“Membrane-Associated Accessory Protein (MAAP): Discovery and its Effects on AAV Production and Quality”

 

Abstract: Adeno-associated viruses (AAVs) are small, non-enveloped, single-stranded DNA viruses that belong to the Dependoparvovirus genus within the Parvoviridae family. They have become the leading vectors in clinical gene therapy, with eight AAV-based gene therapies currently approved by the EMA and FDA. However, the increasing demand for high-titer and high-quality AAV is challenging to meet with current production technologies. The compact AAV genome (4.7 kb), flanked by inverted terminal repeats (ITRs), encodes four non-structural (Rep) proteins, three structural (Cap) proteins, and the assembly-activating protein (AAP). Recently, we discovered a new gene in an alternative reading frame within the AAV cap gene that encodes a 13 kDa protein not homologous to any known protein. It was named membrane-associated accessory protein (MAAP) as it localizes into cellular membranes and extracellular vesicles (exosomes) in microscopy. MAAP plays a role in viral egress, viral protein (VP) stability, and the packaging of genomic and contaminating DNA into the capsid, though the detailed molecular mechanisms underlying these functions remain to be elucidated. Notably, the engineering of MAAP can significantly enhance recombinant AAV generation in a serotype-dependent manner, while preserving the desired serotype properties and production process.

 

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