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NIHNATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASESR01

Dissecting AAV silencing in humanized mice

Active
Institution
Duke University, NC
Principal investigator
Karl-Dimiter Bissig
Funding
$616K
Duration
2023–2027
Open portfolio

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Abstract

PROJECT SUMMARY The liver has emerged as a promising target for expressing therapeutic transgenes utilizing Adeno-Associated Viral (AAV) vector-mediated delivery. Despite numerous clinical trials and continued progress several challenges have been identified for AAV gene therapy. In this proposal we will dissect a major clinical hurdle, e.g. AAV transgene silencing in the human liver and molecular mechanisms underlying this phenomenon. To achieve such, we first propose to utilize and characterize a novel humanized liver model, which will allow precise and selective interrogation of the mechanisms underlying AAV transgene silencing in normal as well as diseased human hepatocytes in vivo. The second aim will build on a recent observation from our lab showing AAV transgene expression mediated by the Human Silencing Hub (HUSH) complex. We will further dissect and gather mechanistic inside on this process using human hepatocytes from methylmalonic acidemia (MMA) patients in vivo. Hence MMA will serve as a proof of concept disorder for liver directed AAV gene therapy. Finally, we will explore different vector design and pharmacological strategies to rescue AAV gene silencing.

Research team

  • Aravind AsokanPI
  • Karl-Dimiter BissigPI

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R01NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASESGene and Drug Delivery Systems Study Section[GDD]transgenehepatocyteshumanizeddissectgene therapyliveraavsilencing

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