siRNA takes a jab at hypertension.

Hypertension is a modifiable risk factor for cardiovascular disease, the leading cause of death worldwide, yet most US adults with hypertension do not meet goal blood pressure. KARDIA-1 demonstrates the efficacy of zilebesiran, a subcutaneously administered small interfering RNA, for lowering blood pressure, presenting a novel treatment option for this deadly disease.1.

Effect of Clemizole on Alpha-Synuclein-Preformed Fibrils-Induced Parkinson's Disease Pathology: A Pharmacological Investigation.

Parkinson's disease (PD) is a neurodegenerative disorder associated with mitochondrial dysfunctions and oxidative stress. However, to date, therapeutics targeting these pathological events have not managed to translate from bench to bedside for clinical use. One of the major reasons for the lack of translational success has been the use of classical model systems that do not replicate the disease pathology and progression with the same degree of robustness. Therefore, we employed a more physiologically relevant model involving alpha-synuclein-preformed fibrils (PFF) exposure to SH-SY5Y cells and Sprague Dawley rats. We further explored the possible involvement of transient receptor potential canonical 5 (TRPC5) channels in PD-like pathology induced by these alpha-synuclein-preformed fibrils with emphasis on amelioration of oxidative stress and mitochondrial health. We observed that alpha-synuclein PFF exposure produced neurobehavioural deficits that were positively ameliorated after treatment with the TRPC5 inhibitor clemizole. Furthermore, Clemizole also reduced p-alpha-synuclein and diminished oxidative stress levels which resulted in overall improvements in mitochondrial biogenesis and functions. Finally, the results of the pharmacological modulation were further validated using siRNA-mediated knockdown of TRPC5 channels, which also decreased p-alpha-synuclein expression. Together, the results of this study could be superimposed in the future for exploring the beneficial effects of TRPC5 channel modulation for other neurodegenerative disorders and synucleopathies.

Potential roles of PIWI-interacting RNAs in breast cancer, a new therapeutic strategy.

Breast cancer (BC) has been the focus of numerous studies aimed at identifying novel biological markers for its early detection. PIWI-interacting RNAs (piRNAs), a subset of small non-coding RNAs, have emerged as potential markers due to their aberrant expression in various cancers. PiRNAs have recently gained attention due to their aberrant expression in various cancers, including BC. PiRNAs, exhibit diverse biological activities, such as epigenetic regulation of gene and protein expression and their association with cell proliferation and metastasis has been well-established. As the field of non-coding RNAs rapidly evolves, there is great anticipation that therapies targeting piRNAs will advance swiftly. This review will delve into the various biological functions of piRNAs, such as gene suppression, transposon silencing, and epigenetic regulation of genes. The review will also highlight the role of piRNAs as either progenitors or suppressors in cancers, with a particular focus on BC. Lastly, it will touch upon the potential of piRNAs as biomarkers and therapeutic targets for BC.

Ordered Mesoporous Silica Delivering siRNA as Cancer Nanotherapeutics: A Comprehensive Review.

Nanosized mesoporous silica has emerged as a promising flexible platform delivering siRNA for cancer treatment. This ordered mesoporous nanosized silica provides attractive features of well-defined and tunable porosity, structure, high payload, and multiple functionalizations for targeted delivery and increasing biocompatibility over other polymeric nanocarriers. Moreover, it also overcomes the lacunae associated with traditional administration of drugs. Chemically modified porous silica matrix efficiently entraps siRNA molecules and prevents their enzymatic degradation and premature release. This Review discusses the synthesis of silica using the sol-gel approach and the advantages with different silica mesostructure. Herein, the factors affecting the synthesis of silica at nanometer scale, shape, porosity and nanoparticle surface modification are also highlighted to attain the desired nanostructured silica carriers. Additional emphasis is given to chemically modified silica delivering siRNA, where the silica nanoparticle surface was modified with different chemical moieties such as amine modified with (3-aminoropyl) triethoxysilane, polyethylenimine, chitosan, poly(ethylene glycol), and cyclodextrin polymer modification to attain high therapeutic loading, improved dispersibility and biocompatibility. Upon systemic administration, ordered mesoporous nanosized silica encounters blood cells, immune cells, and organs mainly of the reticuloendothelial system (RES). Thereby, biocompatibility and biodistribution of silica based nanocarriers are deliberated to design principles for smart and efficacious nanostructured silica-siRNA carriers and their clinical trial status. This Review further reports the future scopes and challenges for developing silica nanomaterial as a promising siRNA delivery vehicle demanding FDA approval.

