Modulating expression of inhibitory and stimulatory immune 'checkpoints' using nanoparticulate-assisted nucleic acid delivery.

Immune checkpoints are regulatory molecules responsible for determining the magnitude and nature of the immune response. The aim of immune checkpoint targeting immunotherapy is to manipulate these interactions, engaging the immune system in treatment of cancer. Clinically, the use of monoclonal antibodies to block immunosuppressive interactions has proven itself to be a highly effective immunotherapeutic intervention. Within the literature there are numerous candidates for next generation of immune checkpoint targeting strategies. One such example is the use of nucleic acid to alter expression levels of immune checkpoint molecules, either as antisense oligo nucleotides/siRNA, to downregulate inhibitory molecules, or mRNA/DNA, to express co-stimulatory molecules. A significant component of nucleic acid delivery is its formulation within a nanoparticulate system. In this review we discuss the progress of the preclinical application of nucleic acid-based immunotherapies to target a selection of co-inhibitory/co-stimulatory molecules. Furthermore, we identify the potential and current gaps within the literature which may form the basis of future work.

Acupoint injection of Bacillus Calmette-Guerin polysaccharide nucleic acid for patients with chronic urticaria: A protocol for systematic review.

BACKGROUND: To investigate the efficacy and safety of acupoint injection of Bacillus Calmette-Guerin polysaccharide nucleic acid (BCG-PSN) in the treatment of chronic urticaria (CU). METHODS: The following databases will be searched from their inception: Medline, Embase, Pubmed, Web of Science, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure Database, China Biomedical Literature Database, China Science Journal Database, and Wanfang Database. All databases will be searched from the date of creation until October 2019. In addition, we will manually search the list of medical journals as a supplement. The scope of the search included randomized controlled clinical studies related to acupoint injection of BCG-PSN for CU. The primary outcome is the disease activity control. Secondary outcomes include response rate, adverse events, and recurrence rates. The Cochrane RevMan V5.3 Deviation Assessment Tool will be used to assess bias assessment risk, data integration risk, meta-analysis risk, and subgroup analysis risk (if conditions are met). The average difference, standard mean difference and binary data will be used to represent continuous results. RESULTS: This study will comprehensively review the existing evidence on the treatment of CU by acupoint injection of BCG-PSN. CONCLUSION: This systematic review will provide a judgment basis for the effectiveness and safety of acupoint injection of BCG-PSN in the treatment of CU. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42019139885.

Mycobacterium phlei cell wall-nucleic acid complex in the treatment of nonmuscle invasive bladder cancer unresponsive to bacillus Calmette-Guerin.

INTRODUCTION: Current guidelines recommend cystectomy in patients with high risk NMIBC who fail to respond to BCG. However due to the significant morbidity and mortality of the procedure, many are not candidates or refuse it. No new treatments for this indication have been approved by the US FDA since 1998. AREAS COVERED: A cell wall-nucleic acid complex (MCNA) from M. phlei has been investigated for possible application in patients with BCG refractory NMIBC. The development of this biological from the original studies is reviewed, together with the clinical trials leading to a submission to the FDA. Its efficacy and safety are presented together with comparative analysis of alternative treatments, most of which are used off-label. In addition, new combinations of standard therapies are described as well as single agents exhibiting activity against these tumors. EXPERT OPINION: MCNA has shown activity against high risk BCG refractory bladder cancer and offers an alternative to current treatments. The clinical experience remains limited and the optimal therapeutic regimen (dose, frequency) have not been firmly established. Patients and clinicians would welcome the introduction of a compound that may delay or prevent the risks and negative impact in quality of life of cystectomy and urinary diversion.

[Comparison of therapeutic effects between acupoint-injection and intramuscular-injection of Bacillus Calmette-Guerin polysaccharide nucleic acid for bronchial asthma].

