How Does Gene Addition Work?

An overview of gene addition, how it works, and its application in complex and infectious diseases

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Complex and Infectious Diseases


Complex Diseases

In contrast to monogenic diseases, which are caused by modifications in a single gene, complex diseases are disorders caused by a combination of factors, as shown here1-3

Unmet Need

Complex diseases are common, and there is an unmet medical need for effective treatments3

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Infectious Diseases

Infectious diseases are caused by pathogenic microorganisms, such as bacteria, viruses, and fungi4

Unmet Need

Similar to complex diseases, there is an unmet medical need for treating patients with infectious diseases, which are associated with high morbidity and mortality globally3,5

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Gene Addition

Gene addition is a therapeutic strategy that involves the introduction of a new gene into the body to target a specific aspect of the disease pathway3

Gene replacement and the genetic modulation of immune cells are specific forms of gene addition, which are covered in more detail elsewhere on the Gene Therapy Network3,6

Gene Addition in Complex and Infectious Diseases

  • Gene addition can be used in complex diseases, where correcting one particular mutation may not be effective, but the addition of a therapeutic gene may contribute to the mitigation of the disease phenotype3,7
  • It can also be applied for the treatment of infectious diseases that cannot be treated adequately with standard clinical management3,5

Multiple factors may cause diseases, including genetic, environmental, and lifestyle factors in the case of complex diseases and exposure to pathogens in infectious diseases3,4,8


Gene addition works by adding a new therapeutic gene into the body.3 This new gene leads to the production of proteins that help ease the disease3

Figure adapted from Figure 1B in Wang D, Gao G. 2014.3

Advantages and Disadvantages of Gene Addition

ADVANTAGE

Gene addition provides an important therapeutic option for treating complex and infectious diseases where there is still a significant unmet medical need3,7

DISADVANTAGES

The approach targets diseases where there may be a variety of factors and genes involved in their pathophysiology3,7


Therefore, depending on the strategy or target, gene addition may only be able to contribute toward mitigating the disease phenotype as opposed to alleviating it completely7

Gene Transfer

Gene addition can involve the addition of either a therapeutic gene or an antibody gene3

The gene is transferred into cells via the use of a vector, which can be viral or nonviral in nature9

The gene may be integrated into the cell\'s DNA or maintained as episomal/plasmid DNA10


DNA, deoxyribonucleic acid.

Gene Transfer of Therapeutic Genes:
Potential Applications

The addition of a therapeutic gene can involve delivering a gene that targets cellular processes7

Proliferation and Apoptosis

Gene addition can be used to introduce genes that arrest cell proliferation, which include:7

  • cyclin-dependent kinase inhibitors
  • cell cycle checkpoint regulators

It can also be used to introduce genes that trigger cellular apoptosis7

  • This is particularly useful in cancer, where the evasion of apoptosis results in the uncontrollable multiplication of cells11
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Example:

A recombinant human p53 adenovirus was approved in China in 2003 for the treatment of head and neck cancers12

p53 is a tumor suppressor protein that arrests cell growth and is implicated in apoptosis, autophagy, and cellular senescence12

Clinical trials of this gene therapy have not been carried out outside of China, and this therapy has not been approved in the US or Europe12

Survival and Homeostasis

Gene addition can be used to deliver genes encoding growth factors7

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Example:

Growth factor gene addition is being investigated in complex neurodegenerative diseases, for example in a Phase 1 trial investigating the delivery of glial cell line-derived neurotrophic factor to patients with Parkinson\'s disease13-15

Degradation Systems

Cellular degradation systems are potential targets for gene addition.7 An example is autophagy, which is a particularly important research focus in the field of gene addition due to its key role in neurodegenerative diseases and cancer7

Autophagy is a tightly regulated cellular process in which the lysosome degrades damaged proteins and organelles7

  • Defects within the autophagy pathway are implicated in the pathogenesis of a wide range of complex and infectious diseases16
  • The induction of autophagy shows promise for the prevention or treatment of these diseases16
  • The underlying mechanisms for the beneficial effect of autophagy induction are not fully understood but may involve:16
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The BECN1 gene is involved in autophagy, and research has shown that its deletion in mice results in a number of negative effects16

  • These effects include susceptibility to Alzheimer\'s disease and an increased incidence of spontaneous malignancies16

Based on its key role in inducing autophagy and the negative effects associated with its deletion, delivery of the BECN1 gene has been investigated preclinically for the potential treatment of complex diseases, such as cancer and Parkinson\'s disease16

Proteostasis

Proteostasis is another target for gene addition7

It is defined as the interconnection of processes within the cell that ensure the production of functioning proteins.17 Processes include protein synthesis, localization, quality control, and degradation17

The endoplasmic reticulum (ER) plays a key role in proteostasis, as it is a major site for protein synthesis and processing17

ER stress can occur following noxious inputs to the cell. These inputs can activate a signaling pathway called the unfolded protein response, which is implicated in the early stages of several pathological conditions17

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Gene addition has been investigated preclinically for the delivery of genes that reduce ER stress in a range of complex diseases17,18

The types of genes encoded for include transcription factors, ER chaperones, and enzymes17

Gene Transfer of Antibody Genes: Potential Applications

Recombinant monoclonal antibodies (mAbs) are used widely in complex diseases but are associated with:19,20

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To overcome some of the drawbacks associated with mAbs, strategies involving antibody gene transfer have been investigated

Antibody gene transfer involves the expression of an antibody-encoding nucleotide sequence20

The nucleotide sequence can be delivered by viral or nonviral vectors and has applications in both complex and infectious diseases20

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Potential Use in Complex Diseases

In the context of complex diseases, the encoded antibodies may target specific aspects of the disease pathway

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Example of potential targets include:

  • Vascular endothelial growth factor, which is implicated in tumor angiogenesis20,21
  • C-C chemokine receptor 4, which is overexpressed in cutaneous T-cell lymphoma22
  • Amyloid-β, which is implicated in the pathophysiology of Alzheimer\'s disease23

Potential Use in Infectious Diseases

For infectious diseases, the encoded antibody targets the pathogenic microorganism

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  • The delivery of an antibody gene targeting the V1V2 loop of the human immunodeficiency virus (HIV) type 1 envelope glycoprotein gp120 for the prevention of HIV24
    • This therapy has been investigated in healthy humans in a Phase 1 clinical trial24

Summary

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Gene addition is a therapeutic strategy that can be used in complex and infectious diseases3

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It involves introducing a new gene into the body to target a specific aspect of the disease pathway, with the gene in question being either a therapeutic or antibody gene3

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The addition of a therapeutic gene may be used to target various cellular processes and can be used in complex diseases3,7

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The addition of an antibody gene involves the delivery of a nucleotide sequence encoding an antibody; also, it has applications in both complex and infectious diseases9,20

References

  1. Craig J. Complex diseases: Research and applications. Available at: https://www.nature.com/scitable/topicpage/complex-diseases-research-and-applications-748/. Accessed November 4, 2020.
  2. He B, et al. J Cell Mol Med 2016;20(12):2231-2240.
  3. Wang D, Gao G. Discov Med 2014;18(98):151-161.
  4. National Center for Emerging and Zoonotic Infectious Diseases. Emerging & zoonotic infectious diseases. Available at: https://www.cdc.gov/ncezid/pdf/ncezid_brochure_2012.pdf. Accessed November 3, 2020.
  5. Bunnell BA, Morgan RA. Clin Microbiol Rev 1998;11(1):42-56.
  6. Strachan T, Read A. Genetic approaches to treating disease. In: Human Molecular Genetics. 4th edn. Boca Raton, FL: CRC Press, 2018:696-699.
  7. Nóbrega C. Gene therapy strategies: Gene augmentation. In: Nóbrega C, et al. (eds). A Handbook of Gene and Cell Therapy. Switzerland: Springer, Cham, 2020:117-126.
  8. Craig J. Complex Diseases: Research and Applications. Nature Education. Available at: https://www.nature.com/scitable/topicpage/complex-diseases-research-and-applications-748/. Accessed June 16, 2020.
  9. Wang D, Gao G. Discov Med 2014;18(97):67-77.
  10. Perwitasari O, et al. Pharmaceuticals (Basel) 2013;6(2):124-160.
  11. Jan R, Chaudhry GE. Adv Pharm Bull 2019;9(2):205-218.
  12. Zhang WW, et al. Hum Gene Ther 2018;29(2):160-179.
  13. ClinicalTrials.gov. NCT01621581. Available at: https://clinicaltrials.gov/ct2/show/NCT01621581. Accessed October 21, 2020.
  14. Hudry E, Vandenberghe LH. Neuron 2019;101(5):839-862.
  15. Sudhakar V, Richardson RM. Neurotherapeutics 2019;16(1):166-175.
  16. Levine B, et al. J Clin Invest 2015;125(1):14-24.
  17. Valenzuela V, et al. Mol Ther 2018;26(6):1404-1413.
  18. Castillo V, et al. Neural Regen Res 2015;10(7):1053-1054.
  19. Focosi D, et al. Clin Microbiol Infect 2011;17(12):1759-1768.
  20. Hollevoet K, Declerck PJ. J Transl Med 2017;15(1):131.
  21. Gardner V, et al. Anti-VEGF Therapy in Cancer: A Double-Edged Sword. Available at: https://www.intechopen.com/books/physiologic-and-pathologic-angiogenesis-signaling-mechanisms-and-targeted-therapy/anti-vegf-therapy-in-cancer-a-double-edged-sword. Accessed November 4, 2020.
  22. Han T, et al. PLoS One 2012;7(9):e44455.
  23. Elmer BM, et al. PLoS One 2019;14(12):e0226245.
  24. Priddy FH, et al. Lancet HIV 2019;6(4):e230-e239.