Applications and developments of gene therapy drug delivery systems for genetic diseases

Genetic diseases seriously threaten human health and have always been one of the refractory conditions facing humanity.Currently,gene therapy drugs such as siRNA,shRNA,antisense oligonucleotide,CRISPR/Cas9 system,plasmid DNA and miRNA have shown great potential in biomedical applications.To avoid the degradation of gene therapy drugs in the body and effectively deliver them to target tissues,cells and organelles,the development of excellent drug delivery vehicles is of utmost importance.Viral vectors are the most widely used delivery vehicles for gene therapy in vivo and in vitro due to their high transfection efficiency and stable transgene expression.With the development of nanotechnology,novel nanocarriers are gradually replacing viral vectors,emerging superior performance.This review mainly illuminates the current widely used gene therapy drugs,summarizes the viral vectors and non-viral vectors that deliver gene therapy drugs,and sums up the application of gene therapy to treat genetic diseases.Additionally,the challenges and opportunities of the field are discussed from the perspective of developing an effective nano-delivery system.

Cholestatic liver diseases:An era of emerging therapies

Recently the field of cholestasis has expanded enormously reflecting an improved understanding of the molecular mechanisms underlying bile secretion and its perturbation in chronic cholestatic disease. Novel anti-cholestatic therapeutic options have been developed for patients not favorably responding to ursodeoxycholic acid (UDCA), the current standard treatment for cholestatic liver disease. Important novel treatment targets now also include nuclear receptors involved in bile acid (BA) homoeostasis like farnesoid X receptor and G proteincoupled receptors e.g., the G-protein-coupled BA receptor “transmembrane G coupled receptor 5”. Fibroblast growth factor-19 and enterohepatic BA transporters also deserve attention as additional drug targets as does the potential treatment agent norUDCA. In this review, we discuss recent and future promising therapeutic agents and their potential molecular mechanisms in cholestatic liver disorders.

Advances in Drug Therapy for Alzheimer’s Disease

Alzheimer’s disease(AD)is a chronic neurodegenerative disease that mainly causes dementia.It is a serious threat to the health of the global elderly population.Considerable money and effort has been invested in the development of drug therapy for AD worldwide.Many drug therapies are currently under development or in clinical trials,based on two known mechanisms of AD,namely,Aβtoxicity and the abnormal Tau hyperphosphorylation.Numerous drugs are also being developed for other AD associated mechanisms such as neuroinflammation,neurotransmitter imbalance,oxidative damage and mitochondrial dysfunction,neuron loss and degeneration.Even so,the number of drugs that can successfully improve symptoms or delay the progression of the disease remains very limited.However,multi-drug combinations may provide a new avenue for drug therapy for AD.In addition,early diagnosis of AD and timely initiation of treatment may allow drugs that act on the early pathological processes of AD to help improve the symptoms and prevent the progression of the condition.

Current evidence of drug-elution therapy for infrapopliteal arterial disease

New and sophisticated endovascular devices, such as drug-eluting stents(DES)and drug-coated balloons(DCB), provide targeted drug delivery to affected vessels. The invention of these devices has made it possible to address the reparative cascade of arterial wall injury following balloon angioplasty that results in restenosis. DESs were first used for the treatment of infrapopliteal lesions almost 20 years ago. More recently, however, DCB technology is being investigated to improve outcomes of endovascular below-the-knee arterial procedures, avoiding the need for a metallic scaffold. Today, level IA evidence supports the use of infrapopliteal DES for short to medium length lesions,although robust evidence that justifies the use of DCBs in this anatomical area is missing. This review summarizes and discusses all available data on infrapopliteal drug-elution devices and highlights the most promising future perspectives.

Real world studies are essential for drug therapy in Parkinson's disease

Prospective real-world data from large patient samples, which re- port on the long-term effectiveness of the employed different drug therapies, are rare in Parkinson＇s disease （PD）. The non interven- tional ＂Transdermal Rotigotine User Surveillance Study＂ （TRUST） trial represents such a real-world study. It investigated long-term treatment with different dopamine substituting treatment regimens in 2195 PD patients （Mfiller et al., 2018）. Participation in TRUST meant that the treating neurologists were only asked to document and modify the dopaminergic drug regimen without any prior PD patient selection criteria. Thus this unique trial design reflects the real world of patient maintenance.

