OR07

Bioconjugation of the capsid of adeno-associated viruses for osteoarthritis treatment by gene therapy

H Delépée(1,2) M Bouzelha(1) K Pavageau(1) D Alvarez-Dorta(2) S G Gouin(2) O Adjali(1) J Guicheux(3) C Vinatier(3) D Deniaud(2) M Mével(1,2)

1:TaRGeT, Inserm, UMR 1089, Nantes University; 2:CEISAM, CNRS, UMR 6230, Nantes University; 3:RMeS, Inserm, UMR 1229, Nantes University

This project focuses on chemically engineering adeno-associated viruses (AAV) through bioconjugation to enhance specificity toward cartilage tissue to treat osteoarthritis.

Cartilage is a non-vascularized tissue in which chondrocytes, the sole extracellular matrix (ECM) producing cells, generate a highly negatively charged matrix due to its major component, glycosaminoglycans. In osteoarthritis, chondrocyte dysfunction leads to cartilage degradation, affecting over 500 million people worldwide. Despite its prevalence, osteoarthritis remains incurable, due to the challenges of delivering therapeutic agents to chondrocytes embedded in the dense ECM.

AAV are promising gene therapy vectors, as demonstrated by four ongoing clinical trials targeting cartilage. However, their broad tropism and limited ability to reach targeted cells reduce their efficiency. To address these limitations, our team developed a chemical modification strategy to enhance AAV specificity and efficacy for targeted cells or tissues.

The AAV capsid is chemically modified in two steps: biotin ligands are bioconjugated to capsid lysines, followed by non-covalent binding of avidin, a positively charged protein. This modification exploits the strong biotin-avidin interaction and imparts an overall positive charge to the vector. This charges facilitates electrostatic interactions with the negatively charged ECM, enhancing vector retention, adhesion, and penetration into deeper cartilage layers.

Preliminary results demonstrate that these modifications preserve AAV infectivity in human chondrocytes. Ongoing work assesses vector retention and penetration in cartilage explants, along with in vivo studies in a rat model to evaluate biodistribution and cartilage targeting. This approach presents a promising strategy to overcome challenges in cartilage-targeted gene therapy and develop osteoarthritis treatments.