DNA THERAPEUTICS What is the siDNA concept technology? The siDNA concept is a pathway-targeted/mechanism-oriented approach, using substrate mimic of DNA damages. siDNA technology is an alternative approach to all existing molecular therapies. It targets DNA lesions’ sensing, signaling and repair pathway, hence disabling key cancers’ defenses towards existing treatments. What is new in the siDNA concept / technology? The siDNA concept is a paradigm-shift, from single-gene/protein targeting to multi-gene/protein and pathway targeting, enhancing the efficiency of conventional therapies. Thus it is the most recent breakthrough in molecular therapy, based on a unique pathway-targeted/mechanism-oriented approach. As such, siDNA technology exploits a new field of molecular therapy beyond gene/protein-targeted approaches, and beyond siRNA/miRNA. What are Dbait molecules? Dbait molecules are proprietary modified double stranded DNA molecules that mimic double strand breaks in genomic DNA caused by genotoxic agents, such as chemotherapeutic agents and ionizing irradiation used in cancer treatment. How do Dbait molecules / siDNA approach enhance efficacy of radio - and chemotherapy? Dbait molecules jam DSB signaling and thus neutralize transiently the DSB repair systems which, otherwise, allow cancer cells to escape from radio - and chemotherapy, in the treated cancer cells. Dbait is a first-in-class drug candidate, to overcome radio - and chemo-resistance of tumors. Therefore, it considerably adds value to the existing therapies, not only radio - and chemotherapies, but also other emerging molecular therapies, instead of running into a head-to-head competition with other players. Is Dbait toxic to normal cells/tissues? In cell culture, it was observed in the unstressed, normal cells treated by Dbait molecules that: i) the cell cycle was not affected; ii) Comet test which measures the extent of DNA damages was negative. These data indicate the absence of DNA damages induced by Dbait molecules. In animals, the treatment of Dbait in healthy tissue did not show any sign of toxicity at the therapeutically active dose to tumors. This suggests again that the short term DNA repair inhibition is not lethal to normal cells and tissues.

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