NF-κB-activated oncogene inhibition strategy for cancer gene therapy

Area of Science:

• Oncology
• Gene Therapy
• Molecular Biology

Background:

• Nuclear factor-kappa B (NF-κB) is overactive in most cancers, making it a therapeutic target.
• Existing NF-κB inhibitors often cause side effects, limiting clinical success.
• A novel approach is needed to target cancer effectively while minimizing toxicity.

Purpose of the Study:

• To develop and evaluate a novel gene therapy approach, HOPE, for cancer treatment.
• To utilize NF-κB activity to activate CRISPR-Cas13a for targeted oncogene suppression.
• To assess the efficacy and safety of HOPE in preclinical cancer models.

Main Methods:

• Constructed a system (HOPE) using an NF-κB-specific promoter (DMP) to activate CRISPR-Cas13a.
• HOPE targets and suppresses oncogenes (TERT, PLK1, KRAS, MYC) at the mRNA level.
• Evaluated HOPE's anti-tumor effects in cell cultures and in a mouse model of colorectal cancer using adeno-associated virus (AAV) delivery.

Main Results:

• HOPE selectively induced cancer cell death in vitro without harming normal cells.
• Intravenous injection of rAAV-HOPE significantly inhibited tumor growth in mice.
• HOPE treatment activated the immune system and reduced cancer cell stemness.
• No significant side effects were observed in the in vivo model.

Conclusions:

• HOPE demonstrates potent anti-tumor activity both in vitro and in vivo.
• This novel gene therapy approach offers a promising strategy for cancer treatment.
• HOPE represents a potential advancement in cancer gene therapy by targeting oncogenes and modulating the immune response.