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Application range of adenovirus vector in gene therapy

2020-05-22 来源: 51Due教员组 类别: Essay范文

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下面为大家整理一篇优秀的essay代写范文- Application range of adenovirus vector in gene therapy。本文摘要腺病毒(Ad)是临床试验中最常用的载体。在这篇综述中,我简单介绍了基因疗法的发展。其次,我将尝试弄清进入宿主时Ad载体的结构及其机制。但是,转录和基因表达并不像我们想象的那么简单,在此过程中,成功表达存在四个困难。先天性免疫应答是阻碍外源基因更多复制的主要障碍。有两种解决方案可以提高基因转移的效率,可以对载体进行基因结构修饰,还可以使用Nomomedicine的构建方法将载体包裹到靶向位点。

 

Abstract Adenovirus (Ad) is the most frequently used vectors in clinical trials. In the review, I give a simple introduce of the development of gene therapy. Secondly, I would try to figure out the structure of Ad vectors and its mechanism when entering into the host. However, the transcription and gene expression is not as simple as we think, in the process, we meet four difficulties on successfully expressions. The innate immune response is the major hurdle which blocking more replication of exogenous gene. There are two solutions to improve the efficiency of the gene transfer, the gene structure modification of vectors and the constructions of Nomomedicine which shell the vectors to targeting sites.

Keywords Adenovirus (Ad); gene therapy; structure; innate immune system

 

Introduction

Since 1960s, gene therapy become a controversial medical technology, with the development of recombinant DNA technology, the ability to transfer and express exogenous genes in mammalian cells, it becomes attractive and some clinical trails which use gene transfer vectors in therapeutic trails is successful in patients with serious genetic conditions. Ad vectors based on Mononey murine leukemia virus become the prominent choose in Gene therapy. However, pulmonary administration of the Ad vectors caused self-limiting toxicity in a patient with cystic fibrosis. The death of patient arouse lots of debates toward gene therapy. Obviously, there are far more patients who was cured than the actual death. In recent years, using gene therapy become a promising strategy in curing cancer (see Table 1). Zhenzhen Tu, et al, recombine Adenoviruses with human ERβgene to suppress colorectal tumors and has achieved a positive results. (1)

The definition and classification of Gene therapy

Gene therapy is defined as introduction, using a vector which including nucleic acid into cells, aiming to alter gene expression to prevent, halt or reverse a pathological process. Some scientist suggests that the process include exogenous nucleic acids of a vector that provide a transcriptional template for the expression of a protein-coding or non-coding nucleic acid. The viral vectors is the main ways for transferring the genes to human cells and it can be classified into two main categories(2), the integrating vectors that inserting themselves into the host genome and nointergating vectors(episome) which usually is an extra chromosomal genetic element. Gamma-retroviral and lentiviral vectors are integrating vectors which will are stably inherited and they are usually used to transfect in actively dividing cells such as tumor cells. Adenoviral and Adeno-associated virus (AAV) are nointergating vectors which would quickly lost from the rapid dividing cells and they are usually used to transfect in quiescent or slowing dividing cells. Gene therapy will be carried out in three ways, gene addition, gene correction and gene knockdown, sometimes, it was used in combination. Gene addition is used to provide therapeutic benefit or to supply a protein. Gene correction aims to alter genomic sequence to correct a mutation or create a mutation to resist the diseases and gene knockdown can eliminate a gene product using RNAi technology.

The structure of Ad vectors (3) (see Figure 2)

Ad vectors are widely used in clinical trials because of its high efficiency of transgene expression and it also can easily be purified to high titres. (see Figure 1). It remain episomal in cells and has a 36kb double-stranded non-enveloped linear DNA which packed within the icosahedral capsid. The capsid is formed by three principal proteins, the hexon, the penton base and the protruding flexible fiber. The hexon and penton subnnits compose of icosahedral shell while fiber protrusions help the virus to anchor to the cell surface. The Adenovirus vectors is continuously expanding class of at least 51 immunologically distinct serotypes which was classified into 6 species (A-F).

The mechanism of Ad vector enter into the host.

Ad’s entering into the cytoplasm

The fiber knob domain of Ad vector use Coxsackie-Adenoviral Receptor (CAR) as its primary attachement receptor. After the ligand-receptor interaction, the clathrin-medicated endocytosis was triggered, partial virus was disassembled, that is, came into uncoating process. The endosome and a series of reactions can result in the degradation of the Ad vectors. But Ad vectors can escape from endosome by entering low PH endosome with the release of the VI protein and lyse the endosome.  

