SiDNA

Signal interfering DNA (siDNA) is a class of short modified double stranded DNA molecules, 8-64 base pairs in length.^[1] siDNA molecules are capable of inhibiting DNA repair activities by interfering with multiple repair pathways. In general, these molecules act by mimicking DNA breaks and interfering with recognition and repair of DNA damage induced on chromosomes by irradiation or genotoxic products.

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 chromatine. 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.^[2] Dbait-dependent unspecific phosphorylation of H2AX results in inefficient double strand break recognition and repair.^[3][4]

Possible Therapeutic application

Most of the anticancer therapies act by induction of DNA damage (chemotherapy and radiation therapy). DNA breaks are the most lethal damage for cells, as 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,^[5] glioblastoma^[6] and colorectal cancer.^[7] Preclinical proof of concept of the synergic effect of the clinical candidate, DT01, with radiation therapy lead to a first-in-human Phase I, which is currently underway to evaluate the tolerance and efficacy of local DT01 administration in association with RT in patients suffering from in-transit metastases of melanoma.

References