Levon Michael Khachigian (born 6 March 1964 in Beirut, Lebanon)[1] is an Australian medical research scientist notable for his work in vascular cell and molecular biology.[2] He is a Professor in the Faculty of Medicine at the University of New South Wales.[3]

Khachigian is known for his studies in the area of transcriptional control and for translating basic discoveries into potential novel therapeutics. He is the inventor of the experimental drug Dz13, which may help treat a range of common diseases or complications including skin cancer, post-angioplasty restenosis, macular degeneration and asthma.[1][2][4]

Early life and education

Khachigian was born to Armenian parents who served as evangelical protestant missionaries in the Middle East[5] and migrated to Australia at age 18 months. He was raised in Naremburn, New South Wales, Australia[1] and attended Naremburn Public School and later Crows Nest Boys' High School.[6]

Khachigian obtained a B.Sc. with first-class honours in biochemistry in 1986 and Ph.D. in growth factor biochemistry and cell biology in 1993 from the University of New South Wales. He performed doctoral research at the School of Medicine, St George Hospital (Sydney), Division of Biomolecular Engineering, Commonwealth Scientific and Industrial Research Organisation and Department of Haematology, Prince of Wales Hospital (Sydney). He obtained a D.Sc. in vascular biology and transcriptional control in 2004 from the University of New South Wales.[2][3]

Research

Khachigian is a vascular biologist with a strong focus on "bench to bedside" translational research. His research has centered mainly on interrogating the roles of immediate-early genes (such as Egr1 and c-Jun) as molecular switches in the pathogenesis of disease. He and his collaborators have uncovered regulatory networks underpinning waves of transcriptional change in cellular activation in a range of single gene[7][8][9][10][11] and systems-based approaches.[12][13] Khachigian has developed a range of interventional approaches to target key regulatory genes for the development of novel therapeutics, particularly catalytic DNA.[14]

Khachigian invented Dz13, a molecule that targets the transcription factor c-Jun, implicated in a range of common proliferative, occlusive and inflammatory diseases. In 1999 Khachigian reported the first use of catalytic DNA as new experimental drugs in an animal model of any kind.[15] In 2013 he reported the first clinical use of catalytic DNA in human subjects.[16] This was later followed by numerous other independent, some multi-center, clinical trials evaluating DNAzymes in humans, including DNAzymes targeting EBV-LMP1 in patients with nasopharyngeal cancer[17] and DNAzymes targeting another nuclear transcription factor GATA3 in patients with allergic asthma[18] demonstrating DNAzyme efficacy and safety. Targeted catalytic DNA-based molecular therapy may represent a novel, effective and less invasive therapeutic approach in humans.[19]

Career

After obtaining his Ph.D. and with the support of a CJ Martin Research Fellowship from the National Health and Medical Research Council of Australia and Fulbright Program, Khachigian studied vascular biology and transcriptional control with Professor Tucker Collins[20] at Brigham and Women’s Hospital, Harvard Medical School, Boston USA. On returning to Australia in 1996 he established the Transcription Laboratory within the Centre for Vascular Research, Faculty of Medicine at the University of New South Wales.[6] He has been supported by an NHMRC RD Wright Fellowship, Principal Research Fellowship, Senior Principal Research Fellowship and the Australia Fellowship.[3] In 2004 Khachigian was appointed Professor in Medicine and in 2009 appointed Director of the Centre for Vascular Research, succeeding its Foundation Director Scientia Professor Colin Chesterman AO.[2][21]

Service

Khachigian has a strong record of service to international and national scientific societies and has been at the helm of numerous international conferences in vascular biology, drug design and discovery, and interdisciplinary health and medical research, including the International Vascular Biology Meeting and Congress of the International Society on Thrombosis and Haemostasis.[2] He has served as president of the Australian Society for Medical Research and president of the Australian Vascular Biology Society.[1][3] He is a member of the Faculty of 1000.[22]

Awards

Khachigian has received numerous prestigious national and international awards including the Commonwealth Health Minister's Award for Excellence in Health and Medical Research, GlaxoSmithKline Award for Research Excellence,[23] Gottschalk Medal from the Australian Academy of Science, Khwarizmi International Award for Science and Technology, and 3 separate Eureka Prizes from the Australian Museum for scientific research, medical research and international scientific collaboration.[3]

Investigations

The University of New South Wales investigated matters involving Khachigian in accordance with the Australian Code for the Responsible Conduct of Research. Khachigian maintained there was no wrongdoing[24][25] and a trial involving Dz13 was put on hold “to err on the side of caution”.[26] Six research articles co-authored by Khachigian have been retracted and one corrected.[27] None of the multiple different, independent external expert panels of inquiry or investigations conducted under the Australian Code made any finding of research misconduct on the part of Khachigian and concluded that breaches arose from genuine error or honest oversight.[26][28][29] In 2017, a fifth independent external expert panel, set up following the Australian Research Integrity Committee’s review of all previous independent external expert investigations came to the same conclusion that there was no finding of research misconduct.[30] This decision was discussed in a news article by the Australian Broadcasting Corporation in October 2019.[30]

