Plasmid DNA Nanoparticles for Nonviral Oral Gene Therapy

Area of Science:

• Biotechnology
• Gene Therapy
• Nanomedicine

Background:

• Diabetes mellitus poses a significant global health challenge requiring effective therapeutic strategies.
• Current diabetes treatments often involve invasive procedures or frequent administration.
• Oral gene delivery offers a promising alternative for sustained therapeutic effects.

Purpose of the Study:

• To develop a bile acid-inspired oral gene delivery platform for enhanced protection and intestinal targeting of therapeutic genes.
• To evaluate the efficacy of this nonviral nanoparticle system in managing hyperglycemia in preclinical diabetes models.
• To assess the long-term effects of the optimized dosage form on glucose control and metabolic parameters.

Main Methods:

• Development of a triple padlock nanoparticle system inspired by bile acid structure.
• Utilizing bile acid transporters for selective intestinal accumulation of pDNA nanoparticles.
• Assessment of gene expression and therapeutic efficacy in vitro, in vivo (mouse models), and ex vivo (monkey models).
• Evaluation of long-term glycemic control and metabolic changes over 20 weeks of weekly administration.

Main Results:

• The platform successfully protected genes from gastrointestinal degradation and achieved selective intestinal delivery.
• A single oral dose demonstrated sustained normoglycemia for up to 7 days in diabetic mice and 14 days in diabetic monkeys.
• Weekly administration over 20 weeks normalized fasting blood glucose and HbA1c levels, alongside reduced weight gain.
• The nonviral nanoparticle system showed excellent gene expression kinetics across all tested models.

Conclusions:

• The bile acid-inspired oral gene delivery platform represents a significant advancement in nonviral gene therapy for diabetes.
• This approach offers a potentially painless and effective alternative to current diabetes management strategies.
• The developed nanoparticle system holds promise for improving the quality of life for diabetic patients through convenient oral administration.