The advent of RNA-based therapeutics for metabolic syndrome and associated conditions: a comprehensive review of the literature.

Metabolic syndrome (MetS) is a prevalent and intricate health condition affecting a significant global population, characterized by a cluster of metabolic and hormonal disorders disrupting lipid and glucose metabolism pathways. Clinical manifestations encompass obesity, dyslipidemia, insulin resistance, and hypertension, contributing to heightened risks of diabetes and cardiovascular diseases. Existing medications often fall short in addressing the syndrome's multifaceted nature, leading to suboptimal treatment outcomes and potential long-term health risks. This scenario underscores the pressing need for innovative therapeutic approaches in MetS management. RNA-based treatments, employing small interfering RNAs (siRNAs), microRNAs (miRNAs), and antisense oligonucleotides (ASOs), emerge as promising strategies to target underlying biological abnormalities. However, a summary of research available on the role of RNA-based therapeutics in MetS and related co-morbidities is limited. Murine models and human studies have been separately interrogated to determine whether there have been recent advancements in RNA-based therapeutics to offer a comprehensive understanding of treatment available for MetS. In a narrative fashion, we searched for relevant articles pertaining to MetS co-morbidities such as cardiovascular disease, fatty liver disease, dementia, colorectal cancer, and endocrine abnormalities. We emphasize the urgency of exploring novel therapeutic avenues to address the intricate pathophysiology of MetS and underscore the potential of RNA-based treatments, coupled with advanced delivery systems, as a transformative approach for achieving more comprehensive and efficacious outcomes in MetS patients.

RNAi-based drug design: considerations and future directions.

More than 25 years after its discovery, the post-transcriptional gene regulation mechanism termed RNAi is now transforming pharmaceutical development, proved by the recent FDA approval of multiple small interfering RNA (siRNA) drugs that target the liver. Synthetic siRNAs that trigger RNAi have the potential to specifically silence virtually any therapeutic target with unprecedented potency and durability. Bringing this innovative class of medicines to patients, however, has been riddled with substantial challenges, with delivery issues at the forefront. Several classes of siRNA drug are under clinical evaluation, but their utility in treating extrahepatic diseases remains limited, demanding continued innovation. In this Review, we discuss principal considerations and future directions in the design of therapeutic siRNAs, with a particular emphasis on chemistry, the application of informatics, delivery strategies and the importance of careful target selection, which together influence therapeutic success.

Harnessing the potential of nanoengineered siRNAs carriers for target responsive glioma therapy: Recent progress and future opportunities.

Past scientific testimonials in the field of glioma research, the deadliest tumor among all brain cancer types with the life span of 10-15 months after diagnosis is considered as glioblastoma multiforme (GBM). Even though the availability of treatment options such as chemotherapy, radiotherapy, and surgery, are unable to completely cure GBM due to tumor microenvironment complexity, intrinsic cellular signalling, and genetic mutations which are involved in chemoresistance. The blood-brain barrier is accountable for restricting drugs entry at the tumor location and related biological challenges like endocytic degradation, short systemic circulation, and insufficient cellular penetration lead to tumor aggression and progression. The above stated challenges can be better mitigated by small interfering RNAs (siRNA) by knockdown genes responsible for tumor progression and resistance. However, siRNA encounters with challenges like inefficient cellular transfection, short circulation time, endogenous degradation, and off-target effects. The novel functionalized nanocarrier approach in conjunction with biological and chemical modification offers an intriguing potential to address challenges associated with the naked siRNA and efficiently silence STAT3, coffilin-1, EGFR, VEGF, SMO, MGMT, HAO-1, GPX-4, TfR, LDLR and galectin-1 genes in GBM tumor. This review highlights the nanoengineered siRNA carriers, their recent advancements, future perspectives, and strategies to overcome the systemic siRNA delivery challenges for glioma treatment.

