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Discovery of tumoricidal DNA aptamers by effect-directed in-vitro evolution

Noam Mamet, Yaniv Amir, Erez Lavi, Liron Bassali, Gil Harari, Itai Rusinek, Nir Skalka, Elinor Debby, Mor Greenberg, Adva Zamir, Anastasia Paz, Neria Reiss, Gil Loewenthal, Irit Avivi, Avichai Shimoni, Guy Neev, Almogit Abu-Horowitz, View ORCID ProfileIdo Bachelet
doi: https://doi.org/10.1101/629105
Noam Mamet
1Augmanity, Rehovot, Israel. Website:
2Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel
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Yaniv Amir
3Aummune, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. Website:
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  • For correspondence: ido@augm.com yaniv@aummune.tech
Erez Lavi
3Aummune, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. Website:
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Liron Bassali
1Augmanity, Rehovot, Israel. Website:
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Gil Harari
1Augmanity, Rehovot, Israel. Website:
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Itai Rusinek
1Augmanity, Rehovot, Israel. Website:
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Nir Skalka
3Aummune, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. Website:
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Elinor Debby
3Aummune, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. Website:
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Mor Greenberg
1Augmanity, Rehovot, Israel. Website:
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Adva Zamir
1Augmanity, Rehovot, Israel. Website:
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Anastasia Paz
3Aummune, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. Website:
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Neria Reiss
3Aummune, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. Website:
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Gil Loewenthal
1Augmanity, Rehovot, Israel. Website:
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Irit Avivi
4Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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Avichai Shimoni
5BMT Department, Division of Hematology, Sheba Medical Center Tel Hashomer, Ramat-Gan, Israel
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Guy Neev
3Aummune, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. Website:
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Almogit Abu-Horowitz
1Augmanity, Rehovot, Israel. Website:
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Ido Bachelet
1Augmanity, Rehovot, Israel. Website:
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  • ORCID record for Ido Bachelet
  • For correspondence: ido@augm.com yaniv@aummune.tech
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Abstract

Our current model of drug discovery is challenged by the relative ineffectiveness of drugs against highly variable and rapidly evolving diseases and their relatively high incidence of adverse effects due to poor selectivity. Here we describe a robust and reproducible platform which could potentially address these limitations. The platform enables rapid, de-novo discovery of DNA aptamers evolved in-vitro to exert specific biological effects on target cells. Unlike conventional aptamers, which are selected by their ligand binding capacity, this platform is driven directly by therapeutic effect and selectivity towards target vs negative target cells. The process could, therefore, operate without any a-priori knowledge (e.g. mutations, biomarker expression, or known drug resistance) of the target. We report the discovery of DNA aptamers with direct and selective cytotoxicity towards several tumor cell lines as well as primary, patient-derived solid and hematological tumors, some with chemotherapy resistance. Aptamers discovered by this platform exhibited favorable biodistribution in animals, persistence in target tumors up to 48 hours after injection, and safety in human blood. These aptamers showed remarkable efficacy in-vivo as well as ex-vivo in freshly obtained, 3D cultured human tumors resistant to multiple chemotherapies. With further improvement, these findings could lead to a drug discovery model which is target-tailored, mechanism-flexible, and nearly on-demand.

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Posted May 07, 2019.
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Discovery of tumoricidal DNA aptamers by effect-directed in-vitro evolution
Noam Mamet, Yaniv Amir, Erez Lavi, Liron Bassali, Gil Harari, Itai Rusinek, Nir Skalka, Elinor Debby, Mor Greenberg, Adva Zamir, Anastasia Paz, Neria Reiss, Gil Loewenthal, Irit Avivi, Avichai Shimoni, Guy Neev, Almogit Abu-Horowitz, Ido Bachelet
bioRxiv 629105; doi: https://doi.org/10.1101/629105
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Discovery of tumoricidal DNA aptamers by effect-directed in-vitro evolution
Noam Mamet, Yaniv Amir, Erez Lavi, Liron Bassali, Gil Harari, Itai Rusinek, Nir Skalka, Elinor Debby, Mor Greenberg, Adva Zamir, Anastasia Paz, Neria Reiss, Gil Loewenthal, Irit Avivi, Avichai Shimoni, Guy Neev, Almogit Abu-Horowitz, Ido Bachelet
bioRxiv 629105; doi: https://doi.org/10.1101/629105

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