent manner. These results suggest that Argonaute association with cellular degradation products which are processed into priRNAs might serve as a surveillance mechanism to guard the genome against invading genomic elements (Marasovic et al. 2013).

Background: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterised by accumulation of activated (myo)fibroblasts and excessive extracellular matrix deposition. The enhanced accumulation of (myo)fibroblasts may be attributed, in part, to the process of transforming growth factor textgreekb1 (TGFtextgreekb1)-induced epithelial--mesenchymal transition (EMT), the phenotypic switching of epithelial to fibroblast-like cells. Although alveolar epithelial type II (ATII) cells have been shown to undergo EMT, the precise mediators and mechanisms remain to be resolved. The objective of this study is to investigate the role of SNAI transcription factors in the process of EMT and in IPF.Methods: Using quantitative reverse transcription-PCR (RT-PCR), immunofluorescence, immunohistochemistry, western blotting, as well as gain- and loss-of-function studies and functional assays, the role of SNAI1 and SNAI2 in TGFtextgreekb1-induced EMT in ATII cells in vitro was assessed; and the expression of SNAI transcription factors was analysed in experimental and human IPF in vivo.Results: TGFtextgreekb1 treatment increased the expression and nuclear accumulation of SNAI1 and SNAI2, in concert with induction of EMT in ATII cells. SNAI overexpression was sufficient to induce EMT, and small interfering RNA (siRNA)-mediated SNAI depletion attenuated TGFtextgreekb1-induced ATII cell migration and EMT. SNAI expression was elevated in experimental and human IPF and localised to hyperplastic ATII cells in vivo.Conclusions: The results demonstrate that TGFtextgreekb1-induced EMT in ATII cells is essentially controlled by the expression and nuclear translocation of SNAI transcription factors. Increased SNAI1 and SNAI2 expression in experimental and human IPF in vivo suggests that SNAI-mediated EMT may contribute to the fibroblast pool in idiopathic pulmonary fibrosis.

Cathepsine sind lysosomale Cysteinproteasen, die neben der allgemeinen Proteindegradation in Lysosomen auch spezifische Funktionen ausüben, die eine limitierte Proteolyse erfordern. Zudem werden Cathepsine sezerniert, weshalb man sie auch im Extrazellulärraum findet, wo sie ebenfalls an verschiedenen biologischen Vorgängen, wie etwa der Zellmigration/Invasion, teilnehmen. Über Cathepsin X, einen relativ neu entdeckten Vertreter dieser Proteinklasse, war zu Beginn der Promotionsarbeit noch wenig bekannt. Die Struktur und das Aktivitätsprofil konnten zwar bereits gelöst werden, über mögliche (patho-)physiologische Funktionen gab es jedoch noch keine Erkenntnisse. Das Hauptziel meiner Untersuchungen war daher, mittels geeigneter Methoden nähere Aufschlüsse über die Rolle von Cathepsin X oder seiner Proform innerhalb und außerhalb der Zelle zu erlangen. Dies sollte vorwiegend durch die Analyse der Expression und Sekretion dieser Protease, sowie durch das Auffinden von Interaktionspartnern erfolgen. Wie sich in Vorversuchen zeigte, wird Cathepsin X in humanen Leukozyten unterschiedlich stark exprimiert. Da eine hohe Expression insbesondere in Monozyten vorlag, wurde für weitere Analysen das Zellmodell THP-1 eingesetzt, das auch für die Differenzierung zu Makrophagen-ähnlichen Zellen durch Stimulation mit Phorbol-12-Myristat-13-Acetat (PMA) oder all-trans Retinsäure (ATRA) verwendet werden kann. Interessanterweise zeigten diese Agenzien unterschiedliche Auswirkungen auf die Expression und Sekretion von Cathepsin X. So wurde mit PMA eine starke intra- und