Hepatocyte and non-muscle cell-surface receptors mediating off-target AAV transduction

Hepatocyte and other non-muscle cell-surface receptors mediating off-target AAV transduction represent a diverse group of molecules that facilitate the entry of Adeno-Associated Virus (AAV) vectors into unintended tissues. Primary among these is the Adeno-Associated Virus Receptor (AAVR, also known as KIAA0319L), which has been identified as an essential host factor for the trafficking of most AAV serotypes (Pillay et al., 2016). Other key receptors include Heparan Sulfate Proteoglycans (HSPG) for AAV2, and the 37/67-kDa Laminin Receptor (LamR) for AAV8 and AAV9 (Summerford & Samulski, 1998; Akache et al., 2006). In systemic gene therapy, particularly for neuromuscular diseases, the high density of these receptors on hepatocytes leads to significant viral sequestration in the liver, often referred to as the liver sink effect (Zincarelli et al., 2008). This off-target binding reduces the concentration of the vector available for target tissues like skeletal or cardiac muscle and is a primary driver of dose-limiting hepatotoxicity. Clinical manifestations of this interaction include elevated liver transaminases and potential systemic inflammatory responses, which have been observed in high-dose AAV trials (Huang et al., 2014). Consequently, engineering AAV capsids to reduce affinity for these receptors—a process known as detargeting—is a critical area of research to enhance the safety and therapeutic index of gene medicines.

Other names

Adeno-associated virus receptor (AAVR)Heparan sulfate proteoglycan (HSPG)KIAA0319L37/67-kDa laminin receptor (LamR)AAV off-targetsHepatocyte AAV entry factorsLiver sink receptors

Binding of AAV capsid proteins to cell-surface receptors (e.g., HSPG, AAVR) followed by receptor-mediated endocytosis and intracellular trafficking.