Comment on "Inclisiran siRNA technology in the management of dyslipidemia: A narrative review of clinical trials".

The study "Inclisiran siRNA technology in the management of dyslipidemia: A narrative review of clinical trials" evaluates inclisiran's efficacy and safety in reducing LDL cholesterol levels across diverse patient populations. Twelve clinical trials were reviewed, demonstrating consistent LDL-C reduction, even in statin intolerance or resistance cases, with sustained efficacy observed over various durations, some extending up to four years. Inclisiran exhibited a favorable safety profile, suggesting its potential as a well-tolerated treatment option. Despite promising findings, the limitations include the short duration of some trials and the exclusion of non-English language studies, warranting further research. Future studies should focus on the long-term safety and efficacy in diverse patient populations and explore the broader clinical implications of inclisiran. Although inclisiran shows promise in dyslipidemia management, comprehensive research is needed to understand its full potential in cardiovascular medicine.

siRNA as potential therapeutic strategy for hypertension.

Hypertension, a well-known cardiovascular disorder noticed by rise in blood pressure, poses a significant global health challenge. The development RNA interfering (RNAi)-based therapies offers a ground-breaking molecular tool, holds promise for addressing hypertension's intricate molecular mechanisms. Harnessing the power of small interfering RNA (siRNA), researchers aim to selectively target and modulate genes associated with hypertension. Furthermore, they aim to downregulate the levels of mRNA by activating cellular nucleases in response to sequence homology between the siRNA and the corresponding mRNA molecule. As a result, genes involved in the cause of disorders linked to a known genetic background can be silenced using siRNA strategy. In the realm of hypertension, siRNA therapy emerges as a potential therapy for prognostics, diagnostics and treatments. It plays an important role in execution of targeting suppression of genes involved in vascular tone regulation, sodium handling, and pathways contributing to high blood pressure. A clinical trial involving intervention like angiotensinogen siRNA (AGT siRNA) is currently being carried out to treat hypertension. Genetic correlations between uromodulin (UMOD) and hypertension are investigated as emerging Non AGT siRNA target. Furthermore, expression of UMOD is responsible for regulation of sodium by modulating the tumor necrosis factor-α and regulating the Na + -K + -2Cl-cotransporter (NKCC2) in the thick ascending limb, which makes it an important target for blood pressure regulation.

SiRNA-HIF-1α delivered by attenuated Salmonella enhances the efficacy of Lenvatinib against hepatocellular carcinoma.

The treatment of hepatocellular carcinoma (HCC) remains a major challenge in the medical field. Lenvatinib, a multi-target tyrosine kinase inhibitor, has demonstrated anti-HCC effects by targeting and inhibiting pathways such as vascular endothelial growth factor receptor 1-3 (VEGFR1-3). However, the therapeutic efficacy of Lenvatinib is subject to various influences, with the hypoxic microenvironment of the tumor being a pivotal factor. Consequently, altering the hypoxic milieu of the tumor emerges as a viable strategy to augment the efficacy of Lenvatinib. Hypoxia-inducible factor-1α (HIF-1α), synthesized by tumor cells in response to oxygen-deprived conditions, regulates the expression of resistance genes, promotes tumor angiogenesis and cell proliferation, enhances tumor cell invasion, and confers resistance to radiotherapy and chemotherapy. Thus, we constructed a self-designed siRNA targeting HIF-1α to suppress its expression and improve the efficacy of Lenvatinib in treating HCC. The therapeutic efficacy of siRNA-HIF-1α in combination with Lenvatinib on HCC were evaluated through in vivo and in vitro experiments. The results showed that the recombinant Salmonella delivering siRNA-HIF-1α in combination with Lenvatinib effectively inhibited tumor growth and prolonged the survival of tumor-bearing mice. This treatment approach reduced cell proliferation and angiogenesis in HCC tissues while promoting tumor cell apoptosis. Additionally, this combined therapy significantly increased the infiltration of T lymphocytes and M1 macrophages within the tumor microenvironment, as well as elevated the proportion of immune cells in the spleen, thereby potentiating the host's immune response against the tumor.

