In the rat liver, Adenoviral gene transfer efficiency is comparable to AAV

Area of Science:

• Gene therapy
• Hepatology
• Viral vector technology

Background:

• Inherited liver disorders like Crigler-Najjar syndrome type 1 cause severe hyperbilirubinemia.
• Adenoviral (AdV) and Adeno-associated virus (AAV) vectors are used for in vivo gene therapy.
• AdV offers large cloning capacity, while AAV has advanced clinical trials.

Purpose of the Study:

• To directly compare the in vivo efficacy of AdV and self-complementary AAV (scAAV) vectors in the Gunn rat model.
• To determine the vector genome dose required for therapeutic correction of hyperbilirubinemia.

Main Methods:

• Gunn rats received tail vein injections of AdV or scAAV vectors with identical UGT1A1 liver-specific expression cassettes.
• Efficacy was assessed by the vector genome amount needed for sustained correction of serum bilirubin.
• UGT1A1 mRNA expression per genome and therapeutic correction were quantified.

Main Results:

• Both AdV and scAAV vectors achieved sustained correction of hyperbilirubinemia in Gunn rats.
• UGT1A1 mRNA expression per genome was comparable between AdV and scAAV.
• Flanking the AdV expression cassette with AAV-ITRs enhanced UGT1A1 expression eightfold, significantly improving efficacy.
• Fewer AdV genomes were required compared to scAAV for complete correction.

Conclusions:

• AdV vectors, particularly when modified with AAV-ITRs, demonstrate high efficacy for treating inherited liver disorders in vivo.
• AdV vectors show potential as a therapeutic option, requiring a lower genome dose than AAV for comparable correction.
• This study provides a direct comparison of AdV and AAV efficacy in a relevant disease model.