The Skeletal Muscle Environment and Its Role in Immunity and Tolerance to AAV Vector-Mediated Gene Transfer
Since the early days of gene therapy, muscle has been one the most studied tissue targets for
the correction of enzyme deficiencies and myopathies. Several preclinical and clinical studies have
been conducted using adeno-associated virus (AAV) vectors. Exciting progress has been made in the
gene delivery technologies, from the identification of novel AAV serotypes to the development of
novel vector delivery techniques. In parallel, significant knowledge has been generated on the host
immune system and its interaction with both the vector and the transgene at the muscle level. In particular,
the role of underlying muscle inflammation, characteristic of several diseases affecting the
muscle, has been defined in terms of its potential detrimental impact on gene transfer with AAV vectors.
At the same time, feedback immunomodulatory mechanisms peculiar of skeletal muscle involving resident regulatory
T cells have been identified, which seem to play an important role in maintaining, at least to some extent, muscle homeostasis
during inflammation and regenerative processes. Devising strategies to tip this balance towards unresponsiveness
may represent an avenue to improve the safety and efficacy of muscle gene transfer with AAV vectors.
Keywords: AAV vectors, Muscle, Clinical trials, Immune responses, Tolerance.
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