Research at the Center for Gene and Cell Therapy
Current research in the center circles around the generation of novel gene therapy vectors (particularly lentiviral and adenoviral in origin) designed to be effective in the treatment of diabetes in general. Special emphesis is given to the genetic modification of pancreatic islets and islet cell transplantation.
Gene and Cell Therapy Against Diabetes and Cancer
Novel gene and cell therapy methods have been developed against Diabetes, autoimmune diseases such as Rheumatoid Arthritis as well as Cancer. Some of these publications are listed below.
Tip 1 diyabetli hastalarda insulin tedavisinde ve insulin gen terapisinde guncel gelismeler. Sanlioglu AD, Altunbas HA, Balci MK and Sanlioglu S. Klinik Tip Bilimleri Dergisi, Clinical Medical Sciences, Diyabet ozel sayisi. Nisan 2012 1-5
Tracing of xenogeneic islet graft survival by way of in vivo fluorescence imaging. Kahraman S, Dirice E, Hapil FZ, Ertosun MG, Ozturk S, Griffith TS, Sanlioglu S and Sanlioglu AD. Diabetes Metab Res Rev 2011 27(6):575-83.
In Vivo Fluorescence Imaging is Well-Suited for the Monitoring of Adenovirus Directed Transgene Expression in Living Organisms. Kahraman S, Dirice E, Sanlioglu AD, Yoldas B, Bagci H, Erkilic M, Griffith TS and Sanlioglu S. Molecular Imaging and Biology. 2010 Jun; 12 (3):278-85.
Adenovirus mediated TRAIL gene (Ad5hTRAIL) delivery into pancreatic islets prolongs normoglycemia in STZ-induced diabetic rats. Dirice E, Sanlioglu AD, Kahraman S, Ozturk S, Balci MK, Omer A, Griffith TS and Sanlioglu S. Human Gene Therapy. Oct 2009, 20(10): 1177-1189.
Molecular mechanisms of death ligand-mediated immune modulation: A gene therapy model to prolong islet survival in type 1 diabetes. Sanlioglu AD, Griffith TS, Omer A, Dirice E, Sari R, Altunbas HA, Balci MK, and Sanlioglu S. J Cell Biochem 2008 June 1; 104(3):710-720.
High levels of endogenous TRAIL expression correlate with increased cell death in human pancreas. Sanlioglu AD, Dirice E, Elpek O, Korcum AF, Balci MK, Omer A, Griffith TS and Sanlioglu S. Pancreas 2008 May; 36(4):385-393.
Gene Therapy of Lung Cancer:
NF-kappaB targeting by way of IKK inhibition sensitizes lung cancer cells to adenovirus delivery of TRAIL. Aydin C, Sanlioglu AD, Bisgin A, Yoldas B, Dertsiz L, Karacay B, Griffith TS and Sanlioglu S. BMC Cancer. 2010, 10:584.
A DcR2 siRNA strategy employing three different siRNA constructs in combination defeats adenovirus transferred TRAIL resistance in lung cancer cells. Aydin C, Sanlioglu AD, Karacay B, Ozbilim G, Dertsiz L, Ozbudak O, Akdis CA and Sanlioglu S. Human Gene Therapy. 2007 Jan; 18: 39-50.
Fundamental Principals of Tumor Necrosis Factor-alpha gene therapy approach and implications for patients with lung carcinoma. Sanlioglu AD, Aydin C, Bozcuk H, Terzioglu E and Sanlioglu S. Lung Cancer. 2004 44: 199-211.
Gene Therapy for Prostate Cancer:
DcR2 (TRAIL-R4) siRNA and adenovirus delivery of TRAIL (Ad5hTRAIL) break down in vitro tumorigenic potential of prostate carcinoma cells. Sanlioglu AD, Karacay B, Koksal IT, Griffith TS and Sanlioglu S. Cancer Gene Therapy. 2007 Dec; 14(12):976-984.
Adenovirus mediated IKKbKA expression sensitizes prostate carcinoma cells to TRAIL induced apoptosis. Sanlioglu AD, Koksal IT, Karacay B, Baykara M, Luleci G and Sanlioglu S. Cancer Gene Therapy. 2006 Jan; 13(1): 21-31.
Gene Therapy of Breast Cancer:
Surface TRAIL decoy receptor-4 expression is correlated with TRAIL resistance in MCF7 breast cancer cells. Sanlioglu AD, Dirice E, Aydin C, Erin E, Koksoy S and Sanlioglu S. BMC Cancer. 2005 25;5(1):54.
Neuroblastoma Targeted Gene Therapy:
Inhibition of the NF-kB Pathway Enhances TRAIL-Mediated Apoptosis in Neuroblastoma Cells. Karacay B, Sanlioglu S, Griffith TS, Sandler A and Bonthius DJ. Cancer Gene Therapy. 2004 Oct; 11(10): 681-690.
