A new study has employed adeno-associated virus (AAV) vectors to deliver gene-editing meganucleases to reduce transthyretin (TTR) levels in mice and rhesus macaques. The study, published in Human Gene Therapy, found the approach could be an effective approach for treating hereditary transthyretin amyloidosis (hATTR).

“The most effective meganuclease produced a sustained >95% reduction from baseline of serum TTR levels in rhesus macaques,” the authors wrote. “This significant reduction in serum TTR levels following genomic editing of the TTR gene indicates that AAV delivery of a TTR-specific meganuclease could represent an effective treatment for ATTR.”

The research team packaged and delivered 3 increasing doses of engineered meganucleases inside AAV8 capsids to target a site on either exon 1 of the TTR gene present in mouse, nonhuman primate, and human genomes or exon 3 of the TTR gene present only in nonhuman primate and human genomes. Blood and liver samples were obtained to analyze serum TTR levels, immunohistochemistry, and DNA.

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The results in the mice showed that at the mid and high doses of the meganuclease vector, significant reductions in TTR levels of 63% and 79%, respectively, were achieved. In rhesus macaques, serum TTR levels were reduced by more than 95% at the highest dose of 3×1013 genome copies/kg of an AAV8 vector.

Given that current therapeutic approaches for hATTR such as inotersen or patisiran require regular intravenous administration, a gene-editing treatment is appealing because it would be effective after a single administration.

The authors note that by delivering the nuclease via an AAV vector, they can take advantage of the established safety profile of gene therapy vectors. Patients would need to be screened for pre-existing neutralizing antibodies, but the treatment could provide stable genome editing for up to 3 years.


Greig JA, Breton C, Ashley SN, et al. Treating transthyretin amyloidosis via adeno-associated virus vector delivery of meganucleases. Hum Gene Ther. 2022;33(21-22):1174-1186. doi:10.1089/hum.2022.061