In hereditary diseases ( e.g. sickle cell anemia)

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Last updated: June 2, 2019

In themiddle of the 20th century and with the discovery of DNA by Watson and Crick,this discovery led to a revolution in the world of biology and medicine becauseof the great importance of this compound. DNA is a molecule that carry geneticinformation found in all living organisms and viruses, have important role ingrowth, development, reproduction and regulate of many biological processes.DNA in living organisms composed from two strands, each one made up of fourchemical bases: Adenine, Thymine, Cytosine and Guanine, and each one of thestrand is complementary to the other by base pairing which show DNA as doublehelix.  A mutation is any change that occurs in DNAsequence that happen during DNA replication or as result of exposure tochemical and physical factors ,this change might happen in somatic or germcells during replication and it’s related with many hereditary diseases ( e.g.

sickle cell anemia) or non-hereditary diseases (e.g. cancer).  The term of gene therapy emerged during the1960s .In 1972, Theodore Friedmann and Richard Roblin published a paper inScience called “Gene therapy for human genetic disease?” which citedStanfield Roger’s proposal in 1970 that “good DNA” could be used toreplace defective DNA in people with genetic disorders. A 4-year-old girl wasthe first to be treated for congenital disease called adenosine deaminase (ADA)deficiency using a gene therapy technique.

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  Gene therapy is a process to repair thischange in the DNA sequence in an attempt to restore the normal function of the mutantgenes, by inserting the normal gene into the cells or disrupting the gene inwhich the mutation occurred to overcome these diseases, by viral or non-viral vectors.This article will focus on viral vectors due to their efficiency advantages ingene delivery.  What is TheGene Therapy?   Genetherapy is defined by insertion new DNA into a patients with hereditary ornon-hereditary diseases to treat these disease. This is done by viral ornon-viral vectors in order to replacing mutated genes, inactivation mutatedgenes or insert new DNA fragment usually contains a functioning gene to correctthe effects of a disease that result from mutation in genes.  Virusescould be used as vectors to transfer ‘good’ genes into a human cells in vitroand in vivo.

First, it must remove viral genes which cause the diseases. Thenit should replace those genes with genes encoding the desired effect (e.g.insulin production in the case of diabetics), the insertion of foreign DNA intoviral vectors done by many techniques, one of them done by using restrictionenzymes to cut the viral genome at specific sites and insert the foreign DNAinto viral genome and ligate it by using DNA ligase which produce recombinantDNA (viral genes and insertion genes). This procedure must be done in such away that the genes which allow the virus to insert its genome into its host’sgenome.  Targetcells like the patient’s nerve or germ cells are infected with the vectors. Thevectors then transfer its genome containing the normal gene into the targetcells. The production of a functional protein product from the normal generestores the target cell to a normal state.

  Thereare two types of gene therapy according to target cells treatment:1.      Somaticgene therapy: transfer DNAfragments into all cells body except germ cells which produce eggs and spermsand it is effect confined to the patient and didn’t pass to children.2.

      Germlinegene therapy: transfer DNAfragments into germ cell and it is effect pass to children patients.   ViralVectors   A viruses is an infectiousparticles that don’t reproduces only within host body, contain genetic material(DNA or RNA genome) inside a protein shell called a capsid, geneticmaterial can be single or double strands. Some viruses have an internal orexternal membrane envelope. Virusesdon’t have organelles and that means they can’t make ATP or energy forthemselves.

  Viralreplication starts when the viruses enter to host and attach to receptorsintegrated in host cell membrane, then viruses inject genetic material intohost cell. When viruses enter into host cells, it must transfer its geneticmaterial into the nucleus of the host. The virus can enter to the nucleusdirectly, or inject its genetic material into the nuclear envelop without entrance into the nucleus. The virus then uses the own cellmaterials (enzymes) and organelles to produce capsid proteins and replicate the viralgenome. These parts then self-assemble into new virus particles, which can exitthe cell and infecthealthier host cells.

  There are types of viruses that classifiedaccording to genetic material, size, shape or mode of replication.  There are four types of viruses used mainlyas vectors in gene therapy – Retroviruses, Adenoviruses, Herpes-simplex virusand Adeno-associated virus and others. 1.

