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<p>Not all medical procedures that introduce alterations to a patient's genetic makeup can be considered gene therapy. <a href="https://en.wikipedia.org/wiki/Bone_marrow_transplantation" title="Bone marrow transplantation">Bone marrow transplantation</a> and <a href="https://en.wikipedia.org/wiki/Organ_transplants" title="Organ transplants">organ transplants</a> in general have been found to introduce foreign DNA into patients.<sup><a href="https://en.wikipedia.org/wiki/Gene_therapy#cite_note-5">[5]</a></sup> Gene therapy is defined by the precision of the procedure and the intention of direct therapeutic effect.</p>
<h2>Approaches</h2>
<p>Following early advances in <a href="https://en.wikipedia.org/wiki/Genetic_engineering" title="Genetic engineering">genetic engineering</a> of bacteria, cells, and small animals, scientists started considering how to apply it to medicine. Two main approaches were considered – replacing or disrupting defective genes.<sup><a href="https://en.wikipedia.org/wiki/Gene_therapy#cite_note-28">[28]</a></sup> Scientists focused on diseases caused by single-gene defects, such as <a href="https://en.wikipedia.org/wiki/Cystic_fibrosis" title="Cystic fibrosis">cystic fibrosis</a>, <a href="https://en.wikipedia.org/wiki/Haemophilia" title="">haemophilia</a>, <a href="https://en.wikipedia.org/wiki/Muscular_dystrophy" title="Muscular dystrophy">muscular dystrophy</a>, <a href="https://en.wikipedia.org/wiki/Thalassemia" title="Thalassemia">thalassemia</a>, and <a href="https://en.wikipedia.org/wiki/Sickle_cell_anemia" title="Sickle cell anemia">sickle cell anemia</a>. <a href="https://en.wikipedia.org/wiki/Glybera" title="Glybera">Glybera</a> treats one such disease, caused by a defect in <a href="https://en.wikipedia.org/wiki/Lipoprotein_lipase" title="Lipoprotein lipase">lipoprotein lipase</a>.<sup><a href="https://en.wikipedia.org/wiki/Gene_therapy#cite_note-Gallagher-27">[27]</a></sup></p>
<p><a href="https://en.wikipedia.org/wiki/DNA" title="DNA">DNA</a> must be administered, reach the damaged cells, enter the cell and either express or disrupt a protein.<sup><a href="https://en.wikipedia.org/wiki/Gene_therapy#cite_note-29">[29]</a></sup> Multiple delivery techniques have been explored. The initial approach incorporated DNA into an engineered <a href="https://en.wikipedia.org/wiki/Virus" title="Virus">virus</a> to deliver the DNA into a <a href="https://en.wikipedia.org/wiki/Chromosome" title="Chromosome">chromosome</a>.<sup><a href="https://en.wikipedia.org/wiki/Gene_therapy#cite_note-pmid23015375-30">[30]</a></sup><sup><a href="https://en.wikipedia.org/wiki/Gene_therapy#cite_note-pmid23435812-31">[31]</a></sup> <a href="https://en.wikipedia.org/wiki/Naked_DNA" title="Naked DNA">Naked DNA</a> approaches have also been explored, especially in the context of <a href="https://en.wikipedia.org/wiki/Vaccine" title="Vaccine">vaccine</a> development.<sup><a href="https://en.wikipedia.org/wiki/Gene_therapy#cite_note-pmid23111168-32">[32]</a></sup></p>
<p>Generally, efforts focused on administering a gene that causes a needed protein to be expressed. More recently, increased understanding of <a href="https://en.wikipedia.org/wiki/Nucleases" title="Nucleases">nuclease</a> function has led to more direct DNA editing, using techniques such as <a href="https://en.wikipedia.org/wiki/Zinc_finger_nucleases" title="Zinc finger nucleases">zinc finger nucleases</a> and <a href="https://en.wikipedia.org/wiki/CRISPR" title="CRISPR">CRISPR</a>. The vector incorporates genes into chromosomes. The expressed nucleases then knock out and replace genes in the chromosome. As of 2014 these approaches involve removing cells from patients, editing a chromosome and returning the transformed cells to patients.<sup><a href="https://en.wikipedia.org/wiki/Gene_therapy#cite_note-pmid20717154-33">[33]</a></sup></p>
