Scientific background

Scientific background Cancer treatment mainly consists of surgical removal whenever it is possible, chemotherapy and radiotherapy. Combined radio - and chemotherapies can increase the likelihood of success but are limited by the accumulation of their toxic and side effects. Molecular therapies for cancer treatment have emerged in the last decade, such as: monoclonal antibodies targeting the cell membrane receptors, inhibitors of tyrosine kinase receptor or other kinases involved in signal transduction for cell proliferation, pro-apoptotic and immunostimulating agents. As they are basically cytostatic agents, their monotherapy regimen is rarely of sufficient clinical benefit. Synergistic outcomes are often obtained by their combination with chemo - or radiotherapy. Most traditional cancer treatments, either radio - or chemotherapy, are cytotoxic. They directly or indirectly cause DNA damages in the treated cells, which ultimately lead to their death. Their anticancer action relies on the proliferating feature of tumor cells. However, several intrinsic and acquired resistances of tumor to these treatments are, at least in part, due to the tumor cells’ efficient DNA repair activities, among other mechanisms of treatment resistances. Instead of targeting specifically a key gene-protein whatever its biological importance and clinical relevance, the innovative molecular therapy must deal with one or several key pathways as a global target, in conjunction with conventional therapies, so as to reach the most efficient cancer treatment. Technology rationale and descriptionDNA bait Technology is an alternative approach to all existing molecular therapies. It was conceived and developed by the company's founders’ teams in four French public research institutions, and based on the mechanistically targeted DNA lesions sensing, signaling and repair pathways in order to disable cancers’ defense to existing treatments. These short inhibiting DNA, applied to the DSB repair processes, named Dbait, constitute a totally innovative approach: Specifically, it consists of introducing short modified DNA molecules mimicking double strand breaks into cells that up till then could efficiently inhibit DSB repair, and thus survive. Antitumor efficacy of DNA bait in association with radiotherapy or chemotherapy is explained by the fact that, with a DSB repair pathway blocked, the cancer cells can no more escape their death. These short inhibiting DNAs, applied to the DSB repair processes constitute an innovative approach for cost effective and efficient therapeutics focused on highly unmet medical needs. The DNA bait concept represents a paradigm shift, from single-gene-protein targeting to multi-gene-protein targeting, improving the efficiency of emerging molecular therapies. Thus it is the most recent breakthrough in molecular therapy, based on a unique pathway-targeted/mechanism-oriented approach. As such, DNA bait technology exploits a new field of molecular therapy beyond gene-protein-targeted approaches or siRNAs. siDNA will be a first-in-class drug, to overcome radio - and chemoresistance 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. Scientific advancement and proofs of conceptDNA Therapeutics’ first molecule currently under early stage preclinical development, targets the non homologous end joining DNA repair pathway which is the main DNA repair mechanism of the most lethal double strand DNA breaks in all vertebrate kingdoms including human. DSBs are caused directly or indirectly by ionizing irradiation and several classes of chemotherapeutic agents. The effects of DT1 molecules were studied and characterized in vitro and in vivo. Their chemical structure and size have been optimized. Their interaction with proteins involved in the NHEJ DNA reparation pathway has been proven in vitro. The bioactivity of DT1 molecules in increasing the efficiency of radio - and chemotherapy has been shown in human cell cultures, and in four human tumors xenografted on nude mice, as well as in one spontaneous colon cancer in genetically engineered mice. Significant increases of tumor growth delay and of survival have been observed, including complete tumor regression without reoccurrence after 250 days, following the administration of DT1 molecules in tumors and combined with fractionated radiotherapy regimens. Selective effect on cancer cellsCancer cells are more sensitive to the inhibition of DNA repair than normal cells for a number of reasons: they divide rapidly and have less time to carry out DNA repair; they usually replicate under conditions of stress, increasing levels of endogenous DNA damage; their greater instability than that of normal cells and their reliance on fewer DNA repair pathways ensures that disrupting a specific DNA repair pathway has a greater effect on such cells. Our data on siDNA and data available in the literature on low molecular weight inhibitors of DNA repair enzymes suggest that short term DNA repair inhibition is not lethal to normal cells. Differentiation and positioning of the technologyThe trend of the pharmaceutical industry is to develop drugs that are increasingly specific to a given gene-protein target which is involved in one or several types of cancer. Pharmacogenomics will soon allow, in theory, the prescription of drugs to patients who have specific genetic backgrounds. This increases the effectiveness of the treatment, but greatly reduces the commercial potential of such drugs. After the emergence of molecular therapies led by, among others, monoclonal antibodies, and kinase inhibitors that act on the pathways of cell proliferation, differentiation and apoptosis, and beyond siRNAs, inhibiting the DNA repair pathway is becoming a necessary and compelling target, clearly addressed by our DNA bait technology allowing us to create siDNA molecules. The strong point of DNA Bait technology is that it can virtually apply to all cancer types since it acts on the common mechanisms of cell’s DNA maintenance. Therefore unlike what occurs for any other products on the market or under development, DNA Therapeutics is developing a family of specific products for a few categories of cancer therapies based on the mechanism of action on DNA and its repair during the use of key therapies: chemotherapeutic agents, ionizing irradiation, and their combination with other molecular therapies.

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