Adeno-associated virus (AAV) vectors in cancer gene therapy

Abstract

Gene delivery vectors based on adeno-associated virus (AAV) have been utilized in a large number of gene therapy clinical trials, which have demonstrated their strong safety profile and increasingly their therapeutic efficacy for treating monogenic diseases. For cancer applications, AAV vectors have been harnessed for delivery of an extensive repertoire of transgenes to preclinical models and, more recently, clinical trials involving certain cancers. This review describes the applications of AAV vectors to cancer models and presents developments in vector engineering and payload design aimed at tailoring AAV vectors for transduction and treatment of cancer cells. We also discuss the current status of AAV clinical development in oncology and future directions for AAV in this field.

Multifunctionalized polyethyleneimine-based nanocarriers for gene and chemotherapeutic drug combination therapy through one-step assembly strategy

“…After 12 days of treatment, the average tumor volume of mice treated with NS reached about 550 mm 3 ( Figure 13B), which was larger than that for the Dox (P,0.05), mPCT (P,0.05), and mPDT groups (P,0.01). For the mPDT group, average tumor volume was about 200 mm 3 , which was smaller than both the Dox group (P,0.05) and the mPCT group (P,0.05). Moreover, Figure 13C shows a direct visual representation of the tumor-suppression effect, in accordance with Figure 13B.…”

“…Briefly, H22 tumor-bearing BALB/c female mice were prepared by subcutaneous injection at the right axillary space with 0.1 mL cell suspension containing 10 6 H22 tumor cells. Ten days later, when tumor volumes were approximately 100 mm 3 , mice were randomly assigned to four treatment groups (n=3 for each group). Then, mice were treated every 2 days with normal saline (NS; intravenous [IV]), Dox solution (Dox 1 mg/kg, IV), mPCT (mouse TRAIL 1 mg/kg, IV) and mPDT (Dox 1 mg/kg, mouse TRAIL 1 mg/kg, IV).…”

“…3,4 Even though gene therapy has been increasingly applied in clinical trials for cancer treatment over the past decade, its clinical applications have not been growing as expected. 5,6 Till now, only two cancer-gene therapies have been approved in China, and none has been approved by the US Food and Drug Administration.…”

Preclinical study of rAAV2-sTRAIL: pharmaceutical efficacy, biodistribution and safety in animals

“…It greatly stimulates the enthusiasm using AAV as a targeted gene carrier for gene therapy. There is now a large body of data relating to the use of recombinant AAV-mediated gene therapy for various diseases such as eye diseases, 30 brain diseases, 31 tumors, 19 blood diseases 32 and so on. 33 Soon, additional data will become available on clinical trials of rAAV-mediated gene therapy to treat eye diseases, hemophilia B, Alzheimer's disease, Parkinson's disease and so on.…”

“…AAV mediates long-term and efficient target gene expression, infects and stably integrates into dividing and non-dividing cells, and stimulates low immune response without resulting in human diseases; 10 therefore, it evokes more and more interests and usage in treating various diseases. Recently, rAAV vectors have been used to treat eye diseases, 11,12 brain diseases, 13,14 muscle diseases, 15 blood diseases, [16][17][18] cancers 19 and so on. [20][21][22][23] In particular, the European Medicines Agency (EMA) had approved the first ever gene therapy of modified adeno-associated virus AAV-LPL S447X for the clinical use to treat a rare inherited metabolic disease called lipoprotein lipase deficiency in the Western world in 2013, 24 which greatly stimulates the enthusiasm using AAV as the targeted gene carrier for gene therapy.…”