A multiscale modeling study of nanoparticle-based targeting therapy against atherosclerosis.

Although researches on nanoparticle-based (NP-based) drug delivery system for atherosclerosis treatment have grown rapidly in recent years, there are limited studies in quantifying the effects of targeting drugs on plaque components and microenvironment. The purpose of the present study was to quantitatively assess the targeting therapeutic effects against atherosclerosis by establishing a multiscale mathematical model. The multiscale model involved subcellular, cellular and microenvironmental scales to simulate lipid catabolism, macrophage behaviors and dynamics of microenvironmental components, respectively. In vitro and in vivo experimental data were integrated into the mathematical model according to Bayesian statistics, in order to evaluate the therapeutic effects of a proposed NP-based platform for macrophage-specific delivery to simultaneously deliver SR-A siRNA (to reduce LDL uptake) and LXR-L (to stimulate cholesterol efflux). Dosage variation analysis was then performed to investigate the drug efficacy under varied dosage combinations of SR-A siRNA and LXR-L. The simulation results demonstrated that the dynamics of the microenvironmental components presented different developments in Untreated and Treated groups. We also found that the balance of lipid metabolism between uptake and efflux resulted in the improvement of lipid and inflammatory microenvironment, consequently in the plaque regression. In addition, the model predicted optimized dosage combinations according to the co-effect analysis of the two drugs on the lipid microenvironment. This study suggests that multiscale modeling can be a powerful quantitative tool for estimating the therapeutic effects of targeting drugs for plaque regression and designing the enhanced treatment strategies against atherosclerosis.

RNA interference-based therapies for atherosclerosis: Recent advances and future prospects.

Atherosclerosis represents a pathological state that affects the arterial system of the organism. This chronic, progressive condition is typified by the accumulation of atheroma within arterial walls. Modulation of RNA molecules through RNA-based therapies has expanded the range of therapeutic options available for neurodegenerative diseases, infectious diseases, cancer, and, more recently, cardiovascular disease (CVD). Presently, microRNAs and small interfering RNAs (siRNAs) are the most widely employed therapeutic strategies for targeting RNA molecules, and for regulating gene expression and protein production. Nevertheless, for these agents to be developed into effective medications, various obstacles must be overcome, including inadequate binding affinity, instability, challenges of delivering to the tissues, immunogenicity, and off-target toxicity. In this comprehensive review, we discuss in detail the current state of RNA interference (RNAi)-based therapies.

Advances in the polymeric nanoparticulate delivery systems for RNA therapeutics.

RNA therapeutics have emerged as potential treatments for genetic disorders, infectious diseases, and cancer. RNA delivery to target cells for efficient therapeutic applications remains challenging due to instability and poor uptake. Polymeric nanoparticulate delivery systems offer stability, protection, and controlled release. These systems shield RNA from degradation, enabling efficient uptake and extended circulation. Various polymeric nanoparticle platforms have been explored, including lipid-based nanoparticles, polymeric micelles, dendrimers, and polymer-drug conjugates. This review outlines recent breakthroughs of recent advances, design principles, characterization techniques, and performance evaluation of these delivery systems. It highlights their potential in translating preclinical studies into clinical applications. Additionally, the review discusses the application of polymeric nanoparticles in ophthalmic drug delivery, particularly for medications that dissolve poorly in water, and the progress made in siRNA-based therapies for viral infections, autoimmune diseases, and cancers. SiRNA holds great promise for precision medicine and therapeutic intervention, with the ability to target specific genes and modulate disease-associated pathways. The versatility and potency of siRNA-based drugs offer a broader scope for therapeutic intervention compared to traditional biological drugs. As research in RNA therapeutics continues to advance, these technologies hold tremendous potential to revolutionize the treatment of various diseases and improve patient outcomes.