TRAIL Death Receptor-4, Decoy Receptor-1 and Decoy Receptor-2 Expression on CD8+ T Cells Correlate with the Disease Severity in Patients with Rheumatoid Arthritis. Bisgin A, Terzioglu E, Aydin C, Yoldas B, Yazisiz V, Balci N, Bagci H, Gorczynski RM, Akdis CA, Sanlioglu S. BMC Musculoskelet Disord. 2010 Aug 27;11:192.
Concurrent gene therapy strategies effectively destroy synoviocytes of patients with rheumatoid arthritis. Terzioglu E, Bisgin A, Sanlioglu AD, Ulker M, Yazisiz V, Tuzuner S, and Sanlioglu S. Rheumatology (Oxford). 2007 May; 46(5): 783-789.
Addional Research Topics
Understanding molecular mechanisms of disease development is of paramount importance in order to find a cure for a particular genetic disease. Using gene delivery to accomplish this task is a novel way to approach the issue in hand. In addition, molecular profiling has widely been used to determine susceptibility of an individual to a disease. Discovering of a novel profiling scheme can lead early diagnosis of a genetic disease and better follow up of the prognosis easing disease management.
Increased serum sTRAIL levels were correlated with survival in bevacizumab-treated metastatic colon cancer. Bisgin A, Kargi A, Yalcin AD, Aydin C, Ekinci D, Savas B, Sanlioglu S. BMC Cancer. 2012 Feb 7;12:58
Clinical significance of TRAIL and TRAIL receptors in patients with head and neck cancer. Yoldas B, Ozer C, Ozen O, Canpolat T, Dogan I, Griffith TS, Sanlioglu S, Ozluoglu LN. Head Neck. 2011 33(9):1278-84.
Importance of TNF-Related Apoptosis Inducing Ligand in pathogenesis of interstitial cystitis. Kutlu O, Akkaya E, Koksal IT, Bassorgun IC, Ciftcioglu MA, Sanlioglu S, Kukul E. Int Urol Nephrol. 2010 Jun;42(2):393-9.
CTLA-4 gene polymorphism of exon 1(+49 A/G) in Turkish systemic lupus erythematosus patients. Ulker M, Yazisiz V, Sallakci N, Avci AB, Sanlioglu S, Yegin O, Terzioglu E. Int J Immunogenet. 2009 Aug;36(4):245-50.
High TRAIL Death Receptor-4 (DR4) and Decoy Receptor-2 (DcR2) expression correlates with significant cell death in pancreatic ductal adenocarcinoma (PDAC) patients. Sanlioglu AD, Dirice E, Elpek O, Korcum AF, Ozdogan M, Suleymanlar I, Balc? MK, Griffith TS and Sanlioglu S. Pancreas 2009 Mar;38(2):154-60.
TRAIL-R4 decoy receptor gene expression is correlated with high Gleason scores, PSA recurrence and decreased survival in patients with prostate carcinoma. Koksal IT, Sanlioglu AD, Karacay B, Griffith TS and Sanlioglu S. Urologic Oncology 2008 Mar-Apr; 26(2):158-165.
TRAIL death receptor-4 (DR4) expression positively correlates with the tumor grade in breast cancer patients with invasive ductal carcinoma. Sanlioglu AD, Korcum AF, Pestereli E, Erdogan G, Karaveli S, Savas B, Griffith TS and Sanlioglu S. Int J Radiat Oncol Biol Phys. 2007 Nov; 69(3): 716-723.
Differential expression of TRAIL and its receptors in benign and malignant prostate tissues. Sanlioglu AD, Koksal IT, Ciftcioglu MA, Baykara M, Luleci G and Sanlioglu S. Journal of Urology. 2007 Jan; 177(1): 359-364.
Differential PTEN protein expression profiles in superficial versus invasive bladder cancers. Koksal IT, Yasar D, Dirice E., Usta MF, Karauzum S, Luleci G, Baykara M and Sanlioglu S. Urol Int. 2005 75(2): 102-106.
The assessment of PTEN tumor suppressor gene in combination with Gleason scoring and serum PSA to evaluate progression of prostate carcinoma. Koksal IT., Dirice E, Yasar D, Sanlioglu AD, Gulkesen KH, Ciftcioglu A., Ozes ON, Baykara M, Luleci G and Sanlioglu S. Urol Oncol. 2004 22(4): 307-312.
Dajani R, Sanlioglu S, Zhang Y, Li Q, Monick MM, Lazartigues E, Eggleston T, Davisson RL, Hunninghake GH, Engelhardt JF. Pleiotropic Functions of TNF alpha Determine Distinct IKK beta-Dependent Hepatocellular Fates in Response to LPS. Am J Physiol Gastrointest Liver Physiol. 2007 Jan; 292(1): G242-252.
