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Treating Transthyretin Amyloidosis via Adeno-Associated Virus Vector Delivery of Meganucleases
Jenny A Greig 1, Camilo Breton 1, Scott N Ashley 1, Kelly M Martins 1, Cassandra Gorsuch 2, Joanna K Chorazeczewski 1, Thomas Furmanak 1, Melanie K Smith 1, Yanqing Zhu 1, Peter Bell 1, Wendy Shoop 2, Hui Li 2, Jeff Smith 2, Ginger Tomberlin 2, Peter Clark 1, Thomas W Mitchell 1, Elizabeth L Buza 1, Hanying Yan 1, Derek Jantz 2, James M Wilson 1
Abstract:
...We evaluated adeno-associated virus (AAV) vector-delivered, gene-editing meganucleases to reduce TTR levels. We used engineered meganucleases targeting two different sites within the TTR gene. AAV vectors expressing TTR meganuclease transgenes were first tested in immunodeficient mice expressing the human TTR sequence delivered using an AAV vector and then against the endogenous TTR gene in rhesus macaques. Following a dose of 3 × 1013 genome copies per kilogram, we detected on-target editing efficiency of up to 45% insertions and deletions (indels) in the TTR genomic DNA locus and >80% indels in TTR RNA, with a concomitant decrease in serum TTR levels of >95% in macaques. The significant reduction in serum TTR levels following TTR gene editing indicates that this approach could be an effective treatment for ATTR.
