Browsing by Author "Turan, Raife Dilek"

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Development of Small Molecule MEIS Inhibitors that modulate HSC activity
(NATURE RESEARCH, 2020-01-01) Turan, Raife Dilek; Albayrak, Esra; Uslu, Merve; Siyah, Pinar; Alyazici, Lamia Yazgi; Kalkan, Batuhan Mert; Aslan, Galip Servet; Yucel, Dogacan; Aksoz, Merve; Tuysuz, Emre Can; Meric, Neslihan; Durdagi, Serdar; Gulbas, Zafer; Kocabas, Fatih
Meis1, which belongs to TALE-type class of homeobox gene family, appeared as one of the key regulators of hematopoietic stem cell (HSC) self-renewal and a potential therapeutical target. However, small molecule inhibitors of MEIS1 remained unknown. This led us to develop inhibitors of MEIS1 that could modulate HSC activity. To this end, we have established a library of relevant homeobox family inhibitors and developed a high-throughput in silico screening strategy against homeodomain of MEIS proteins using the AutoDock Vina and PaDEL-ADV platform. We have screened over a million druggable small molecules in silico and selected putative MEIS inhibitors (MEISi) with no predicted cytotoxicity or cardiotoxicity. This was followed by in vitro validation of putative MEIS inhibitors using MEIS dependent luciferase reporter assays and analysis in the ex vivo HSC assays. We have shown that small molecules named MEISi-1 and MEISi-2 significantly inhibit MEIS-luciferase reporters in vitro and induce murine (LSKCD34(l)degrees (w) cells) and human (CD34(+), CD133(+), and ALDH(hi) cells) HSC self-renewal ex vivo. In addition, inhibition of MEIS proteins results in downregulation of Meis1 and MEIS1 target gene expression including Hif-1 alpha, Hif-2 alpha and HSC quiescence modulators. MEIS inhibitors are effective in vivo as evident by induced HSC content in the murine bone marrow and downregulation of expression of MEIS target genes. These studies warrant identification of first-in-class MEIS inhibitors as potential pharmaceuticals to be utilized in modulation of HSC activity and bone marrow transplantation studies.
Gamma-irradiated SARS-CoV-2 vaccine candidate, OZG-38.61.3, confers protection from SARS-CoV-2 challenge in human ACEII-transgenic mice
(NATURE PORTFOLIO, 2021-01-01) Turan, Raife Dilek; Tastan, Cihan; Kancagi, Derya Dilek; Yurtsever, Bulut; Karakus, Gozde Sir; Ozer, Samed; Abanuz, Selen; Cakirsoy, Didem; Tumentemur, Gamze; Demir, Sevda; Seyis, Utku; Kuzay, Recai; Elek, Muhammer; Kocaoglu, Miyase Ezgi; Ertop, Gurcan; Arbak, Serap; Elmas, Merve Acikel; Hemsinlioglu, Cansu; Ng, Ozden Hatirnaz; Akyoney, Sezer; Sahin, Ilayda; Kayhan, Cavit Kerem; Tokat, Fatma; Akpinar, Gurler; Kasap, Murat; Kocagoz, Ayse Sesin; Ozbek, Ugur; Telci, Dilek; Sahin, Fikrettin; Yalcin, Koray; Ratip, Siret; Ince, Umit; Ovali, Ercument
The SARS-CoV-2 virus caused the most severe pandemic around the world, and vaccine development for urgent use became a crucial issue. Inactivated virus formulated vaccines such as Hepatitis A and smallpox proved to be reliable approaches for immunization for prolonged periods. In this study, a gamma-irradiated inactivated virus vaccine does not require an extra purification process, unlike the chemically inactivated vaccines. Hence, the novelty of our vaccine candidate (OZG-38.61.3) is that it is a non-adjuvant added, gamma-irradiated, and intradermally applied inactive viral vaccine. Efficiency and safety dose (either 10(13) or 10(14) viral RNA copy per dose) of OZG-38.61.3 was initially determined in BALB/c mice. This was followed by testing the immunogenicity and protective efficacy of the vaccine. Human ACE2-encoding transgenic mice were immunized and then infected with the SARS-CoV-2 virus for the challenge test. This study shows that vaccinated mice have lowered SARS-CoV-2 viral RNA copy numbers both in oropharyngeal specimens and in the histological analysis of the lung tissues along with humoral and cellular immune responses, including the neutralizing antibodies similar to those shown in BALB/c mice without substantial toxicity. Subsequently, plans are being made for the commencement of Phase 1 clinical trial of the OZG-38.61.3 vaccine for the COVID-19 pandemic.