Ad’s entering into nucleus

Transport to the nucleus is required for successful therapy. After entering the cytoplasm, the cytosolic Ad binds dynein and is transported along microtubules towards microtubule organizing center. The nuclear pore complex receptor CAN/Nup214 is the dock site of the cytosolic Ad. Finally, Ad was transported into the nucleus for subsequent transcription.

Difficulties

With the transportation and expression of the transfer gene, we still met four difficulties (4). (See Figure 3)

A. During the Uptake, transport and uncoating process. Vectors must successfully integrate and enter into nucleus. Escaping from the endosome is the key factor for Vectors move into the transcription and expression process.

B. Once the vector reaches the nucleus, the Ad Vector exist as a episomal molecule genome, in the following reactions, the ad vectors must persist and it cannot be degradation.

C. The third step is come into transcription and expression process. Many factors will influence the transcriptional activity and transgene, all those can determine whether a transfer gene can be expressed or not.

D. The immune response can limit the viability of the transduced cells and/or the expression of the transgene product and is also the important hurdles of the gene transcription and expression.

Discussion

Nowadays, the major hurdle to adenoviral-mediated gene therapy is innate immune system. (5) Cell-mediated recognition of virus via capsid components or nucleic acid initiate innate immune response by the infected cells, which activates the interferon (IFN) to block viral replication, at the same time, releasing chernokines to recruit the factors and cells which speed up the engulf and destroy the exogenous vectors.

Recombinant adenoviral vectors will improve the possibilities of systemic gene transfer into many issues in mammals and system delivery can induce severe toxicity.

Thus in order to escape the IFN and cellular recruit pathways, we need to overcome innate immune response and develop the immune escape mechanisms by adenoviruses.

The relevant solution

Modification of the vectors

In order to decrease the innate immune response, the development of vectors has been through three generation. The first-generation adenoviral retained many wild-type viral gene, which can be expressed at low-levels in transduced cells and can cause toxicity. The second- and third generation deletes the additional viral genes so the expression of the undesired gene can reduced.

The constructions of Nomomedicine

What’s more, Nomomedicine based on the use of adenovirus vectors for therapeutic gene shows broad potential. (6) Scientists suggest Chemical modification that establish Ad nanoparticle by using polymers to‘shield’ capsid proteins from host interactions, in which Polyethylene glycol (PEG) are generally used because its special advantage, (PEG) is synthesized by repeating CH2CH2O subunits and is uncharged, hydrophilic, nonimmunogenic polymer. Therefore, targeting the diseased tissue by using Ad nanoparticles is an alternative, well established targeting strategy.

Conclusion

Although at the beginning, gene therapy arouse great debates because of its immature development, gene therapy has been widely used in recent years, and it is promising with the development of new technology. Severe diseases can be treated by using gene therapy, and especially, the Ad vectors are frequently used in gene therapy because of its high efficiency of transgene expression and it also can easily be purified to high titres. Knowing the structure of Ad vectors and its mechanism when entering into nucleus will help us find new ways to overcome those difficulties. Finding new methods to make Ad vectors escape from innate immune response is a new challenge. Specific targeting for many gene therapy applications such as metastatic cancers or cardiovascular diseases requires intravascular delivery of the vectors. The development of recombinant gene technology give us more chances to modify the gene of Ad and make it suitable for gene therapy. The constructions of Nomomedicine which shells the vectors under protection is a new concept and it seems promising because of its specific targeting.

 

Legend to Figure and Table

Table 1    Selected gene therapy clinical trials (paper 2)

 

 

Figure 1: Breakdown of vectors used in gene therapy trials. (paper 2) 

 

(Source: The Journal of Gene Medicine, Wiley and Sons).

 

 

Figure 2. Adenovirus capsid structure. ( Paper 6)

 

Figure 3 Four difficulties in the transfer gene process (Paper 4)

 

Reference

(1) http://link.springer.com/article/10.1007/s00432-014-1611-9

(2)http://www.nature.com/nbt/journal/v29/n2/abs/nbt.1769.html

(3)http://www.sciencedirect.com/science/article/pii/S1471491412000718

(4) http://www.nature.com/nrg/journal/v12/n5/full/nrg2971.html

(5) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3092742/citedby/

(6) http://www.futuremedicine.com/doi/full/10.2217/nnm.11.186

 

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