Two DNA strand icons joined by plus sign representing gene addition

Gene addition

Gain knowledge about a gene-therapy approach and how it is delivered

Gene addition targets a faulty gene within a patient’s cells by adding a functional copy of that gene to affect protein expression or by inserting a different gene that circumvents the defect and restores cell function.1-4 With several therapies approved in the past decade and research ongoing across various delivery vectors, make sure you understand how gene addition works.5-7

Two DNA strand icons joined by plus sign representing gene addition

Gene addition

Gain knowledge about a gene-therapy approach and how it is delivered

Gene addition targets a faulty gene within a patient’s cells by adding a functional copy of that gene to affect protein expression or by inserting a different gene that circumvents the defect and restores cell function.1-4 With several therapies approved in the past decade and research ongoing across various delivery vectors, make sure you understand how gene addition works.5-7

How a new gene gets added

Gene-addition tools introduce a functional gene, sometimes called a therapeutic gene or transgene, directly into the nucleus of target cells using a molecular delivery vehicle known as a vector.8 When adding a new gene, it is typical to use a viral-based vector delivered ex vivo or in vivo.9,10 Vectors are critical components of gene addition.8 Learn more as we explore one of the most common techniques in detail below.

Viral vector delivery

Viruses are used as vectors because of their efficiency at entering cells, and there are several different types of viral vectors used for gene addition.9,10 Before carrying a transgene into a patient’s cells, the vectors are modified to remove the viral disease-causing genes as well as their ability to replicate.2,4

Integrating versus nonintegrating gene addition
Once a vector delivers the transgene inside the nucleus—where DNA is packaged in chromosomes—the cell begins to generate new proteins to improve functioning.4 The gene then either remains as an extra segment of DNA in the cell or inserts into the chromosomes and integrates into the cell’s own DNA, with both techniques resulting in functional protein production.4,11,12

Gene addition viral vector illustration representing retroviral, lentiviral, adeno-associated viral, and adenoviral vectors


Integrating viral vectors

For integrating gene addition, the functional gene fully integrates and becomes part of the host genome, achieving sustained protein expression even if the cells divide.11
Common vectors include:
 

Retroviral vector illustration representing integrating gene addition

Retroviral vectors

Retroviruses are composed of double-stranded RNA, reverse transcriptase, and a lipid envelope with receptor-binding proteins.2 As vectors, they have the ability to deliver large genetic packages of RNA, which then convert into DNA before integrating, and are often used in ex-vivo approaches.10

Lentiviral vector illustration representing integrating gene addition

Lentiviral vectors

Lentiviruses are a subclass of retroviruses that have a similar structure, including genetic material consisting of double-stranded RNA and reverse transcriptase.2 These vectors are suitable for ex-vivo treatment and have the ability to both carry large loads of material into the targeted cell’s genome and integrate with nondividing cells.2,10

Nonintegrating viral vectors

For nonintegrating gene addition, the functional gene does not permanently integrate into the host genome, providing stable expression in nondividing cells but limited expression in proliferating cells.12
Common vectors include:
 

Adeno-associated viral vector illustration representing nonintegrating gene addition

Adeno-associated viral (AAV) vectors

AAV vectors are small, single-stranded DNA viruses that rely on an adenovirus to replicate—hence the name.2 These vectors can be applied for in-vivo approaches and typically deliver small genes or DNA packages due to size limitations.10

Adenoviral vector illustration representing nonintegrating gene addition

Adenoviral vectors (AV)

Adenoviruses feature double-stranded DNA as their genetic material.2 Similar to AAVs, these vectors are often used to deliver genetic material into nondividing cells, but they can carry much larger genes if needed for the application.10

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References:  1. DeWeerdt S. Gene therapy: a treatment coming of age. Pharm J. 2014;293(7831). doi:10.1211/PJ.2014.20066677.  2. Nowakowski A, Andrzejewska A, Janowski M, Walczak P, Lukomska B. Genetic engineering of stem cells for enhanced therapy. Acta Neurobiol Exp. 2013;73:1-18.  3. Dong AC, Rivella S. Gene addition strategies for ß-thalassemia and sickle cell anemia. Adv Exp Med Biol. 2017;1013:155-176. doi:10.1007/978-1-4939-7299-9_6.  4. Genetic therapies. National Heart, Lung, and Blood Institute. Accessed April 14, 2023. https://www.nhlbi.nih.gov/health-topics/genetic-therapies.  5. Approved cellular and gene therapy products. US Food & Drug Administration. Updated October 26, 2021. Accessed April 14, 2023. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products.  6. Gene therapy. ClinicalTrials.gov. Accessed April 14, 2023. https://clinicaltrials.gov/ct2/results?cond=&term=gene+therapy&cntry=US&state=&city=&dist.  7. Bulaklak K, Gersbach CA. The once and future gene therapy. Nat Commun. 2020;11(1):5820. doi:10.1038/s41467-020-19505-2.  8. Ramamoorth M, Narvekar A. Non viral vectors in gene therapy—an overview. J Clin Diagn Res. 2015;9(1):GE01-GE06. doi:10.7860/JCDR/2015/10443.5394.  9. Bulcha JT, Wang Y, Ma H, Tai PWL, Gao G. Viral vector platforms within the gene therapy landscape. Signal Transduct Target Ther. 2021;6(1):53. doi:10.1038/s41392-021-00487-6.  10. Vectors 101. American Society of Gene + Cell Therapy. Updated November 5, 2021. Accessed April 14, 2023. https://patienteducation.asgct.org/gene-therapy-101/vectors-101.  11. Apolonia L. The old and the new: prospects for non-integrating lentiviral vector technology. Viruses. 2020;12(10):1103. doi:10.3390/v12101103.  12. Papanikolaou E, Bosio A. The promise and the hope of gene therapy. Front Genome Ed. 2021;3:618346. doi:10.3389/fgeed.2021.618346.