First generation adenovirus vectors shorten survival time in a murine model of sepsis. Sanlioglu, S, Doerschug K, Flaherty, DM, Wilson RL, Yarovinsky TO, Monick MM, Engelhardt JF and Hunninghake GW. J. Immunology. 2002 169: 6539-6545.
Mitochondrial K(ATP) channel openers activate the ERK kinase by an oxidant- dependent mechanism. Samavati L, Monick MM, Sanlioglu S, Buettner GR, Oberley LW, and Hunninghake GW. Am J Physiol Cell Physiol. 2002 Jul;283(1): C273-81.
LPS induces Rac1 dependent reactive oxygen species (ROS) formation and coordinates TNFa secretion through IKK regulation of NFkB. Sanlioglu S, Williams CM, Samavati L, Butler NS, Wang G, McCray PB, Ritchie TC, Hunninghake GW, Zandi E and Engelhardt JF. JBC. 2001 Aug 276(32): 30188-30198.
GPx-1 gene delivery modulates NFkB activation following diverse environmental injuries through a specific subunit of the IKK complex. Li Q, Sanlioglu S, Li S, Ritchie T, Oberley L and Engelhardt JF. Antioxidant and Redox Signaling. 2001 3(3): 415-431.
Rate Limiting Steps of AAV transduction and Implications for Human Gene Therapy. Sanlioglu S, Monick MM, Luleci G, Hunninghake GW and Engelhardt JF. Review. Current Gene Therapy. 2001 June; 1(2): 137-147.
Endocytosis and Nuclear Trafficking of Adeno-Associated Virus Type-2 is Controlled by Rac1/PI3-kinase Activation. Sanlioglu S, Benson PK, Yang J, Atkinson EM, Reynolds T and Engelhardt JF. Journal of Virology. 2000 Oct; 74(19): 9184-9196.(Cover illustration)
Loss of ATM Function Enhances Recombinant Adeno-Associated Virus Transduction and Integration through Pathways Similar to UV Irradiation. Sanlioglu S, Benson P, Engelhardt JF. Virology. 2000 Mar 1; 268(1): 68-78.(Cover illustration)
Two Independent Molecular Pathways for Recombinant Adeno-Associated virus genome conversion occur after UV-C and E4orf6 augmentation of transduction. Sanlioglu S, Duan D and Engelhardt JF. Human Gene Therapy. 1999 March 1; 10(4): 591-602.
Formation of adeno-associated virus circular genomes is differentially regulated by adenovirus E4-ORF6 and E2a gene expression. Duan D, Sharma P, Dudus L, Zhang Y, Sanlioglu S, Yan Z, Yue Y, Lester R, Yang J, Fisher KJ, Engelhardt, J.F. Journal of Virology. 1999 73(1): 161-169.
Genetic redox preconditioning differentially modulates AP-1 and NFkappaB responses following cardiac ischemia/reperfusion injury and protects against necrosis and apoptosis. Yang J, Marden JJ, Fan C, Sanlioglu S, Weiss RM, Ritchie TC, Davisson RL, Engelhardt JF. Molecular Therapy. 2003 Mar;7(3): 341-353.
Selective disruption of "late onset" sagittal banding patterns by ectopic expression of engrailed-2 in cerebellar Purkinje cells. Baader SL, Vogel MW, Sanlioglu S, Zhang X, Oberdick J. Journal of Neuroscience. 1999 Jul 1; 19(13): 5370-5379.
Regulation of a Purkinje cell-specific promoter by homeodomain proteins: repression by engrailed-2 vs. synergistic activation by Hoxa5 and Hoxb7. Sanlioglu S, Zhang X, Baader SL, Oberdick J. Journal of Neurobiology. 1998 Sep 15; 36(4): 559-571.
Ectopic overexpression of engrailed-2 in cerebellar Purkinje cells causes restricted cell loss and retarded external germinal layer development at lobule junctions. Sanlioglu S, Baader SL, Berrebi AS, Parker-Thornburg J, Oberdick J. Journal of Neuroscience. 1998 Mar 1; 18(5): 1763-1773.
Functional cloning of candidate genes that regulate Purkinje cell-specific gene expression. Sanlioglu S. and Oberdick J. Progress in Brain Research. 1997 114: 3-19.
Local control of granule cell generation by cerebellar Purkinje cells. Smeyne R, Chu T, Lewin A, Bian F, Sanlioglu S, Kunsch C, Lira SA and Oberdick J. Mol Cell Neuroscience. 1995 6: 230-251.
Understanding molecular mechanism of a disease is the first step even to talk about curing a human genetic disease. Without a doubt, accumulation of human genetic information will lead to better genetic treatment options in the near future. Development of safer and more effective vectors will be instrumental in the demonstration of the efficacy of gene and cell therapy for the treatment of human genetic diseases.
Our gene and cell therapy approach for Type 1 Diabetes is featured as the cover of HGT Journal, 2009.