extrazelluläre Erhöhung der Protease verzeichnet, während mit ATRA das Gegenteil der Fall war. Da eine differenzielle Expression von Cathepsin X in Leukozyten auf eine mögliche Funktion in der Entzündungsantwort hindeutet, schien eine Untersuchung der Wirkung von proinflammatorischen Zytokinen und extrazellulären Matrix (EZM)-Proteinen sinnvoll, weil diese Faktoren ebenfalls die Sekretion von Proteasen beeinflussen können. Die untersuchten Zytokine hatten allerdings keinen Effekt auf die Sekretion von Cathepsin X aus THP-1-Zellen, wohingegen mit dem EZM-Protein Vitronektin eine Verdopplung der Cathepsin-X-Konzentration im Medium beobachtet wurde. In diesem Kontext konnte nachgewiesen werden, dass Vitronektin durch die Interaktion mit dem Zelloberflächenrezeptor Integrin avb3 den Sekretionsapparat der Zelle beeinflusst, wobei offensichtlich das Sequenzmotiv Arginin-Glyzin-Aspartat (RGD), welches in Vitronektin enthalten ist, für diesen Vorgang entscheidend ist. Neben Cathepsin X wurde auch für die Cathepsine B und L eine erhöhte Freisetzung nach Inkubation mit Vitronektin gemessen, was zeigt, dass dieser durch das EZM-Protein ausgelöste Mechanismus nicht auf Cathepsin X beschränkt ist. Umgekehrt ließ sich in einem weiteren Zellmodell (HUVEC) durch den Einsatz von „small-interfering RNA“ (siRNA) die Expression von Cathepsin X erniedrigen, was zu einer verminderten Migration der HUVEC in einem Invasionsversuch führte. Dies deutet auf eine Funktion von Cathepsin X in der Zellmotilität hin. Weil Cathepsin X, ähnlich wie Vitronektin, ein exponiertes RGD-Motiv in seiner Proregion aufweist, sollte nun eine mögliche Interaktion mit Integrinen untersucht werden. Tatsächlich ließ sich eine RGD-abhängige Interaktion von Procathepsin X mit dem Integrin avb3 zeigen. Somit werden in dieser Arbeit zwei wesentliche neue Aspekte in der Regulation der Sekretion und seiner Beteiligung an Migrationsvorgängen gezeigt, wobei die Interaktion von Procathepsin X mit dem Integrin avb3 eine besondere Rolle zu spielen scheint. Ob diese beiden Vorgänge miteinander gekoppelt sind, konnte mit den bisherigen Ergebnissen noch nicht bewiesen werden. Insgesamt deuten die Ergebnisse jedoch darauf hin, dass extrazelluläres (Pro)Cathepsin X neben seiner Rolle als Protease auch nicht-proteolytische Funktionen, beispielsweise als Ligand bestimmter Zelloberflächenstrukturen ausüben kann. Dieser Aspekt könnte im Hinblick auf eine therapeutische Inhibition von Angiogenese und Metastasierung von Tumorzellen durch Antikörper gegen Cathepsin X und/oder Integrine von großem Nutzen sein.

Epilepsien zählen zu den häufigsten neurologischen Erkrankungen bei Hund, Katze und Mensch. Sie sind mit einer fortschreitenden Schädigung des zentralen Nervensystems und mit erheblichen Einschränkungen im täglichen Leben verbunden. Trotz Entwicklung zahlreicher neuer Antiepileptika über die letzten Jahrzehnte spricht etwa ein Drittel der Veterinär- und Humanpatienten nicht auf eine Pharmakotherapie an. Diese Pharmakoresistenz von Epilepsien stellt ein schwerwiegendes und bisher ungelöstes Problem für die betroffenen Patienten dar und macht neue Therapiestrategien dringend erforderlich. Eine Ursache der Pharmakoresistenz bei Epilepsien stellt die Überexpression von Multidrug-Transportern in den Endothelzellen der Blut-Hirn-Schranke dar. Die physiologische Funktion dieser Efflux-Transporter besteht darin, den Eintritt von Xenobiotika in das Gewebe bestimmter Körperregionen zu verhindern. Eine Überexpression bei pharmakoresistenten Patienten führt zu einem vermehrten Efflux-Transport von Antiepileptika in die Blutbahn, so dass trotz therapeutischer Plasma-Konzentrationen keine ausreichenden Wirkstoffspiegel