Preclinical Assessment of Efficacy and Safety Analysis of CAR-T Cells (ISIKOK-19) Targeting CD19-Expressing B-Cells for the First Turkish Academic Clinical Trial with Relapsed/Refractory ALL and NHL Patients
(GALENOS YAYINCILIK, 2020-01-01) Tastan, Cihan; Kancagi, Derya Dilek; Turan, Raife Dilek; Yurtsever, Bulut; Cakirsoy, Didem; Abanuz, Selen; Yilanci, Muhammet; Seyis, Utku; Ozer, Samed; Mert, Selin; Kayhan, Cavit Kerem; Tokat, Fatma; Elmas, Merve Acikel; Birdogan, Selcuk; Arbak, Serap; Yalcin, Koray; Sezgin, Aslihan; Kizilkilic, Ebru; Hemsinlioglu, Cansu; Ince, Umit; Ratip, Siret; Ovali, Ercument
Objective: Relapsed and refractory CD19-positive B-cell acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) are the focus of studies on hematological cancers. Treatment of these malignancies has undergone recent transformation with the development of new gene therapy and molecular biology techniques, which are safer and well-tolerated therapeutic approaches. The CD19 antigen is the most studied therapeutic target in these hematological cancers. This study reports the results of clinical-grade production, quality control, and in vivo efficacy processes of ISIKOK-19 cells as the first academic clinical trial of CAR-T cells targeting CD19-expressing B cells in relapsed/refractory ALL and NHL patients in Turkey. Materials and Methods: We used a lentiviral vector encoding the CD19 antigen-specific antibody head (FMC63) conjugated with the CD8-CD28-CD3 zeta
Preclinical efficacy and safety analysis of gamma-irradiated inactivated SARS-CoV-2 vaccine candidates
(NATURE RESEARCH, 2021-01-01) Karakus, Gozde Sir; Tastan, Cihan; Kancagi, Derya Dilek; Yurtsever, Bulut; Tumentemur, Gamze; Demir, Sevda; Turan, Raife Dilek; Abanuz, Selen; Cakirsoy, Didem; Seyis, Utku; Ozer, Samed; Elibol, Omer; Elek, Muhammer; Ertop, Gurcan; Arbale, Serap; Elmas, Merve Acikel; Hermsinlioglu, Canso; Kocagoz, Ayse Sesin; Ng, Ozden Hatirnaz; Akyoney, Sezer; Sahin, Ilayda; Ozbek, Ugur; Telci, Dilek; Sahin, Fikrettin; Yalcin, Koray; Ratip, Siret; Ovali, Ercument
COVID-19 outbreak caused by SARS-CoV-2 created an unprecedented health crisis since there is no vaccine for this novel virus. Therefore, SARS-CoV-2 vaccines have become crucial for reducing morbidity and mortality. In this study, in vitro and in vivo safety and efficacy analyzes of lyophilized vaccine candidates inactivated by gamma-irradiation were performed. The candidate vaccines in this study were OZG-3861 version 1(V1), an inactivated SARS-CoV-2 virus vaccine, and SK-01 version 1 (V1), a GM-CSF adjuvant added vaccine. The candidate vaccines were applied intradermally to BALB/c mice to assess toxicity and immunogenicity. Preliminary results in vaccinated mice are reported in this study. Especially, the vaccine models containing GM-CSF caused significant antibody production with neutralization capacity in absence of the antibody-dependent enhancement feature, when considered in terms of T and B cell responses. Another important finding was that the presence of adjuvant was more important in T cell in comparison with B cell response. Vaccinated mice showed T cell response upon restimulation with whole inactivated SARS-CoV-2 or peptide pool. This study shows that the vaccines are effective and leads us to start the challenge test to investigate the gamma-irradiated inactivated vaccine candidates for infective SARS-CoV-2 virus in humanized ACE2+ mice.