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THERAPEUTIC USES

Most anti-cancer therapies act by induction of DNA damage (chemotherapy and radiation therapy). DNA breaks are the most lethal damage for cells, as double-stranded breaks can lead to loss of entire chromosomal fragments, and even one single double-strand break if unrepaired is sufficient to lead to cell death. Dbait enhances the efficacy of the DNA damaging agents as demonstrated with radiation therapy and/or chemotherapy in multiple in vivo experimental models such as melanoma, glioblastoma and colorectal cancer. Preclinical proof of concept of the synergic effect of the clinical candidate, DT01, with radiation therapy lead to a first-in-human Phase I, to evaluate the tolerance and efficacy of local DT01 administration in association with RT in patients suffering from in-transit metastases of melanoma. Encouraging results were published in May 2016.

-> Current edits: talking about dsDNA breaks as leading to loss of chromosomal fragments

MECHANISM OF ACTION

The siDNA family, led by Dbait, consists of 32 base pairs deoxyribonucleotide forming an intramolecular double helix, which mimicks DNA double-strand break lesions. Dbait binds to and hyperactivate DNA-PK, an enzyme involved in DNA breaks signaling and repair. DNA-PK hyperactivation induces pan-nuclear phosphorylation of histone H2AX among all the chromatin. H2AX phosphorylation is the signal, which allows double-strand break repair proteins (from NHEJ and homologous recombination pathways) to form DNA repair complexes selectively on DNA double-strand breaks. Dbait-dependent unspecific phosphorylation of H2AX results in inefficient double strand break recognition and repair.

-Potentially change mechanism of action to Dbait mechanism of action? Dbait is the only type of siRNA that has been studied as well as been the topic of reviews.

-siDNA functions in similar method of siRNA; inhibiting homologous targets.

-In the event of a double-stranded break in the genome, the cell most commonly repairs the damaged segment via non-homologous end joining (NHEJ). NHEJ involves the ligation of the damaged segment without using a homologous strand as a template, and can lead to frameshift mutations and the presence of tumors. siDNA functions primarily by targeting the NHEJ pathway, with the cell detecting the presence of siDNA molecules as double stranded breaks (DSBs).

-Dbait is a type of signal interfering DNA that is recognized as a DSB by repair factors that respond to DSBs in order to initiate NHEJ. Dbait baits the activation of signalling enzymes involved in NHEJ-mediated genome repair, such as DNA-PK (DNA-dependent protein kinase) and PARP (polyadenyl-ribose polymerase). DNA-PK overactivation through Dbait in turn triggers the activity of numerous cofactors in the NHEJ signalling cascade.