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.
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]
Effects
Dz13 has been shown to inhibit skin cancer growth, angiogenesis and tumor angiogenesis and improve survival in mice infected with H5N1.[5][6][7]
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.[8] 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.[9] 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 a Epstein–Barr virus latent membrane protein 1 targeting DNAzyme[10] and the latter a DNAzyme targeting the transcription factor GATA3 which involved 7 trial sites.[11] 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.[10][11]
References
- ↑ 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.
- 1 2 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.
- 1 2 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
- 1 2 Cao, Y. et al (2014) Therapeutic evaluation of Epstein-Barr virus-encoded latent membrane protein-1 targeted DNAzyme for treating of nasopharyngeal carcinomas.
- 1 2 Krug, N. et al (2015) Allergen-induced asthmatic responses modified by a GATA3-specific DNAzyme. N Engl J Med. 372(21):1987-95.