OBJECTIVE: To observe the curative effect of acupoint-injection and intramuscular-injection of Bacillus Calmette-Guerin (BCG) Polysaccharide Nucleic Acid for bronchial asthma. METHODS: Sixty patients with bronchial asthma were equally randomized into acupoint-injection group and intramuscular-injection group. For patients of the acupoint-injection group, 2 mL of BCG was injected into bilateral Feishu (BL 13, 1 mL for one side) once per day in the first 15 days, and once every other day in the rest 2.5 months except weekends. Intramuscular-injection was conducted at the lateral sites of the left or right buttock, 2 mL/time for each site, and the injection frequency was the same to that of the acupoint-injection. The therapeutic effect was assessed according to the standards of Guide Principles for Clinical Research of New Chinese Herbal Drugs (2002) and Asthma Group of Breathing Diseases of China Medical Association (2008). Changes of FEV 1 (forced expiratory volume in the first second)/FVC (forced vital capacity) and PEF% (peak expiratory flow) were detected using a pulmonary function detector. Serum IgA, IgM, IgG and IgE contents were assayed by using an autonomic biochemical analyzer. RESULTS: After 3 months' treatment, the scores of patients' symptoms and signs and serum IgE and IgG levels were significantly decreased in both muscular-injection and acupoint-injection groups (P<0.01), while asthma controlled test (ACT) scores FEV 1/FVC% and PEF% values were considerably increased in both groups compared to pre-treatment in the same one group (P<0.01). The effects of acupoint-injection were markedly superior to those of the intramuscular-injection in reducing clinical symptom-sign score, and serum IgE content, and in up-regulating ACT score, FEV 1/FVC% and PEF% levels (P<0.05, P<0.01). There were no significant differences in serum IgG, IgA and IgM levels between the two groups 3 months following the treatment (P>0.05). CONCLUSION: Acupoint-injection of BCG polysaccharide nucleic acid can effectively improve bronchial asthma patients' clinical symptoms and sings and pulmonary function, which may be closely associated with its function in down-regulating serum IgE and IgG levels.

Recent advances in characterization of nonviral vectors for delivery of nucleic acids: impact on their biological performance.

INTRODUCTION: Nucleic acid delivery is a complex process that requires transport across numerous extracellular and intracellular barriers, whose impact is often neglected during optimization studies. As such, the development of nonviral vectors for efficient delivery would benefit from an understanding of how these barriers relate to the physicochemical properties of lipoplexes and polyplexes. AREAS COVERED: This review focuses on the evaluation of parameters associated with barriers to delivery such as blood and immune cells compatibility which, as a collective, may serve as a useful prescreening tool for the advancement of nonviral vectors in vivo. An outline of the most relevant rationally developed polyplexes and lipoplexes for clinical application is also given. EXPERT OPINION: The evaluation of scientifically recognized parameters enabled the identification of systemic delivered nonviral vectors' behavior while in blood as one of the key determinants of vectors function and activity both in vitro and in vivo. This multiparametric approach complements the use of in vitro efficacy results alone for prescreening and improves in vitro-in vivo translation by minimizing false negatives. Further, it can aid in the identification of meaningful structure-function-activity relationships, improve the in vitro screening process of nonviral vectors before in vivo use and facilitate the future development of potent and safe nonviral vectors.

Drug delivery trends in clinical trials and translational medicine: challenges and opportunities in the delivery of nucleic acid-based therapeutics.

The ability to deliver nucleic acids (e.g., plasmid DNA, antisense oligonucleotides, siRNA) offers the potential to develop potent vaccines and novel therapeutics. However, nucleic acid-based therapeutics are still in their early stages as a new category of biologics. The efficacy of nucleic acids requires that these molecules be delivered to the interior of the target cell, which greatly complicates delivery strategies and compromises efficiency. Due to the safety concerns of viral vectors, synthetic vectors such as liposomes and polymers are preferred for the delivery of nucleic acid-based therapeutics. Yet, delivery efficiencies of synthetic vectors in the clinic are still too low to obtain therapeutic levels of gene expression. In this review, we focus on some key issues in the field of nucleic acid delivery such as PEGylation, encapsulation and targeted delivery and provide some perspectives for consideration in the development of improved synthetic vectors.

[Acupoint-injection of BCG polysaccharide nuclear acid for treatment of condyloma acuminatum and its immunoregulatory action on the patient].