Drug delivery in ocular diseases: Barriers and strategies

The eye is a complex organ made up of diversified cells with specified functions. Presence of anatomical, physiological and physiochemical barriers make it difficult to deliver drugs in therapeutic amounts at intended sites. To overcome these, drug delivery scientists have followed two distinct yet complimentary approaches. The first involves using alternate delivery routes to conventional ones allowing for more direct access to intended target sites. Second approach involves development of novel drug delivery systems providing better permeability, treatability and controlled release at target site. Combination of both these approaches are being utilized and optimized in order to achieve optimal therapy with minimal adverse effects.

Molecular biology and the diagnosis and treatment of liver diseases

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Current status and future prospects of stem cell therapy in Alzheimer’s disease

Alzheimer’s disease is a common progressive neurodegenerative disorder, pathologically characterized by the presence of β-amyloid plaques and neurofibrillary tangles. Current treatment approaches using drugs only alleviate the symptoms without curing the disease, which is a serious issue and influences the quality of life of the patients and their caregivers. In recent years, stem cell technology has provided new insights into the treatment of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Currently, the main sources of stem cells include neural stem cells, embryonic stem cells, mesenchymal stem cells, and induced pluripotent stem cells. In this review, we discuss the pathophysiology and general treatment of Alzheimer’s disease, and the current state of stem cell transplantation in the treatment of Alzheimer’s disease. We also assess future challenges in the clinical application and drug development of stem cell transplantation as a treatment for Alzheimer’s disease.

Effect of periodontal treatment on adipokines in type 2 diabetes

The association between adipokines and inflammatory periodontal diseases has been studied over the last two decades. This review was intended to explore the observation that periodontal therapy may lead to an improvement of adipokines in diabetic patients. In summary, substantial evidence suggests that diabetes is associated with increased prevalence, extent and severity of periodontitis. Numerous mechanisms have been elucidated to explain the impact of diabetes on the periodontium. However, current knowledge concerning the role of major adipokines indicates only some of their associations with the pathogenesis of periodontitis in type 2 diabetes. Conversely, treatment of periodontal disease and reduction of oral inflammation may have positive effects on the diabetic condition, although evidence for this remains somewhat equivocal.

Pharmacology of tetrandrine and its therapeutic use in digestive diseases

INTRODUCTIONTetrandrine (Tet) is a dibenzylisoquinoline alkaloid isolatedfrom Stephania tetrandra S. Moore, a Chinese herbalmedicine. In the past decade, lots of studies demonstrated that Tet has multiple bioactivities, It is promising to use Tet as an antifibrogenetic in liver or lung fibrosis with or without portal or pulmonary hypertension, as well as an immunomodulating and anticarcinoma drug.

Challenges and trends in apomorphine drug delivery systems for the treatment of Parkinson's disease

Parkinson's disease(PD) is a chronic debilitating disease affecting approximately 1% of the population over the age of 60. The severity of PD is correlated to the degree of dopaminergic neuronal loss. Apomorphine has a similar chemical structure as the neurotransmitter dopamine and has been used for the treatment of advanced PD patients. In PD patients,apomorphine is normally administered subcutaneously with frequent injections because of the compound's extensive hepatic first-pass metabolism. There is, hence, a large unmet need for alternative administrative routes for apomorphine to improve patient compliance.The present review focuses on the research and development of alternative delivery of apomorphine, aiming to highlight the potential of non-invasive apomorphine therapy in PD,such as sublingual delivery and transdermal delivery.

Therapeutic drug monitoring in inflammatory bowel disease:The dawn of reactive monitoring