   Retroviruses   Group of viruses that belong to Retroviridaefamily and contained single strand RNA genome. Retroviruses have uniqueenzyme, called reverse transcriptase that help them to transcript their RNAinto DNA after invade host cells, then retroviral DNA can insert and integrate into the chromosomal DNA of thehost cell, to be expressed there. One of the most famous example ofretroviruses is human immunodeficiency virus (HIV).  Retroviruses have many characteristics madethem good vectors in order to gene delivery, some of these characteristics arethe efficient way of these viruses to enter into host cells and its ability tointegration into the host chromosomal DNA without expression of any immunogenicviral particles. The disadvantages of these viruses include that these vectorrequire cell division for stable infection and the limited capacity for thesevectors which prevents the delivery of large DNA fragments.  2.

   Adenoviruses  Another group of viruses that used in genetherapy, these viruses belong to Adenoviridae family, nonenvelopedviruses and contained double stranded DNA genome. The adenoviruses genomeencodes nearly 35 proteins that are expressed in two phases: early phase andlate phase. The early phase happens before the start of viral DNA replicationit is take about 7 hours post-infection, and the late phase which follow theDNA replication. About~20 early proteins have regulatory functions that allow the virus to takecontrol of the cell and to carry out viral DNA replication. The late proteinshave structural role in the virus. Adenoviruses responsible about many ofrespiratory infections.  The advantages of adenoviruses as vectors arethat they can infect large numbers of cell types, including nondividing cells,and the genome of the adenoviruses does not integrate into the host cellschromosomes. The ds DNA of adenoviruses keep free inside nucleus of infectedcells.

The presence of viral genes is necessary to replication and spreading ofthese viruses and immune system stimulation are Classified as disadvantages of adenoviruses.3.   Herpes-simplex viruses   Herpes-simplex viruses oralso known as human herpesviruses, herpesvirus 1 and 2 (HHV-1 and HHV-2),are two members of the herpesvirus family, Herpesviridae, belong to thesubfamily of Alphaherpesvirinae.

Consist of double stranded DNAgenome, contain around 100-200 genes that involved in capsid and lipid bilayerenvelop membrane formation and included in infectivity and genome replicationof these viruses. Previous studies indicate that there are correlation betweenHSV-1 and Alzheimer’s disease.  Herpesviruses are currently used in genedelivery due to some special features over other viral vectors. Some of thesefeatures are the high capacity of these vectors to transfer long sequence ofnew DNA into cells and the ability to targets nerve cells. Some ofdisadvantages of herpesviruses are that the large number of their genes whichis required to replication and spreading inside the host and difficult toproduce. 4.   Adeno-associated viruses  Adeno-associated virus belong to parvovirusfamily, small viruses contain single-stranded DNA genome.

Adeno-associatedviruses don’t associated in causes of diseases, and need to another types ofviruses like Herpes-simplex viruses or adenoviruses to act as helper viruses,help them to replicate.  Adeno-associated virus can integrates atspecific site on chromosomes, these viruses can insert foreign DNA at a specific site on chromosome 19 with near 100%certainty. In addition, these viruses don’t not produce immune response. Thesecharacteristics made them good vector for gene delivery. Conversely, There area few disadvantages to using adeno-associated virus as vectors, including thesmall amount of genetic material it can transfer (low capacity) and thedifficult to produce.GeneTherapy examples  Many achievements have been accomplished inthe field of gene therapy despite many challenges, studies are still ongoingand the results are promising, many diseases have been treated. Patients withinherited immune deficiencies have been fully treated, by treated of blood stemcells taken from patients and then infected with retroviruses carry normalgenes in vitro, after this the treated stem cells returned into patients.

