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
Arthritis is a term often used to mean any disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, swelling, and decreased range of motion of the affected joints. In som ...
and
macular degeneration. Trials of Dz13 were suspended in 2013.
Mechanism of action
Dz13 is a 10-23
DNAzyme
Deoxyribozymes, also called DNA enzymes, DNAzymes, or catalytic DNA, are DNA oligonucleotides that are capable of performing a specific chemical reaction, often but not always catalytic. This is similar to the action of other biological enzymes, ...
that targets
c-Jun
Transcription factor Jun is a protein that in humans is encoded by the ''JUN'' gene. c-Jun, in combination with protein c-Fos, forms the AP-1 early response transcription factor. It was first identified as the Fos-binding protein p39 and only lat ...
, a
transcription factor found in diseased
blood vessels,
eye
Eyes are organs of the visual system. They provide living organisms with vision, the ability to receive and process visual detail, as well as enabling several photo response functions that are independent of vision. Eyes detect light and conv ...
s,
lung
The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of t ...
s and
joints. The treatment works by the DNA-based enzyme binding to and catalytically destroying its target
messenger RNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein.
mRNA is created during the p ...
, thereby inhibiting c-Jun expression in cells.
Dz13 has underpinned the development of a library of programmable DNAzymes operable in a cellular environment.
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
72 kDa type IV collagenase also known as matrix metalloproteinase-2 (MMP-2) and gelatinase A is an enzyme that in humans is encoded by the ''MMP2'' gene. The ''MMP2'' gene is located on chromosome 16 at position 12.2.
Function
Proteins of the ...
,
MMP-9,
VEGF and
FGF-2.
Dz13 also inhibits the expression of pro-inflammatory cytokines such as
TNF-alpha,
interferon gamma and
IL-6.
Dz13 has been used with carriers such as cationic polymers for improved cellular delivery and efficacy.
Dz13 in such polymers inhibits tumor cell proliferation and migration by suppressing levels of c-Jun and MMPs,
reduces H1N1 and H7N2 viral replication and increases survival of mice infected with influenza A
and suppresses c-Jun and solid tumor growth in biomimetic nanoballs.
Dz13 has also been used in dermal drug delivery systems for enhanced skin penetration of DNAzyme.
It has been reported off-target effects of Dz13, not related to the inactivation of c-Jun
Effects
Dz13 has been shown to inhibit
skin cancer growth,
angiogenesis
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
and tumor
angiogenesis
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
and improve survival in mice infected with H5N1.
Anti-cancer effects have been also demonstrated in models of
prostate cancer
Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that sur ...
,
breast cancer and
osteosarcoma.
Clinical trials of Dz13 in patients with
basal cell carcinoma commenced in Australia in 2010.
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.
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 Epstein–Barr virus latent membrane protein 1 (LMP1) is an Epstein–Barr virus (EBV) protein that regulates its own expression and the expression of human genes. It has a molecular weight of approximately 63 kDa, and its expression induces many of ...
targeting DNAzyme
and the latter a DNAzyme targeting the transcription factor
GATA3 which involved 7 trial sites.
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.
Investigations
In 2013, trials of Dz13 were suspended after concerns were raised about alleged duplicated images in a 2010 paper. 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.
[ The Australian] This decision was discussed in a news article by the Australian Broadcasting Corporation in October 2019.
[ ]
References
{{Reflist, refs=
[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.]
[Kahan-Hanum, M. et al (2013) A library of programmable DNAzymes that operate in a cellular environment. Sci Rep. 3:1535.]
[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.]
[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.]
[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.]
[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.]
[Cai, H. et al (2012) DNAzyme targeting c-jun suppresses skin cancer growth. Science Transl Med. 4(139): 139ra82.]
[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)]
[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]
[Krug, N. et al (2015) Allergen-induced asthmatic responses modified by a GATA3-specific DNAzyme. N Engl J Med. 372(21):1987-95.]
[Cao, Y. et al (2014) Therapeutic evaluation of Epstein-Barr virus-encoded latent membrane protein-1 targeted DNAzyme for treating of nasopharyngeal carcinomas.]
[Rivory, L. et al (2006) The DNAzymes Rs6, Dz13, and DzF have potent biologic effects independent of catalytic activity. Oligonucleotides 16, 297–312.]
[Goodchild, A. et al (2007) Cytotoxic G-rich oligode-oxynucleotides: putative protein targets and required sequence motif. Nucleic Acids Res. 35, 4562–4572.]
[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.]
[Kynova, R. et al (2014) Enhancing nucleic acid delivery, insights from the cationic phospholipid carriers. Current Pharmaceutical Biotechnology 15(9), 806-13.]
[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.]
[Zhang, Z. et al (2017) DNAzymes Dz13 target the c-jun possess antiviral activity against influenza A viruses. Microbial Pathogenesis 103, 155-161.]
[Kim, M.-G. et al (2015) Biomimetic DNA nanoballs for oligonucleotide delivery. Biomaterials 62, 155-163.]
[Marquardt, K. et al (2015) Development of a protective dermal drug delivery system for therapeutic DNAzymes. International Journal of Pharmaceutics 479, 150-158.]
External links
New super drug may combat cancer
Experimental cancer drugs