Inflammatory bowel disease(IBD)is a chronic condition that significantly affects the quality of life of its patients.Biologic drugs have been the mainstay treatment in the management of IBD patients but despite their significant contribution,there remains a proportion of patients that do not respond or lose response to treatment.Therapeutic drug monitoring(TDM)involves measuring levels of serum drug concentrations and anti-drug antibodies.TDM of biologic drugs initially emerged to understand treatment failure in other immune mediated inflammatory diseases.This was then introduced in IBD to rationalize primary non-response or secondary loss of response,given that low serum drug concentrations or the formation of anti-drug antibodies are variably associated with treatment failure.The aim of this narrative review is to provide an overview regarding the current use of TDM in clinical practice and to present the evidence available regarding its use in both proactive and reactive clinical settings in preventing and managing treatment failure.This review also presents the existing evidence regarding the association of various clinical outcomes with specific thresholds of drug concentrations,in everyday practice.A narrative review of published articles and conference abstracts regarding the use of TDM in IBD management,through an electronic search using PubMed and ScienceDirect.TDM has proven to be superior and more cost effective in guiding management of patients with treatment failure compared to empiric dose escalation or change in treatment.Despite a trend towards an association between clinical outcomes and drug concentrations,proactive TDM based strategies have not been shown to achieve clear benefit in long-term outcomes.In the clinical setting,TDM has proven to be useful in managing IBD patients,and its use in the reactive setting,as an additional tool to help manage patients with treatment failure,is being promoted as newer guidelines and consensus groups implement TDM as part of the management plan.

Current status of novel biologics and small molecule drugs in the individualized treatment of inflammatory bowel disease

Treatment strategies for inflammatory bowel disease(IBD)are rapidly evolving with the development of biologics and small molecule drugs(SMDs).However,these drugs are not guaranteed to be effective in all patients,and a“ceiling effect”of biologic monotherapy may occur.This issue highlights an unmet need for optimizing the use of biologics and predicting therapeutic responses.Thus,the development of new drugs with novel mechanisms of action is urgently needed for patients with primary nonresponse and secondary loss of response to conventional biologics and SMDs.In addition,combining different biologics or SMDs has been proposed as a novel strategy to enhance treatment efficacy in IBD,which theoretically has multidimensional anti-inflammatory potential.Based on the current evidence available for IBD,dual targeted therapy may be a promising strategy for refractory IBD patients who have failed in multiple biologic treatments or who have extraintestinal manifestation.Additionally,identifying the subgroup of IBD patients who are responding to biological combination therapies is also equally important in stable disease remission.In this review,we summarize the newly developed biologics and SMDs and the current status of biologics/SMDs to highlight the development of individualized treatment in IBD.

Necroptosis in inflammatory bowel disease and other intestinal diseases

For a long time, it was believed that apoptosis and necrosis were the main pathways for cell death, but a growing body of research has shown that there are other pathways. Among these, necroptosis, a regulatory caspase-independent, programmed cell death pathway, is supposed to be of importance in the pathogenesis of many diseases. The mechanism of regulating, inducing and blocking necroptosis is a complex process that involves expression and regulation of a series of molecules including receptor interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase like protein. By blocking or downregulating expression of key molecules in the necroptotic pathway, intestinal inflammation can be affected to some extent. In this paper, we introduce the concept of necroptosis, its main pathway, and its impact on the pathogenesis of inflammatory bowel disease(IBD) and other intestinal diseases, to explore new drug targets for intestinal diseases, including IBD.

Therapeutic drug monitoring in inflammatory bowel disease treatments

Recently,biological drugs have played a leading role in the treatment of inflammatory bowel disease,and therapeutic drug monitoring(TDM)may be useful in maximizing their effectiveness.TDM involves the measurement of serum drug and anti-drug antibodies concentrations as the basis for dosage adjustments or drug conversions to achieve a higher response rate.We believe that concentration thresholds should be individualized based on patients’disease severity,extent and phenotype,and therapeutic purposes should also be considered,with higher cut-offs mainly needed for endoscopic and fistula healing than for symptomatic remission.Proactive and reactive TDM can help optimize treatment,especially in patients receiving anti-tumour necrosis factor,and guide dose adjustment or drug conversion with lower cost.TDM is a promising approach to achieve precision medicine and targeted medicine in the future.

Pharmacogenomics in oral diseases

The availability of newer technologies for identification and characterization of the human genome has enabled our understanding of the genetic variations in a majority of human diseases.Human genomic sequence varies in less than 1%among the different population group and these differences known as gene polymorphisms are the primary reasons for differences in individuals’response to various drug therapy.Also understanding the genetic changes may enable implementation of targeted therapy,thus providing for effective treatment strategies and minimizing the adverse side effects.Pharmacogenomics is a recent development in the field of personalized medicine which focuses on the genetic determinants of drug response at the levels of entire human genome.It primarily deals with tailoring of drug therapy for every individual based on their genetic make-up and identifying new target in various diseases for drug therapy.While the application of pharmacogenomics in systemic illness is well researched,its role in oral diseases needs documentation.Identifying specific targets in periodontitis,head and neck cancer,infections and genetic disorders can be beneficial in discovery of new drugs.This editorial provides an overview of basics of pharmacoge-nomics,its current role in disease management and its potential role in various head and neck diseases.