An update on inclisiran for the treatment of elevated LDL cholesterol.

INTRODUCTION: The burden of atherosclerotic cardiovascular disease (ASCVD) persists globally, demanding innovative therapeutic strategies. This manuscript provides an expert opinion on the significance of managing low-density lipoprotein cholesterol in ASCVD prevention and introduces inclisiran, a novel small interfering RNA targeting proprotein convertase subtilisin/kexin type 9 (PCSK9). AREAS COVERED: This work delves into the intricate mechanism of inclisiran, highlighting its unique approach of hepatic intracellular PCSK9 inhibition, its precision and low off-target effects risk. Pharmacodynamic and pharmacokinetic distinctions from PCSK9 monoclonal antibodies are explored, underlining inclisiran's efficiency, extended duration, and clearance. Clinical trials, including pivotal phase-III placebo-controlled studies (ORION-9, -10, -11), the open-label ORION-3 and pooled safety analysis of these trails including the open-label phase of ORION-8, as well as real-word data are discussed to provide a comprehensive evaluation of inclisiran's efficacy and safety. EXPERT OPINION: Inclisiran stands as a first-in-class breakthrough in lipid-lowering therapies, showing potential in alleviating the global burden of ASCVD and is supported by multiple global regulatory approvals. To optimize inclisiran's utilization and comprehend its long-term effects, future directions include pediatric studies, cardiovascular outcome trials, and extended-duration investigations. Overall, inclisiran emerges as a precise and effective therapeutic option, offering significant promise for preserving cardiovascular health.

Efficacy of GalNAc C3 siRNAs in factor H-deficient mice with C3 glomerulopathy.

Complement alternative pathway (AP) dysregulation drives C3 glomerulopathy (C3G), a rare renal disorder characterized by glomerular C3 deposition and glomerular damage, for which no effective treatments are available. Blockade of complement C3 is emerging as a viable therapeutic option. In an earlier study we showed that SLN500, a small interfering RNA targeting liver C3 synthesis, was able to limit AP dysregulation and glomerular C3d deposits in mice with partial factor H (FH) deficiency (Cfh+/- mice). Here, we assessed the pharmacological effects of SLN501 - an optimized SLN500 version - in mice with complete FH deficiency (Cfh-/- mice) that exhibit a more severe C3G phenotype. SLN501 effectively prevented liver C3 synthesis, thus limiting AP dysregulation, glomerular C3d deposits and the development of ultrastructural alterations. These data provide firm evidence of the use of siRNA-mediated liver C3 gene silencing as a potential therapy for treating C3G patients with either partial or complete FH loss of function.

Nanoparticles and siRNA: A new era in therapeutics?

