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The AsiDNA™ decoy mimicking DSBs protects the normal tissue from radiation toxicity through a DNA-PK/p53/p21-dependent G1/S arrest.

ABSTRACT: AsiDNA, a cholesterol-coupled oligonucleotide mimicking double-stranded DNA breaks, was developed to sensitize tumour cells to radio- and chemotherapy. This drug acts as a decoy hijacking the DNA damage response. Previous studies have demonstrated that standalone AsiDNA administration is well tolerated with no additional adverse effects when combined with chemo- and/or radiotherapy. This lack of normal tissue complication encouraged further examination into the role of AsiDNA in normal cells. The delayed development of pulmonary fibrosis after FLASH-RT compared to CONV-RT might be a known phenomenon but the complexity behind this specific tissue response is completely unidentified. Radiation has been shown to impact various cell types presented in the lung, resulting in changes in cellular activity and numerous pathway activations. Current unpublished data suggest a clear variety between the CONV and FLASH-RT gene signatures examined using single cell RNA sequencing. As the combined treatment of AsiDNA with CONV-RT resulted in a delay in radiation induced lung fibrosis compared to CONV-RT standalone, it is to be questioned if the signature of AsiDNA CONV-RT is similar to FLASH-RT or CONV-RT. To characterize the similarity in cellular changes and expression signatures in lungs 5 months post CONV-RT, FLASH-RT, AsiDNA CONV-RT or non-irradiated (Control) treatment. Single cell RNA sequencing of irradiated lungs revealed a closer resemblance between CONV AsiDNA and FLASH-RT in profibrotic gene signatures within the fibroblast and macrophages population, in comparison to CONV-RT standalone. Collectively, this information indicates that the activity of AsiDNA and FLASH-RT could draw upon identical mechanism interference to result in the protective capacities within the normal tissue.

ORGANISM(S): Mus musculus

PROVIDER: GSE240510 | GEO | 2024/02/27

REPOSITORIES: GEO

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Project description:Purpose: Studies during the past 9 years suggest that delivering radiation at dose rates exceeding 40 Gy/s, known as “FLASH” radiotherapy, enhances the therapeutic index of radiation therapy (RT) by decreasing normal tissue damage while maintaining tumor response compared to conventional (or standard) RT. This study demonstrates the cardioprotective benefits of FLASH proton RT (F-PRT) compared to standard (conventional) proton RT (S-PRT), as evidenced by reduced acute and chronic cardiac toxicities. Methods and Materials: Mice were imaged using cone beam computed tomography to precisely determine the heart’s apex as the beam isocenter. Irradiation was conducted utilizing a shoot-through technique with a 5mm collimator. Bulk RNA-sequencing was performed on non-irradiated (NR) samples, as well as apexes treated with F-PRT or S-PRT, at 2 weeks following a single 40 Gy dose. Inflammatory responses were assessed through multiplex cytokine/chemokine microbead assay and immunofluorescence analyses. Levels of perivascular fibrosis were quantified using Masson’s Trichrome and Picrosirius red staining. Additionally, cardiac tissue functionality was evaluated by 2D echocardiograms at 8 and 30 weeks post-PRT. Results: Radiation damage was specifically localized in the heart’s apex. RNA profiling of cardiac tissues treated with PRT revealed that S-PRT induced unique pathways associated with DNA damage response, induction of tumor necrosis factor superfamily and inflammatory response, while F-PRT primarily affected cytoplasmic translation, mitochondrion organization and ATP synthesis. Notably, F-PRT led to a milder inflammatory response, accompanied by significantly attenuated changes in TGF-1 and SMA levels. Critically, F-PRT decreased collagen deposition, and better preserved cardiac functionality compared to S-PRT. Conclusions: This study demonstrated that F-PRT reduces the induction of an inflammatory environment with lower expression of inflammatory cytokines and profibrotic factors. Importantly, the results indicate that F-PRT better preserves cardiac functionality, as confirmed by echocardiography analysis, while also mitigating the development of long-term fibrosis.

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The AsiDNA™ decoy mimicking DSBs protects the normal tissue from radiation toxicity through a DNA-PK/p53/p21-dependent G1/S arrest.

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