帕金森病药物治疗研究进展

目前帕金森病(Parkinson’s disease,PD)药物治疗依然是以多巴胺替代治疗为主线的症状治疗,长期用药带来的运动并发症及神经精神症状、平衡步态障碍等问题限制了很多中晚期患者的治疗效果。近年来PD药物治疗领域也取得一些进展。在症状治疗方面,一批左旋多巴制剂新剂型和多巴胺受体激动剂新剂型,新型单胺氧化酶-B和儿茶酚胺氧位甲基转移酶抑制剂,多种非多巴胺能药物陆续进入临床或即将进入临床。目前虽然尚无疾病修饰治疗药物在临床使用,但一批针对不同PD发病机制靶点疾病修饰治疗药物正在开展早期临床试验研究,有些药物显示较好的应用前景。一些已在临床使用的药物被再开发用于PD治疗。本文对该领域新进展做一综述。

Pathogenic and therapeutic role of exosomes in neurodegenerative disorders

Neurodegenerative disorders affect millions of people worldwide,and the prevalence of these disorders is only projected to rise as the number of people over 65 will drastically increase in the coming years.While therapies exist to aid in symptomatic relief,effective treatments that can stop or reve rse the progress of each neurodegenerative disease are lacking.Recently,research on the role of extracellular vesicles as disease markers and therapeutics has been intensively studied.Exosomes,30-150 nm in diameter,are one type of extracellular vesicles facilitating cell-to-cell communication.Exosomes are thought to play a role in disease propagation in a variety of neurodegenerative diseases,such as Alzheimer's disease,Parkinson s disease,and amyotrophic lateral sclerosis.Accordingly,the exosomes derived from the patients are an invaluable source of disease biomarkers.On the other hand,exosomes,especially those derived from stem cells,could serve as a therapeutic for these disorders,as seen by a rapid increase in clinical trials investigating the therapeutic efficacy of exosomes in different neurological diseases.This review summarizes the pathological burden and therapeutic approach of exosomes in neurodegenerative disorders.We also highlight how heat shock increases the yield of exosomes while still maintaining their therapeutic efficacy.Finally,this review concludes with outstanding questions that remain to be addressed in exosomal research.

牙周风险评估系统的应用现状

牙周风险评估系统可有效地预测患者的牙周疾病风险,并为个性化治疗方案提供指导。牙周风险评估系统已在临床实践和临床科研领域中得到广泛应用。由于不同牙周风险评估系统所纳入的牙周临床指标和全身危险因素存在差异,其适用范围也相应不同。目前临床中较常用的牙周风险评估系统如下:基于个体层面的牙周风险评估工具牙周风险指数(periodontal risk calculator,PRC),可以同时收集患者牙周和全身状况指标进行预测;牙周评估工具(periodontal assessment tool,PAT),可以量化区分牙周病不同阶段;牙周风险评估(periodontal risk assessment,PRA)及改良牙周风险评估(modified periodontal risk assessment,mPRA)操作简便明了;而分类回归树(classification and regression trees,CART)则可基于单颗患牙周预后牙评估;另外还有在患者需要多学科联合治疗时的正畸-牙周联合风险评估系统、植体周病风险评估系统等。本文对牙周风险评估系统的应用现状进行综述。

铁死亡在口腔疾病中的研究进展

铁死亡是一种可调控的,具有铁依赖性的,由脂质过氧化驱动的细胞死亡形式,是一种重要的细胞死亡形式,在多种疾病中发挥着重要作用。目前铁死亡在癌症、缺血/再灌注损伤疾病、各类神经退行性疾病等方面的研究取得了一定的成果,在口腔疾病中的作用也越来越受关注。铁死亡是口腔癌的新兴治疗靶点。许多炎症损伤疾病与铁死亡相关,牙周炎作为一种慢性炎症性疾病,与铁死亡的发生过程可能存在一定的相关性。本文就目前铁死亡与口腔疾病的相关研究及发现进行综述,旨在为探索口腔疾病的发病机制和诊疗提供参考。