TNA-Mediated Antisense Strategy to Knockdown Akt Genes for Triple-Negative Breast Cancer Therapy

Area of Science:

• Biochemistry and Molecular Biology
• Cancer Therapeutics
• Nucleic Acid Chemistry

Background:

• Triple-negative breast cancer (TNBC) presents significant therapeutic challenges due to chemotherapy limitations, including side effects and drug resistance.
• Targeting key genes like Akt is crucial for developing effective TNBC treatments.
• Existing antisense therapies like miRNA and siRNA face limitations in stability and efficiency.

Purpose of the Study:

• To investigate the potential of threose nucleic acid (TNA)-mediated antisense strategies for targeting therapeutic Akt genes in TNBC.
• To design and evaluate novel TNA strands (anti-Akt2 and anti-Akt3) for their efficacy in inhibiting Akt gene expression and function in TNBC.

Main Methods:

• Design and synthesis of two specific TNA strands targeting Akt2 and Akt3 mRNA.
• Evaluation of TNA properties including enzymatic resistance, specificity, binding affinity, and cellular uptake.
• In vitro assessment in 2D and 3D TNBC cell models and in vivo studies using TNBC-bearing animal models.

Main Results:

• Synthesized TNAs demonstrated superior enzymatic resistance, specificity, binding affinity, and cellular uptake compared to natural nucleic acids.
• TNAs effectively inhibited target mRNA and protein expression in TNBC cell models and reduced tumor size in vivo.
• Targeted gene silencing by TNAs promoted apoptosis and suppressed tumor cell proliferation in vivo.

Conclusions:

• TNA-based antisense polymers offer a novel and promising therapeutic approach for triple-negative breast cancer.
• The TNA system exhibits advantages over conventional miRNA and siRNA therapies, including cost-effectiveness, scalability, and enhanced stability.
• This TNA platform targeting anti-apoptotic proteins represents a significant advancement for developing effective antisense materials for TNBC treatment.