References

  1. 1 2 3 4 "To crack the maze (Sydney Morning Herald 27 April 2006)". 27 April 2006.
  2. 1 2 3 4 5 "Levon M. Khachigian: IJO Editorial Academy (September 2012)".
  3. 1 2 3 4 5 "LM Khachigian website".
  4. ↑ "Wide role for new drug targeting skin cancer gene (Sydney Morning Herald 7 May 2013)". 6 May 2013.
  5. ↑ "Gene result a touch of shear brilliance". Sydney Morning Herald. 14 August 2003.
  6. 1 2 Khachigian, Levon. "Tall Poppies in Flight" (PDF). Australian Institute of Policy and Science.
  7. ↑ Khachigian, LM; et al. (1996). "Egr-1-induced endothelial gene expression: a common theme in vascular injury". Science. 271 (5254): 1427–31. Bibcode:1996Sci...271.1427K. doi:10.1126/science.271.5254.1427. PMID 8596917. S2CID 36935337.
  8. ↑ Khachigian, LM (2006). "Early growth response-1 in cardiovascular pathobiology". Circ Res. 98 (2): 186–91. doi:10.1161/01.res.0000200177.53882.c3. PMID 16456111.
  9. ↑ Tan, NY; et al. (2009). "Sp1 phosphorylation and its regulation of gene transcription". Mol Cell Biol. 29 (10): 2483–2488. doi:10.1128/mcb.01828-08. PMC 2682032. PMID 19273606.
  10. ↑ Zhang, N; et al. (2012). "Repression of PDGF-R-alpha after cellular injury involves TNF-alpha, formation of a c-Fos-YY1 complex, and negative regulation by HDAC". Am J Physiol Cell Physiol. 302 (11): C1590-8. doi:10.1152/ajpcell.00429.2011. PMID 22322974.
  11. ↑ Khachigian, LM (2016). "Early growth response-1 in the pathogenesis of cardiovascular disease". J Mol Med. 94 (7): 747–753. doi:10.1007/s00109-016-1428-x. PMID 27251707. S2CID 15905744.
  12. ↑ Forrest, AR; et al. (2014). "A promoter-level mammalian expression atlas". Nature. 507 (7493): 462–470. Bibcode:2014Natur.507..462T. doi:10.1038/nature13182. PMC 4529748. PMID 24670764.
  13. ↑ Arner, E; et al. (2015). "Transcribed enhancers lead waves of coordinated transcription in transitioning mammalian cells". Science. 347 (6225): 1010–1014. Bibcode:2015Sci...347.1010A. doi:10.1126/science.1259418. PMC 4681433. PMID 25678556.
  14. ↑ Khachigian, LM (2000). "Catalytic DNAs as potential therapeutic agents and sequence-specific molecular tools to dissect biological function". J Clin Invest. 106 (10): 1189–95. doi:10.1172/jci11620. PMC 381443. PMID 11086018.
  15. ↑ Santiago, FS; et al. (1999). "New DNA enzyme targeting Egr-1 mRNA inhibits vascular smooth muscle proliferation and regrowth after injury". Nature Medicine. 5 (11): 1264–1269. doi:10.1038/15215. PMID 10545992. S2CID 9566888.
  16. ↑ Cho, EA; 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)". The Lancet. 381 (9880): 1835–1843. doi:10.1016/s0140-6736(12)62166-7. PMC 3951714. PMID 23660123.
  17. ↑ Krug, N; et al. (2015). "Allergen-induced asthmatic responses modified by a GATA3-specific DNAzyme". N Engl J Med. 372 (21): 1987–95. doi:10.1056/nejmoa1411776. hdl:1854/LU-6862585. PMID 25981191.
  18. ↑ Cao, Y; et al. (2014). "Therapeutic evaluation of Epstein-Barr virus-encoded latent membrane protein-1 targeted DNAzyme for treating of nasopharyngeal carcinomas". Mol Ther. 22 (2): 371–7. doi:10.1038/mt.2013.257. PMC 3916047. PMID 24322331.
  19. ↑ "Dz13 drug targets skin cancer in clinical trial (Asian Scientist 13 May 2013)". 13 May 2013.
  20. ↑ Khachigian, LM (2007). "Science never sleeps: Tucker Collins MD, PhD". Endothelium. 14 (4–5): 173–174. doi:10.1080/10623320701670026.
  21. ↑ "First class honours (UNSW 12 June 2007)". 12 June 2007.
  22. ↑ "F1000 Prime Drug Discovery & Design (14 June 2012)".
  23. ↑ "Novel and pioneering research offers hope for cardiovascular disease (2006)".
  24. ↑ "ABC News (18 April 2014)". Australian Broadcasting Corporation. 17 April 2014.
  25. ↑ "Khachigian statement (11 August 2013)" (PDF). Australian Broadcasting Corporation.
  26. 1 2 "UNSW statement (12 August 2013)". 12 August 2013.
  27. ↑ "Retraction Watch Database".
  28. ↑ "UNSW public statement (26 November 2015)".
  29. ↑ "UNSW clears Levon Khachigian of all allegations of research misconduct (22 December 2015)".
  30. 1 2 "UNSW skin cancer researcher Levon Khachigian". Australian Broadcasting Corporation. 16 October 2019.
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