Systemically administered AAV9-sTRAIL combats invasive glioblastoma in a patient-derived orthotopic xenograft model

Abstract

Adeno-associated virus (AAV) vectors expressing tumoricidal genes injected directly into brain tumors have shown some promise, however, invasive tumor cells are relatively unaffected. Systemic injection of AAV9 vectors provides widespread delivery to the brain and potentially the tumor/microenvironment. Here we assessed AAV9 for potential glioblastoma therapy using two different promoters driving the expression of the secreted anti-cancer agent sTRAIL as a transgene model; the ubiquitously active chicken β-actin (CBA) promoter and the neuron-specific enolase (NSE) promoter to restrict expression in brain. Intravenous injection of AAV9 vectors encoding a bioluminescent reporter showed similar distribution patterns, although the NSE promoter yielded 100-fold lower expression in the abdomen (liver), with the brain-to-liver expression ratio remaining the same. The main cell types targeted by the CBA promoter were astrocytes, neurons and endothelial cells, while expression by NSE promoter mostly occurred in neurons. Intravenous administration of either AAV9-CBA-sTRAIL or AAV9-NSE-sTRAIL vectors to mice bearing intracranial patient-derived glioblastoma xenografts led to a slower tumor growth and significantly increased survival, with the CBA promoter having higher efficacy. To our knowledge, this is the first report showing the potential of systemic injection of AAV9 vector encoding a therapeutic gene for the treatment of brain tumors.

Safety and Efficacy of AAV Retrograde Pancreatic Ductal Gene Delivery in Normal and Pancreatic Cancer Mice

“…In summary, our study demonstrates that scAAV6 targets both normal and neoplastic pancreata via retrograde ductal delivery. Our previous work and that of others support the use of AAV vectors to target a wide variety of neoplasms 54 , 78 , 79 , 80 , 81 , 82 , 83 and target tissues undergoing multiple cycles of degeneration-regeneration. 84 , 85 , 86 However, a number of pre-clinical studies need to be performed before this method reaches clinical settings because of the fact that AAVs are non-integrating vectors, and their expression is lost in rapidly proliferating neoplastic tissue.…”

Efficient Gene Transfer to the Central Nervous System by Single-Stranded Anc80L65

“…Remarkable benefit has already been demonstrated using i.v. delivery of AAV in multiple animal models, 21 , 44 , 72 , 73 , 74 and a first clinical trial has been approved by the FDA to use systemic delivery of AAV9 for the treatment of infantile spinal muscular atrophy type 1. 22 Considering that Anc80L65 is the predicted synthetic ancestor of AAV serotypes 1, 2, 8, and 9, we hypothesized that it may also cross the BBB.…”

New frontiers in oncolytic viruses: optimizing and selecting for virus strains with improved efficacy

“…Engineering of the ubiquitous chicken beta actin (CBA) and neuron-specific enolase (NSE) promoters into an AAV9 vector was monitored for bioluminescent reporter-gene expression after intravenous administration. 64 The AAV9 vector carrying the NSE promoter showed 100-fold lower expression in the liver. The AAV9-CBA vector targeted astrocytes, neurons, and endothelial cells, while the AAV9-NSE vector provided mainly neuron-specific expression.…”

“… 100 Promoter engineering has also allowed enhanced expression targeting, as demonstrated by neuron-specific delivery and 100-fold lower presence in the liver by applying the NSE promoter in AAV9 vectors. 64 Selective targeting of tumors has also been achieved by replacing the HSV1 ICP4 promoter with the tumor-specific survivin promoter. 70 Moreover, retroviruses have been subjected to chimeric antigen-receptor engineering to provide safe treatment of hematological malignancies.…”