Editing Restriction modification system (section)

===Gene therapy===
The bacteria R-M system has been proposed as a model for devising human anti-viral gene or genomic vaccines and therapies since the RM system serves an innate defense-role in bacteria by restricting tropism of bacteriophages.<ref>{{cite journal|author=Wayengera M |title= HIV and Gene Therapy: The proposed [R-M enzymatic] model for a gene therapy against HIV. |journal=Makerere Med J. |year=2003 |volume=38 |pages=28–30}}</ref> Research is on REases and ZFN that can cleave the DNA of various human viruses, including [[Herpes simplex virus|HSV-2]], high-risk [[HPV]]s and [[HIV-1]], with the ultimate goal of inducing target mutagenesis and aberrations of human-infecting viruses.<ref>{{cite journal |vauthors=Wayengera M, Kajumbula H, Byarugaba W |title= Frequency and site mapping of HIV-1/SIVcpz, HIV-2/SIVsmm and Other SIV gene sequence cleavage by various bacteria restriction enzymes: Precursors for a novel HIV inhibitory product |journal= Afr J Biotechnol |year=2007 |volume= 6 |issue=10 |pages=1225–1232 }}</ref><ref>{{cite journal |journal=Journal of Virology |year=2012 |volume=86 |issue=17 |pages=8920–36 |doi= 10.1128/JVI.00052-12 |title=Targeted DNA mutagenesis for the cure of chronic viral infections |vauthors=Schiffer JT, Aubert M, Weber ND, Mintzer E, Stone D, Jerome KR |pmid=22718830 |pmc= 3416169 }}</ref><ref>{{cite journal |journal=Viruses |year= 2013  |volume=5|issue=11 |pages=2748–66| doi= 10.3390/v5112748 |title=Newer gene editing technologies toward HIV gene therapy |vauthors=Manjunath N, Yi G, Dang Y, Shankar P |pmid=24284874 |pmc=3856413|doi-access= free }}</ref> The human genome already contains remnants of retroviral genomes that have been inactivated and harnessed for self-gain. Indeed, the mechanisms for silencing active L1 genomic retroelements by the three prime repair exonuclease 1 (TREX1) and excision repair cross complementing 1 (ERCC) appear to mimic the action of RM-systems in bacteria, and the non-homologous end-joining (NHEJ) that follows the use of ZFN without a repair template.<ref>{{cite journal |vauthors=Stetson DB, Ko JS, Heidmann T, Medzhitov R |year=2008 |title= Trex1 prevents cell intrinsic initiation of autoimmunity |journal= Cell |volume=134 |issue=4 |pages= 587–598 |pmid=18724932 |pmc=2626626 |doi=10.1016/j.cell.2008.06.032}}</ref><ref>{{cite journal |vauthors=Gasior SL, Roy-Engel AM, Deininger PL |year=2008 |title= ERCC1/XPF limits L1 retrotransposition |journal=DNA Repair |volume=7 |pages= 983–989 |doi=10.1016/j.dnarep.2008.02.006 |pmid=18396111 |issue=6 |pmc=2483505}}</ref>

A major advance is the creation of artificial restriction enzymes created by linking the FokI DNA cleavage domain with an array of DNA binding proteins or zinc finger arrays, denoted now as zinc finger nucleases (ZFN).<ref name="kim1996">{{cite journal |vauthors=Kim YG, Cha J, Chandrasegaran S | title = Hybrid restriction enzymes: zinc finger fusions to Fok I cleavage domain | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 93 | issue = 3 | pages = 1156–60 |date=February 1996 | pmid = 8577732 | pmc = 40048 | doi = 10.1073/pnas.93.3.1156 |bibcode = 1996PNAS...93.1156K| doi-access = free }}</ref>  ZFNs are a powerful tool for host genome editing due to their enhanced sequence specificity. ZFN work in pairs, their dimerization being mediated in-situ through the FoKI domain. Each zinc finger array (ZFA) is capable of recognizing 9–12 base-pairs, making for 18–24 for the pair. A 5–7 bp spacer between the cleavage sites further enhances the specificity of ZFN, making them a safe and more precise tool that can be applied in humans. A recent Phase I clinical trial of ZFN for the targeted abolition of the CCR5 co-receptor for HIV-1 has been undertaken.<ref>{{cite journal |vauthors=Tebas P, Stein D, Tang WW, Frank I, Wang SQ, Lee G, etal |year=2014|title= Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV |journal= N Engl J Med |volume= 370 |issue=10|pages=901–910 |pmid= 24597865 |doi=10.1056/NEJMoa1300662 |pmc=4084652}}</ref>