75. Protease-Activated Receptor 2 as a Novel Target for Immune Modulation for AAV-Mediated Gene Transfer to Skeletal Muscle
Year: 2006
Type: article
Abstract: Intramuscular injection (IM) of adeno-associated viral (AAV)-2 vectors is a safe strategy to achieve long-term transgene expression in humans with hemophilia B. The development of AAV-based on alternative serotypes with higher transduction efficiency than AAV-2 is an attractive approach to the use of skeletal muscle as target tissue. However, in a series of studies in large animal models using AAV derived from serotypes (|[minus]|1,|[minus]|5,|[minus]|7,|[minus]|8), the immune response to the transgene has been a major complication. In mice, we showed that IM injection of AAV1-human-FIX induces antibody formation in all injected animals. However, in mice injected with high doses of AAV-1, the inhibitory antibody eventually disappear overtime. Blood proteases play an important role in modulating inflammatory and immune responses through activation of protease-activated receptors (PARs). PARs family is a member of a larger G protein coupled receptor family. To date, four such cleavable receptors have been described (PAR1-4). Mice lacking PAR-1 (|[minus]|/|[minus]|) or PAR-2 (|[minus]|/|[minus]|) alleles presented amelioration of immune- or infectious-mediated diseases. Here we sought to determine whether PAR-1 or PAR-2 inactivation would provide a strategy to prevent immune responses following AAV-mediated gene transfer to skeletal muscle.
Source: Molecular Therapy
Authors: Stefano Baila, Christian Furlan Freguia, Danielle Dunn, Federico Mingozzi, Joerg Schuettrumpf, Valder R. Arruda
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
OpenAlex ID: W2034991432