<p><a href="https://en.wikipedia.org/wiki/Genome_editing" title="Genome editing">Gene editing</a> is a potential approach to alter the human genome to treat genetic diseases,<sup><a href="https://en.wikipedia.org/wiki/Gene_therapy#cite_note-34">[34]</a></sup> viral diseases,<sup><a href="https://en.wikipedia.org/wiki/Gene_therapy#cite_note-35">[35]</a></sup> and cancer.<sup><a href="https://en.wikipedia.org/wiki/Gene_therapy#cite_note-36">[36]</a></sup> As of 2016 these approaches were still years from being medicine.<sup><a href="https://en.wikipedia.org/wiki/Gene_therapy#cite_note-37">[37]</a></sup><sup><a href="https://en.wikipedia.org/wiki/Gene_therapy#cite_note-38">[38]</a></sup></p>
<h2>Vectors</h2>
<p>Main article: <a href="https://en.wikipedia.org/wiki/Vectors_in_gene_therapy" title="Vectors in gene therapy">Vectors in gene therapy</a></p>
<p>The delivery of DNA into cells can be accomplished by multiple <a href="https://en.wikipedia.org/wiki/Vectors_in_Gene_Therapy" title="Vectors in Gene Therapy">methods</a>. The two major classes are <a href="https://en.wikipedia.org/wiki/Recombinant_virus" title="Recombinant virus">recombinant viruses</a> (sometimes called biological nanoparticles or viral vectors) and <a href="https://en.wikipedia.org/wiki/Naked_DNA" title="Naked DNA">naked DNA</a> or DNA complexes (non-viral methods).</p>
<h3>Viruses</h3>
<p>Main article: <a href="https://en.wikipedia.org/wiki/Viral_vector" title="Viral vector">Viral vector</a></p>
<p>In order to <a href="https://en.wikipedia.org/wiki/Viral_replication" title="Viral replication">replicate</a>, <a href="https://en.wikipedia.org/wiki/Virus" title="Virus">viruses</a> introduce their genetic material into the host cell, tricking the host's cellular machinery into using it as blueprints for viral proteins. <a href="https://en.wikipedia.org/wiki/Retrovirus" title="Retrovirus">Retroviruses</a> go a stage further by having their genetic material copied into the genome of the host cell. Scientists exploit this by substituting a virus's genetic material with therapeutic DNA. (The term 'DNA' may be an oversimplification, as some viruses contain RNA, and gene therapy could take this form as well.) A number of viruses have been used for human gene therapy, including <a href="https://en.wikipedia.org/wiki/Retrovirus" title="Retrovirus">retroviruses</a>, <a href="https://en.wikipedia.org/wiki/Adenovirus" title="Adenovirus">adenoviruses</a>, <a href="https://en.wikipedia.org/wiki/Herpes_simplex_virus" title="Herpes simplex virus">herpes simplex</a>, <a href="https://en.wikipedia.org/wiki/Vaccinia_virus" title="Vaccinia virus">vaccinia</a>, and <a href="https://en.wikipedia.org/wiki/Adeno-associated_virus" title="Adeno-associated virus">adeno-associated virus</a>.<sup><a href="https://en.wikipedia.org/wiki/Gene_therapy#cite_note-JGenMed_Database-4">[4]</a></sup> Like the genetic material (DNA or RNA) in viruses, therapeutic DNA can be designed to simply serve as a temporary blueprint that is degraded naturally or (at least theoretically) to enter the host's genome, becoming a permanent part of the host's DNA in infected cells.</p>
<h3>Non-viral</h3>
<p>Non-viral methods present certain advantages over viral methods, such as large scale production and low host <a href="https://en.wikipedia.org/wiki/Immunogenicity" title="Immunogenicity">immunogenicity</a>. However, non-viral methods initially produced lower levels of <a href="https://en.wikipedia.org/wiki/Transfection" title="Transfection">transfection</a> and <a href="https://en.wikipedia.org/wiki/Gene_expression" title="Gene expression">gene expression</a>, and thus lower therapeutic efficacy. Later technology remedied this deficiency.<sup>[<em><a href="https://en.wikipedia.org/wiki/Wikipedia:Citation_needed" title="Wikipedia:Citation needed">citation needed</a></em>]</sup></p>
<p><a href="https://en.wikipedia.org/wiki/Vectors_in_Gene_Therapy#Non-viral_methods" title="Vectors in Gene Therapy">Methods for non-viral gene therapy</a> include the injection of naked DNA, <a href="https://en.wikipedia.org/wiki/Electroporation" title="Electroporation">electroporation</a>, the <a href="https://en.wikipedia.org/wiki/Gene_gun" title="Gene gun">gene gun</a>, <a href="https://en.wikipedia.org/wiki/Sonoporation" title="Sonoporation">sonoporation</a>, <a href="https://en.wikipedia.org/wiki/Magnetofection" title="Magnetofection">magnetofection</a>, the use of <a href="https://en.wikipedia.org/wiki/Oligonucleotide" title="Oligonucleotide">oligonucleotides</a>, lipoplexes, dendrimers, and inorganic nanoparticles.</p>