Red Blood Cell Anchoring Enables Targeted Transduction and Re‐Administration of AAV‐Mediated Gene Therapy

• Published in: Advanced science Vol. 9; no. 24; pp. e2201293 - n/a
• Main Authors: Zhao, Zongmin, Kim, Jayoung, Suja, Vinny Chandran, Kapate, Neha, Gao, Yongsheng, Guo, Junling, Muzykantov, Vladimir R., Mitragotri, Samir
• Format: Journal Article
• Language: English
• Published: Weinheim John Wiley & Sons, Inc 01.08.2022; John Wiley and Sons Inc; Wiley
• Subjects: adeno‐associated virus; Biodistribution; Blood; Blood vessels; Efficiency; Flow cytometry; Gene expression; Gene therapy; Heart; immunomodulation; Lungs; Nanoparticles; neutralizing antibody; red blood cell hitchhiking; Scanning electron microscopy
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202201293

Adeno‐associated virus (AAV)‐mediated gene therapy is a promising therapeutic modality for curing many diseases including monogenic diseases. However, limited tissue‐targeting and restricted re‐administration due to the vector immunogenicity largely restrict its therapeutic potential. Here, using a red blood cell (RBC) as the carrier vehicle for AAV is demonstrated to improve its tissue‐targeted transduction and enable its re‐administration. Anchoring AAV to the RBC surface minimally affected its infectability toward endothelial cells. Meanwhile, AAV anchored onto RBCs is predominantly delivered to and shows efficient transduction in the lungs by virtue of the biophysical features of RBCs. RBC‐anchored AAVs lead to a four‐ to five‐fold enhancement in target gene expression in the lungsas compared to free AAVs following a single‐ or dual‐dosing regimen. While RBC anchoring does not prevent the induction of adaptive immune responses against AAV, it results in successful transgene expression upon re‐administration following prior AAV exposure. The ability to re‐administer is partially attributed to the delayed and reduced AAV neutralization by neutralizing antibodies, resulting from the combination of limited exposure of physically confined AAVs and the short time required to reach the lungs. This study's findings suggest that the RBC‐mediated approach is a promising strategy for repetitive, targeted AAV gene therapy. Clinical implementation of adeno‐associated virus (AAV)‐mediated gene therapy is hindered by its limited tissue‐specificity and inability to re‐dose. Physically anchoring AAV onto RBC surfaces is demonstrated toenable dual functions of contact‐enabled targeting of the lung tissue and kinetics‐based immune evasion by delayed neutralizing antibody detection. This approach represents an effective strategy to overcome anti‐AAV immunity for repetitive, targeted AAV gene therapy.