Harvard study finds synthetic production of Rep proteins could improve gene therapy

A new study published in the journal Nature Communications shows that synthetic production of certain virus vectors could be the key to improving gene therapy.

Researchers Nina Jain, Pierce Ogden and George Church of the Wyss Institute for Biologically Inspired Engineering and Harvard Medical School have made a breakthrough in gene therapy production, according to the study, which appeared on the bioRxiv website. Gene therapy vectors, called recombinant adeno-associated viruses, (rAAVs) have shown promise in treating various diseases, but producing sufficient quantities of rAAVs is difficult, the study notes.

The study focused on AAV rep proteins, which are essential for genome replication and packaging, and explored the effects of all 39,297 possible single codon mutations (or mutations to any three nucleotides that are part of a genetic code) to the AAV2 rep gene on AAV2 production. 

"Most beneficial variants are not observed in nature, indicating that improved production may require synthetic mutations," to improve production, the study says.

The team also discovered that the effects of AAV2 rep mutations are largely consistent across capsid serotypes, indicating that production benefits are not dependent on the capsid, or protein shell of a virus. 

The result's findings provide a detailed sequence-to-function map that enhances understanding of Rep protein function and could lay the groundwork for Rep engineering and large-scale gene therapy production enhancement, the authors wrote.