Abstract
Glioblastoma (GBM) is the most common and malignant Grade IV primary craniocerebral tumor caused by glial cell carcinogenesis with an extremely poor median survival of 12–18 months. The current standard treatments for GBM, including surgical resection followed by chemotherapy and radiotherapy, fail to substantially prolong survival outcomes. Adeno-associated virus (AAV)-mediated gene therapy has recently attracted considerable interest because of its relatively low cytotoxicity, poor immunogenicity, broad tissue tropism, and long-term stable transgene expression. Furthermore, a range of gene therapy trials using AAV as vehicles are being investigated to thwart deadly GBM in mice models. At present, AAV is delivered to the brain by local injection, intracerebroventricular (ICV) injection, or systematic injection to treat experimental GBM mice model. In this review, we summarized the experimental trials of AAV-based gene therapy as GBM treatment and compared the advantages and disadvantages of different AAV injection approaches. We systematically introduced the prospect of the systematic injection of AAV as an approach for AAV-based gene therapy for GBM.
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Introduction
Glioblastoma (GBM) is a tumor located in the central nervous system (CNS) that forms in the supportive tissue of the brain [1]. Human GBM is highly invasive and spreads rapidly to nearby healthy brain tissues before symptoms occur [2]. GBM has been reported to be the most lethal intracranial tumor because of its high resistance to conventional radiotherapy and chemotherapy [3]. Despite advances in surgery, the complex genetic heterogeneity and insidious infiltration of GBM cells result in almost inevitable recurrence with less than 5% 5-year survival rate [4]. Another major obstacle in GBM treatment is the blood–brain barrier (BBB), which limits the diffusion of most small-molecule therapeutic agents and all large molecules into the brain parenchyma and blocks the drug treatment of GBM [6, 7]. More than 2000 clinical trials of gene therapy have been conducted, and most of the vectors have been proven effective and safe [8]. Current studies indicate that approximately 64% of the clinical trials of gene therapy were conducted to treat cancer diseases, and the most common strategy is the delivery of tumor growth-inhibiting or tumor-killing genes [9]. RNA interference has been used in gene therapy to inhibit tumorigenesis and proliferation [34,35,36,37].
In this review, we systematically introduced the prospects of AAV-based gene therapy for GBM and compared the advantages and disadvantages of different AAV injection methods. Most importantly, we will focus on the feasibility of the systematic injection of AAV for the treatment of GBM and the challenge faced by systematic injection.
AAV characteristics and its role in cancer gene therapy
AAV structure and composition
AAV was accidentally found in the 1960s during a laboratory preparation of adenovirus and later found in human tissues [38]. AAV does not cause any human diseases, and its life cycle is connected with a helper virus (such as adenovirus and herpes simplex virus). AAV cannot replicate independently, and its replication and cytolytic functions can only be performed under the presence of helper viruses [39, 40]. AAV does not integrate with the host's genome and can stably express transgenes for a long period. In addition, AAV is widespread in many species, including human and non-human primates, and is highly infectious to a variety of tissue cells in vivo with non-pathogenic quality; thus, AAV has become the star vector for gene therapy [41, 42].
AAV is a single-stranded linear DNA-deficient virus with a genomic DNA of less than 5 kb, and its structure is icosahedral non-enveloped particle. AAV is composed of one single-stranded DNA with inverse terminal repeat (ITR) sequence and two open reading frames Rep and Cap at both ends. ITRs are symmetrical repeats that play important roles in the structure and function of AAV. The Rep gene comprises four overlap** genes Rep78, Rep68, Rep52, and Rep40 and can encode the Rep protein required for AAV replication, package, and genomic integration. Cap gene is composed of overlap** amino acid sequences and encodes the capsid protein, including VP1, VP2, and VP3 with a ratio of 1:1:10 (VP1:VP2:VP3). These three interact with each other to form a symmetrical icosahedron structure, which acts as a vehicle for gene delivery [43, 44].