   Adeno-associated viral vectors are used inhemophilia in order to deliver gene for Factor IX, the missing clotting protein,to liver.   Cystic Fibrosis is an inherited diseasecaused by mutation in the cystic fibrosis transmembrane conductance regulator(CFTR) gene that passed into children, the effect of cystic fibrosis mainly onrespiratory system. Viral and non-viral vectors are used in the treatment ofcystic fibrosis with different techniques. Adeno-associated viruses which issmall viruses to carry CFTR gene, so researchers have attempted to create afunctional CFTR “mini gene”, using techniques such as cutting the CFTR in halfand using two complementary AAVs. Also, Sendai viruses are used as vectors totreat cystic fibrosis because its ability to infect airway epithelial cells dueto the presence of sialic acid and cholesterol receptors on their apicalsurface.   Studies are ongoing in the field of genetherapy on cancer, there are great hopes for effective treatment of varioustypes of cancer, some studies have shown positive results, understanding howcancer is produced is very helpful in research. Previous studies showed thatmodified herpes-simplex viruses type 1 help in skin cancer treatment, thesevectors carry T-VEC drugs, the viruses injected directly into cancer cells andreplicated inside these cells until they decompose the cells and then infectmore cancer cells.

Also, gene therapy used in the blood cancer treatment, specificallywhite blood cell cancer (leukemia), by removed patients’ blood cells andinfected with modified viruses that can recognize specific proteins on thesurface of cancer cell and help in kill cancer cells, after the blood cellswere returned to the patients, the results show completely reduction in theleukemia.  Also, in the fat metabolism disorderresearchers used adeno-associated viruses to transfer normal copy of lipoproteinlipase gene, which have important role fats breakdown in the blood, into musclecells.  Beta-thalassemia is a blood disorder thatarise from mutation in the beta-globin gene, which codes for beta polypeptidesthat are important domains in hemoglobin which responsible about oxygentransfer into all body tissues. Blood stem cells removed from beta-thalassemiapatient and treated with modified retroviruses contain normal beta globin gene,then the infected stem cells backed into patient body where they gave rise intonormal red blood cells.

After Seven years, the patient was still doing wellwithout blood transfusions. GeneTherapy Challenges  There are many challenges to gene therapy,which are related to transport, toxicity, and efficacy and gene delivery. Themost important challenge in gene therapy is the lack of a 100% effective way toensure that the genes reach the nuclei of the targeted cells to be expressed.

This risk is concentrated in that these viralvectors are transferred to abnormal cells and healthy cells alike, and this maylead to problems that may occur in healthy cells.  Another challenge is that there is also no waysensure to transfer the new genes to target sites in target cells chromosomesand this may lead to other more complex diseases, such as cancer. This risk wasobserved in clinical trials where hematopoietic stem cells were transferred toX-linked severe combined immunodeficiency (X-SCID) patients by retrovirusescontaining intact genes, some of these patients have appeared T cell leukemia.There are other concerns that these viralvectors can reach the cells responsible for producing the gametes and causechanges in the DNA they contain, and the possibility of transferring thesechanges to the children.  Other danger of gene therapy based on viralvectors is that the inability to control the amount of the transferred geneexpression, it might be overexpressed, producing large amount of new proteinand this could be harmful, or it might be downexpressed, so the purpose is notto occur.

    Because viruses stimulate the immune system,viral vectors may encounter a large defense of immune cells in the body.Changes in the genetic material of these viruses may lead to the weakening oftheir resistance and thus to their destruction before the target is achieved.  Another challenge is that these viruses maytransported from patients who are undergo to gene therapy into healthy personsor into the environment.  However, gene therapy techniques arecurrently subject to many studies in different fields, and results show manyhopes for patients around the world to overcome these challenges. Experiments are initially conducted on animals to betterunderstand and overcome these risks, before any application occurs in clinicaltrials on humans. SummaryGenetherapy is a process to repair this change in the DNA sequence in an attempt torestore the normal function of the mutant genes, this is done by viral ornon-viral vectors. About 80% of the studies were conducted on viral vectors dueto their efficiency in the gene delivery.

Many types of viruses are used ingene therapy, each type has advantages that make it a good vectors and at thesame time have disadvantages that make it impossible to use it in allexperiments. Experiments are still ongoing in the field of gene therapy, someof which have been effective in treating some diseases, and other studies arestill ongoing on some diseases, notably cancer. There are also challenges togene therapy. One of the most prominent of these challenges is the lack of aneffective way to ensure that DNA is transferred to the target location. 


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