Advances in endothelial cell targeting by AAV vectors.

Area of Science:

• * Gene Therapy
• * Molecular and Cellular Biology
• * Biotechnology

Background:

• * Adeno-associated virus (AAV) vectors are crucial for *in vivo* gene delivery but show limited transduction of endothelial cells (ECs) after systemic administration.
• * This tropism barrier hinders gene therapies for cardiovascular, neurovascular, and inflammatory conditions.
• * Targeting ECs is essential for effective vascular gene therapies.

Purpose of the Study:

• * To review strategies for redirecting AAV tropism toward endothelial cells.
• * To highlight advances in genetic capsid engineering, peptide display, and non-genetic surface modifications for EC targeting.
• * To discuss the potential of modified AAVs for precise vascular gene therapies.

Main Methods:

• * Review of recent literature on AAV capsid engineering for EC tropism.
• * Analysis of strategies including peptide incorporation, genetic modifications to reduce HSPG binding, and polymer-coating.
• * Examination of AAV4 serotype's unique endothelial tropism via O-linked sialic acid recognition.

Main Results:

• * AAV4 serotype demonstrates significant, previously underappreciated, endothelial tropism.
• * Engineered AAV capsids with EC-binding peptides enhance vascular targeting in specific beds.
• * Strategies reducing heparan sulfate proteoglycan (HSPG) binding improve EC transduction and reduce hepatocyte uptake.
• * Polymer-coating enables receptor-specific EC targeting and reduces immunogenicity.

Conclusions:

• * Genetic and non-genetic capsid modifications can effectively redirect AAV tropism to endothelial cells.
• * Targeted AAV vectors show promise for overcoming delivery barriers in vascular gene therapy.
• * Advances in AAV engineering are crucial for developing precise and efficient vascular gene therapies.