Since its discovery in 1998, the use of small interfering RNA (siRNA) has been increasing in biomedical studies because of its ability to very selectively inhibit the expression of any target gene. Thus, siRNAs can be used to generate therapeutic compounds for different diseases, including those that are currently 'undruggable'. This has led siRNA-based therapeutic compounds to break into clinical settings, with them holding the promise to potentially revolutionise therapeutic approaches. To date, the United States Food and Drug Administration (FDA) have approved 5 compounds for treating different diseases including hypercholesterolemia, transthyretin-mediated amyloidosis (which leads to polyneuropathy), hepatic porphyria, and hyperoxaluria. This current article presents an overview of the molecular mechanisms involved in the selective pharmacological actions of siRNA-based compounds. It also describes the ongoing clinical trials of siRNA-based therapeutic compounds for hepatic diseases, pulmonary diseases, atherosclerosis, hypertriglyceridemia, transthyretin-mediated amyloidosis, and hyperoxaluria, kidney diseases, and haemophilia, as well as providing a description of FDA-approved siRNA therapies. Because of space constraints and to provide an otherwise comprehensive review, siRNA-based compounds applied to cancer therapies have been excluded. Finally, we discuss how the use of lipid-based nanoparticles to deliver siRNAs holds promise for selectively targeting mRNA-encoding proteins associated with the genesis of different diseases. Thus, siRNAs can help reduce the cellular levels of these proteins, thereby contributing to disease treatment. As consequence, a marked increase in the number of marketed siRNA-based medicines is expected in the next two decades, which will likely open up a new era of therapeutics.

APOC3 siRNA and ASO therapy for dyslipidemia.

PURPOSE OF REVIEW: The aim of this review is to present the clinical indications of apolipoprotein C-III (apoC3) inhibition in the therapeutic arsenal for the treatment of lipid disorders and associated risks and to compare the most advanced modalities of apoC3 inhibition currently available or in development, specifically APOC3 antisense oligonucleotides (ASO) and small interfering RNA (siRNA). RECENT FINDINGS: ApoC3 inhibition significantly decreases triglyceride levels by mechanisms coupling both lipoprotein lipase (LPL) upregulation and LPL-independent mechanisms. The main apoC3 inhibitors in advanced clinical development are the GalNAc-ASO olezarsen and the GalNAc-siRNA plozasiran. Clinical studies conducted with volanesorsen, the olezarsen precursor, showed a favorable effect on hepatic steatosis (nonalcoholic fatty liver disease, NAFLD). Olezarsen does not appear to be associated with the main side effects attributed to volanesorsen including thrombocytopenia. Plozasiran is in advanced clinical development and requires subcutaneous injection every 3 months and present to-date an efficacy and safety profile comparable to that of the monthly ASO. SUMMARY: Inhibition of apoC3 is effective across all the spectrum of hypertriglyceridemia, might have a favorable effect on hepatic steatosis (NAFLD) and the effect of apoC3 inhibition on cardiovascular risk is not limited to its effect on plasma triglycerides. APOC3 GalNAc-conjugated ASO and siRNA are both effective in decreasing plasma apoC3 and triglyceride levels.

The paradox of tPA in ischemic stroke: tPA knockdown following recanalization improves functional and histological outcomes.

Previous studies have demonstrated that endogenous tissue-type plasminogen activator (tPA) is upregulated in the brain after an acute ischemic stroke (AIS). While mixed results were observed in genetic models, the pharmacological inhibition of endogenous tPA showed beneficial effects. Treatment with exogenous recombinant tPA exacerbated brain damage in rodent models of stroke. Despite the detrimental effects of tPA in ischemic stroke, recombinant tPA is administered to AIS patients to recanalize the occluded blood vessels because the benefits of its administration outweigh the risks associated with tPA upregulation and increased activity. We hypothesized that tPA knockdown following recanalization would ameliorate sensorimotor deficits and reduce brain injury. Young male and female rats (2-3 months old) were subjected to transient focal cerebral ischemia by occlusion of the right middle cerebral artery. Shortly after reperfusion, rats from appropriate cohorts were administered a nanoparticle formulation containing tPA shRNA or control shRNA plasmids (1 mg/kg) intravenously via the tail vein. Infarct volume during acute and chronic phases, expression of matrix metalloproteinases (MMPs) 1, 3, and 9, enlargement of cerebral ventricle volume, and white matter damage were all reduced by shRNA-mediated gene silencing of tPA following reperfusion. Additionally, recovery of somatosensory and motor functions was improved. In conclusion, our results provide evidence that reducing endogenous tPA following recanalization improves functional outcomes and reduces post-stroke brain damage.