OBJECTIVE: To probe into immunological mechanisms and clinical therapeutic effect of acupoint-injection of BCG polysaccharide nuclear acid (BCG-PSN) for treatment of condyloma acuminatum (CA). METHODS: Two hundred cases were randomly divided into 4 groups. After removed the CA by laser, the treatment group (group A) was treated with acupoint-injection of BCG-PSN, the control group I (group B) with intramuscular injection of BCG-PSN, the control group II (group C) with intramuscular injection of interferon, and the blank control group (group D) with no treatment. The levels of cellular immune function were detected before treatment and after treatment of 6 months, and the cases of relapse were recorded. RESULTS: The cured rate of 94.3% in the group A was significantly higher than 78.0% in the group B, 80.4% in the group C and 78.2% in the group D, with significant differences (P < 0.05); in the group A, CD4+ percent increased, CD8+ percent decreased, CD4+ /CD+ ratio increased, and NK cell activity increased with a low relapse rate, and with significant differences as compared with the control groups (P < 0.05, P < 0.01). CONCLUSION: Acupoint-injection of BCG-PSN has a better therapeutic effect and it can obviously reduce the recurrence rate of CA. The cellular immunoregulatory action is one of the mechanisms of this therapy in preventing relapse of CA.

[The search for ways to improve the efficacy of tuberculosis revaccination in children with immunological deficiency]. / Poisk putei povysheniia effektivnosti protivotuberkuleznoi revaktsinatsii detei s immunologicheskoi nedostatochnost'iu.

Clinicoimmunological examination of children to be BCG revaccinated showed 50% of them to have immunodeficiency. Primarily T-cell and macrophagal components of immunity were compromised. The study of immune response to BCG in animals with T-cell and macrophage immunodeficiency validated feasibility of improving antituberculous vaccination efficacy by using thymalin and sodium nucleinate.

[Action of perorally administered sodium ribonucleinate on RNA biosynthesis in the aortic, cardiac, liver and kidney tissue of animals with experimental diabetes mellitus]. / Deistvie peroral'no vvedennogo natriia ribonukleinata na biosintez RNK v tkaniakh aorty, serdtsa, pecheni i pochek u zhivotnykh s éksperimental'nym sakharnym diabetom.

Experiments were made on albino rats with alloxan diabetes. Half of the animals received sodium ribonucleate (20 mg/100 g) per os daily for two weeks. The intensity of RNA biosynthesis was judged from 32P incorporation. It was established that insulin deficiency abolished the biosynthesis of mitochondrial, cytoplasmic and nuclear RNA in the liver and kidneys, of mitochondrial and cytoplasmic RNA in the heart muscle, and of total RNA in the aorta tissue. Oral administration of sodium ribonucleate gave rise to the increased biosynthesis of RNA in these organs. A conclusion is drawn that oral application of the drug may be used in combined treatment of diabetes mellitus in general, and of that complicated by angiopathy, in particular.

Comparison of interferon-inducing activities and antiviral effects of tobacco mosaic virus, tilorone and sodium nucleinate.

Endogenous interferon was produced in animals in response to the administration of tobacco mosaic virus (TMV), tilorone and sodium nucleinate. The relationship between interferon production and the kind of inducer and the route of its administration was studied. TMV was completely innocuous for Macaca rhesus monkeys and mice and caused no untoward effects in humans upon peroral administration. TMV, tilorone and sodium nucleinate given per os exerted a marked protective effect in mice against tick-borne encephalitis, eastern and western equine encephalomyelitis and influenza virus infections.

[Interferonogenic and antiviral activity of the tobacco mosaic virus, tilorone and sodium nucleinate]. / Interferonogennaia i protivovirusnaia aktivnost' virusa tabachnoi mozaiki, tilorona i nukleinata natriia

Production of endogenic interferon in animals in responce to administration of tobaco mozaic virus, tilorone and sodium nucleinate was shown. Dependence of interferon production on the type of the inductor and the route of its administration was studied. Absolute innocuiuty of the tobaco mozaic virus for monkeys (macaco-resus) and mice, as well as the absence of any side effects in humans treated with it perorally was shown. The tobaco mozaic virus, tilorone and sodium nucleinate used perorally in treatment of experimental infections of mice caused by the viruses of East and West encephalomyelitis, influenza and tick encephalitis had a pronounced protective effect.