AAV-based cancer gene therapy
AAV-based gene therapy has been applied in a variety of preclinical and clinical trials to date and has shown a strong safety profile and trustworthy therapeutic effects [16]. In recent years, AAV has shown great value in the treatment of tumor diseases. Two clinical trials of AAV-based cancer gene therapy have been reported. One is the single injection of carcinoembryonic antigen (CEA)-specific cytotoxic T lymphocyte, which is activated by AAV2-CEA-transduced dendritic cells, to treat patients with advanced gastric cancer (ClinicalTrials.gov Identifier: NCT02496273), and the other is AAV2-hAQP1 applied in patients with squamous cell head and neck cancer (ClinicalTrials.gov Identifier: NCT02602249). In the treatment of cancer diseases, AAV can transduce a large number of cancer cells and cancer stromal cells and stably express cancer therapeutic genes (suicide gene, immunostimulatory gene, cytotoxic gene, small interference (siRNA) and anti-angiogenesis gene) to inhibit cancer formation and progression [45, 46]. The biggest problem with AAV-based cancer gene therapy is how to make AAV more specifically transduce to the cancer region [47]. Hence, a variety of rational designs of capsid have been engineered for cancer-specific transduction. Aminopeptidase N (CD13) is highly expressed in tumor tissues. Thus, Grifman et al. engineered AAV2 capsid by inserting an NGR peptide motif, which made AAV2 deliver therapeutic agents more efficiently and specifically to tumor cells [48]. Integrin is highly expressed on cancer vessels and cancer tissues and is used as an indicator of poor cancer prognosis. A study modified the AAV2 capsid by introducing a 4C-RGD peptide, which could efficiently combine αvβ3 and αvβ5 integrins. This modification promotes AAV2-mediated gene delivery to integrin-positive cancer cells in vitro and in vivo [49]. In addition, another study fused designed ankyrin repeat proteins to AAV2 capsid VP2 to target the cancer-associated receptor human epidermal growth factor receptor 2 (HER2)/neu. Her2-AAV selectively and highly transduces Her2-positive tumor cells and weakly transduces other cells, which greatly reduces its toxicity to other normal tissues [50]. AAV5 has also been engineered for cancer-specific transduction. Lee et al. engineered AAV5 with integrin-homing peptides, sialyl Lewis X and tenacin C, which are highly expressed in cancer cells [51]. Cheng et al. mutated tyrosine residues on AAV3 to phenylalanine, which increased the transduction capacity to hepatocellular carcinoma cells [52]. AAV capsid engineering promotes the effect of cancer cell-specific transduction to more effectively deliver therapeutic agents to the tumor site and greatly improve the treatment effect of AAV-based cancer therapy. The specific transduction of AAV is particularly important in AAV-based GBM gene therapy. How to make AAV specifically transduce to CNS regions and greatly reduce the peripheral toxicity of therapeutic genes especially in systematic injection approach are the key steps in AAV-based GBM gene therapy.
AAV-based experimental trials on GBM mice model
AAV has been used to treat experimental GBM model for decades because of their stable and persistent expression of anti-tumor agents in transduced cells [53]. After the first discovery that AAV-encoded tumor suppressor genes could effectively inhibit the growth of GBM cell lines in vitro, AAV emerged as an effective delivery tool for the treatment of experimental GBM model [54]. Previously, AAV-based GBM therapy was administered by local injection because of the BBB, which blocks the path of AAV to the GBM [55]. Researchers have also tried the ICV route to deliver AAV directly into the cerebrospinal fluid to further penetrate into the brain parenchyma to treat experimental GBM mouse models and have achieved certain success [56]. The recent discovery of BBB-crossing AAV introduced a new approach, namely, the systematic injection of AAV, to fight GBM. Systematic injection seems a better treatment approach than local or ICV injection because of its non-invasiveness and broad transduction [57] (Fig. 1). AAV-mediated experimental gene therapy against GBM utilizes a variety of therapeutic strategies, such as tumor suppression and the use of anti-tumor genes, including anti-angiogenesis genes, cytotoxic or suicide genes, and immunostimulatory genes [58]. Next, we will systematically summarize the progress of AAV-based GBM research in several in vivo delivery routes and in vitro findings (Table 1).
Different injection approaches of therapeutic AAV to treat GBM. Intratumoral injection is a common way to deliver therapeutic AAV to treat GBM in early years, but that has the limited transduction and surgical risk. ICV injection of therapeutic AAV can cause the widely transduction in the injected side, but it will lose the killing effect to the opposite side tumors. Systemic injection of therapeutic AAV will cause the widely transduced throughout the brain, and that can effectively inhibit invading GBM cells throughout the brain
Anti-GBM effect of AAV in vitro
It is reported that the hypoxia-regulated AAV was first used to kill GBM cells in 2001 in vitro. They constructed a hypoxia-regulated AAV, which can encode the suicide gene Bax for the hypoxic GBM microenvironment. Their result showed that Bax was abundantly expressed under hypoxic condition after AAV transduction and promoted the death of GBM cells in vitro [54].Tumor necrosis factor-related apoptosis-inducing ligand(TRAIL), which induces tumor cell apoptosis but is less toxic to normal tissues, has been used in the treatment of various tumor diseases. Shawn et al. developed AAV-soluble TRAIL (sTRAIL), which could transduce GBM cells to promote the killing effect on GBM cells and increase pro-apoptotic protein level in GBM cells in vitro [59]. PTEN is the most common mutant tumor suppressor gene in various tumor diseases including GBM. Mutant PTEN rescued by gene editing can inhibit the proliferation of tumor cells. Thus, