Dz13

Dz13 is an experimental treatment developed by scientists at the University of New South Wales. The drug aims to combat a range of illnesses, including skin cancer, restenosis, arthritis and macular degeneration. Trials of Dz13 were suspended in 2013.

Mechanism of action

Dz13 is a 10-23 DNAzyme that targets c-Jun, a transcription factor found in diseased blood vessels, eyes, lungs and joints. The treatment works by the DNA-based enzyme binding to and catalytically destroying its target messenger RNA, thereby inhibiting c-Jun expression in cells.[1] Dz13 has underpinned the development of a library of programmable DNAzymes operable in a cellular environment.[2]

The potential of Dz13 as a therapeutic agent derives from the fact that inactivation of c-Jun can have an effect on downstream genes such as MMP-2, MMP-9, VEGF and FGF-2.[3][4] Dz13 also inhibits the expression of pro-inflammatory cytokines such as TNF-alpha, interferon gamma and IL-6.[5]

Dz13 has been used with carriers such as cationic polymers for improved cellular delivery and efficacy.[6] Dz13 in such polymers inhibits tumor cell proliferation and migration by suppressing levels of c-Jun and MMPs,[7] reduces H1N1 and H7N2 viral replication and increases survival of mice infected with influenza A[8] and suppresses c-Jun and solid tumor growth in biomimetic nanoballs.[9] Dz13 has also been used in dermal drug delivery systems for enhanced skin penetration of DNAzyme.[10]

It has been reported off-target effects of Dz13, not related to the inactivation of c-Jun [11][12][13]

Effects

Dz13 has been shown to inhibit skin cancer growth, angiogenesis and tumor angiogenesis and improve survival in mice infected with H5N1.[5][14][15]

Anti-cancer effects have been also demonstrated in models of prostate cancer, breast cancer and osteosarcoma.[4]

Clinical trials of Dz13 in patients with basal cell carcinoma commenced in Australia in 2010.[16] In 2013 it was reported that Dz13 was safe and well tolerated after single intratumoral injection at all doses. c-Jun expression was reduced in the excised tumors of all patients injected and tumor depth decreased in the majority.[17] This was the first report of the clinical use of a DNAzyme.

The outcome of two other clinical trials evaluating DNAzymes performed in Asia and Europe were reported in 2014 and 2015, the former assessing an Epstein–Barr virus latent membrane protein 1 targeting DNAzyme[18] and the latter a DNAzyme targeting the transcription factor GATA3 which involved 7 trial sites.[19] In both trials, there were no adverse events due to DNAzyme. There was demonstrable efficacy noted in nasopharyngeal cancer patients injected with LMP1 DNAzyme and allergic asthma patients following GATA3 DNAzyme inhalation.[18][19]

Investigations

In 2013, trials of Dz13 were suspended after concerns were raised about alleged duplicated images in a 2010 paper.[20] A series of investigations conducted by independent expert panels of inquiry under the Australian Code for the Responsible Conduct of Research found genuine error and made no finding of misconduct.[21][22] This decision was discussed in a news article by the Australian Broadcasting Corporation in October 2019.[23]

References
  1. Khachigian, L.M. et al (2002) c-Jun regulates vascular smooth muscle cell growth and neointima formation after arterial injury. Inhibition by a novel DNA enzyme targeting c-Jun. J Biol Chem. 277(25):22985-91.
  2. Kahan-Hanum, M. et al (2013) A library of programmable DNAzymes that operate in a cellular environment. Sci Rep. 3:1535.
  3. Zhang, G. et al (2006) Squamous cell carcinoma growth in mice and in culture is regulated by c-Jun and its control of matrix metalloproteinase-2 and -9 expression. Oncogene. 25(55): 7260-6.
  4. Tan, M.L. et al (2010) Direct anti-metastatic efficacy by the DNA enzyme Dz13 and downregulated MMP-2, MMP-9 and MT1-MMP in tumours. Cancer Cell Int. 10: 9.
  5. Xie, J. et al (2014) Regulatory roles of c-jun in H5N1 influenza virus replication and host inflammation. Biochim Biophys Acta. 1842(12 Pt A):2479-88.
  6. Kynova, R. et al (2014) Enhancing nucleic acid delivery, insights from the cationic phospholipid carriers. Current Pharmaceutical Biotechnology 15(9), 806-13.
  7. Yang. J. et al (2019) Inhibition of proliferation and migration of tumor cells through phenylboronic acid-functionalized polyamidoamine-mediated delivery of a therapeutic DNAzyme Dz13. International Journal of Nanomedicine 14, 6371–6385.
  8. Zhang, Z. et al (2017) DNAzymes Dz13 target the c-jun possess antiviral activity against influenza A viruses. Microbial Pathogenesis 103, 155-161.
  9. Kim, M.-G. et al (2015) Biomimetic DNA nanoballs for oligonucleotide delivery. Biomaterials 62, 155-163.
  10. Marquardt, K. et al (2015) Development of a protective dermal drug delivery system for therapeutic DNAzymes. International Journal of Pharmaceutics 479, 150-158.
  11. Rivory, L. et al (2006) The DNAzymes Rs6, Dz13, and DzF have potent biologic effects independent of catalytic activity. Oligonucleotides 16, 297–312.
  12. Goodchild, A. et al (2007) Cytotoxic G-rich oligode-oxynucleotides: putative protein targets and required sequence motif. Nucleic Acids Res. 35, 4562–4572.
  13. Gozar, M.M. et al (2008) Dz13, a DNAzyme Targeting c-jun, Induces Off-Target Cytotoxicity in Endothelial Cells with Features of Nonapoptotic Programmed Cell Death. Oligonucleotides 18(3), 257-268.
  14. Fahmy, R. et al (2006) Suppression of vascular permeability and inflammation by targeting of the transcription factor c-Jun. Nat Biotechnol. 24(7): 856-863.
  15. Cai, H. et al (2012) DNAzyme targeting c-jun suppresses skin cancer growth. Science Transl Med. 4(139): 139ra82.
  16. Australian Cancer Trials (2010) A phase I study of the Dz13 drug targeting the c-Jun gene in subjects with skin cancer (nodular basal cell carcinoma). .
  17. Cho, E.A. et al (2013) Safety and tolerability of an intratumorally injected DNAzyme, Dz13, in patients with nodular basal-cell carcinoma: a phase 1 first-in-human trial (DISCOVER). Lancet. 381(9880):1835-43
  18. Cao, Y. et al (2014) Therapeutic evaluation of Epstein-Barr virus-encoded latent membrane protein-1 targeted DNAzyme for treating of nasopharyngeal carcinomas.
  19. Krug, N. et al (2015) Allergen-induced asthmatic responses modified by a GATA3-specific DNAzyme. N Engl J Med. 372(21):1987-95.
  20. Scott, S. "Trials of skin cancer drug DZ13 suspended pending investigation at UNSW". Australian Broadcasting Corporation. Retrieved 9 April 2019.
  21. Scott, S. "University of NSW defends handling of investigation into prominent scientist Levon Khachigian". Australian Broadcasting Corporation. Retrieved 9 April 2019.
  22. "UNSW clears Levon Khachigian of all allegations of research misconduct". The Australian
  23. https://www.abc.net.au/news/2019-10-17/unsw-skin-cancer-levon-khachigian-allegations-and-retractions/11585768
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