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Defusing antibody neutralisers in AAV gene therapy

Adeno-associated virus (AAV)-mediated gene therapies allow for the treatment of a growing number of diseases; however, the presence of neutralising antibodies can lead to limitations of this technology, particularly for patients who may be excluded due to these pre-existing or developing neutralising antibodies. Recently, a study was published in Nature Medicine showing the elimination of neutralising AAV antibodies and restoration of gene therapy efficacy in controlled in vivo laboratory tests of animal models. Nikki Withers spoke to one of the study’s lead authors, Federico Mingozzi, to discuss the importance of their findings.

antibodies in blue on a purple background

AAV vectors are currently one of the most actively investigated gene therapy vehicles and are being used for the treatment of a growing number of diseases. “AAV vectors derive from a virus and can almost be defined as a very complex biologic drug,” explained Federico Mingozzi, Chief Scientific Officer at Spark Therapeutics. “The difference between the wild‑type virus and the vector is that all the viral coding sequences in the genome of the wild-type virus are replaced by a transgene expression cassette – the promoter region and the gene of interest. However, pre‑existing neutralising antibodies directed against AAV vectors are frequently found in humans.” While AAV-mediated gene therapies are showing great potential for treating various conditions, the presence of neutralising anti-AAV antibodies – an antibody that defends a cell from a pathogen or infectious particle by neutralising any effect it has biologically – can lead to limitations of this technology. “Additionally, because AAV vectors do not integrate in the host genome, genome dilution occurs in proliferating tissues, leading to loss of expression over time and potentially requiring a second treatment. To date, vector redosing is not easily feasible due to the formation of anti-AAV antibodies post vector administration.”











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