Hepatocellular Carcinoma Is a Natural Target for Adeno-Associated Virus (AAV) 2 Vectors

Abstract

Although therapeutic options are gradually improving, the overall prognosis for patients with hepatocellular carcinoma (HCC) is still poor. Gene therapy-based strategies are developed to complement the therapeutic armamentarium, both in early and late-stage disease. For efficient delivery of transgenes with antitumor activity, vectors demonstrating preferred tumor tropism are required. Here, we report on the natural tropism of adeno-associated virus (AAV) serotype 2 vectors for HCC. When applied intravenously in transgenic HCC mouse models, similar amounts of vectors were detected in the liver and liver tumor tissue. In contrast, transduction efficiency, as indicated by the level of transgene product, was moderate in the liver but was elevated up to 19-fold in mouse tumor tissue. Preferred transduction of HCC compared to hepatocytes was confirmed in precision-cut liver slices from human patient samples. Our mechanistic studies revealed that this preference is due to the improved intracellular processing of AAV2 vectors in HCC, resulting, for example, in nearly 4-fold more AAV vector episomes that serve as templates for gene transcription. Given this background, AAV2 vectors ought to be considered to strengthen current—or develop novel—strategies for treating HCC.

Adding recombinant AAVs to the cancer therapeutics mix

“…Indeed, AAV2 was shown in two mouse models of HCC development as well as human precision-cut liver slice experiments to preferentially infect tumor tissue compared with nonmalignant liver area. 120 Additionally, using an AAV3 vector to drive expression of pyruvate dehydrogenase E1α led to cell death in human HCC. 121

Figure 2 Design of rAAVs for various tumors Reported AAV serotypes that target cancers include several common serotypes such as AAV2, 3, and 8.

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“…NSE, neuron-specific enolase. TnC, tenascin-C. 5 , 6 , 8 , 9 , 53 , 55 , 58 , 61 , 101 , 102 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 …”

Adeno-associated virus vector-mediated gene therapy for the treatment of ovarian cancer: a literature review

“…Direct injection into the body has the advantage of ease of use. Recent advances in the study of genetic diseases and cancers have been made thanks to the discovery of AAV as a gene therapy vector, including hemophilia A ( 33 ), Duchenne muscular dystrophy ( 34 ), tumors ( 35 ), HCC ( 36 , 37 ), myocardial infarction ( 38 ), and so on. Drugs for AAV-mediated gene therapy, including Glybera, Luxturna, and Zolgensma, have been commercialized and utilized in patients ( 39 ).…”