im Bereich des epileptischen Fokus erreicht werden können. Auf der Basis der Multidrug-Transporter-Hypothese wurden im Rahmen dieser Dissertation zwei mögliche neue Behandlungsstrategien zur Überwindung der Pharmakoresistenz von Epilepsien im Tiermodell untersucht. In den letzten Jahrzehnten wurde ein direkter intra- oder extraneuronaler Transport von Substanzen nach intranasaler (i.n.) Applikation aus der Nasenhöhle in das Gehirn wiederholt beschrieben. Diese Möglichkeit zur Umgehung der Blut-Hirn-Schranke und der dort lokalisierten Efflux-Transporter wurde im Rahmen dieser Arbeit mittels Untersuchungen zur Gehirngängigkeit von Antiepileptika nach i.n.-Applikation im Rattenmodell näher überprüft. Mikrodialyse-Untersuchungen zur Bestimmung der Extrazellulär-Konzentration von Phenobarbital, Lamotrigin und Carbamazepin im Bereich des frontalen Cortex ergaben keine Hinweise auf einen effektiveren Substanztransport nach i.n.-Applikation im Vergleich zur intravenösen (i.v.) Applikationsform. Die Bestimmung der Phenobarbital-Konzentration im Gesamtgehirngewebe nach i.n.- und i.v.-Verabreichung resultierte ebenfalls in gleichwertigen Konzentrationen. Die Untersuchung einzelner Gehirnregionen 10 min nach i.n. Applikation ergab für den Bulbus olfactorius eine signifikant höhere Gehirn-Plasma-Ratio im Vergleich zur i.v.-Applikation. Im Amygdala-Kindling-Modell der Temporallappen-Epilepsie konnte eine dosisabhängige antikonvulsive Wirkung nach i.n.-Applikation von Phenobarbital beobachtet werden, die in vergleichbarem Maße auch nach i.v.-Applikation zu beobachten war. Insgesamt geben die Untersuchungsergebnisse keinen Hinweis darauf, dass ein direkter Transport von Antiepileptika aus der Nasenhöhle in das Gehirn in therapeutisch relevantem Ausmaß stattfindet und eine Umgehung der Blut-Hirn-Schranke auf diese Weise möglich ist. Eine besondere Eignung der i.n.-Applikation zur Therapie pharmakoresistenter Patienten erscheint daher unwahrscheinlich, kann jedoch endgültig erst durch Untersuchungen in einem Tiermodell für pharmakoresistente Epilepsie beurteilt werden. Die nach i.n.-Applikation von Phenobarbital erreichten Plasma-Konzentrationen in Kombination mit der gezeigten antikonvulsiven Wirksamkeit lassen diesen Applikationsweg jedoch zur nicht invasiven Behandlung eines Status epilepticus oder von Anfalls-Clustern Erfolg versprechend erscheinen. Dem Multidrug-Transporter P-Glycoprotein (P-gp) wird in Zusammenhang mit transporter-basierter Pharmakoresistenz bei Epilepsie besondere Bedeutung beigemessen. Durch pharmakologische Inhibition der P-gp-Funktion gelang im Tiermodell bereits die Überwindung von Pharmakoresistenz. Die Anwendung von Hemmstoffen bringt jedoch den Nachteil einer P-gp-Inhibition in allen Körperregionen mit sich. Eine auf die Blut-Hirn-Schranke begrenzte Reduktion der P-gp-Expression wäre durch den Mechanismus der RNA-Interferenz zu erreichen. Für in vivo-Untersuchungen an Ratten wurde gegen P-gp-mRNA gerichtete „small interfering RNA“ (siRNA) zum Schutz vor endogenen Nukleasen in Liposomen eingeschlossen. Zudem wurde für ein Targeting das Peptid ApoE4 an die Oberfläche der Liposomen gebunden, welches eine Endozytose an Endothelzellen der Blut-Hirn-Schranke vermittelt. Das Ziel einer P-gp-Reduktion auf Protein-Ebene nach i.v.-Applikation derart geschützter und zielgesteuerter siRNA konnte jedoch nicht erreicht werden. Die Quantifizierung der P-gp-Expression in den Endothelzellen der Blut-Hirn-Schranke anhand immunhistochemisch gefärbter Gehirnschnitte ergab 24 h nach Applikation keine Verminderung der P-gp-Expression. Die Ursachen für die ausgebliebene P-gp-Reduktion sind in weiterführenden Untersuchungen zu klären.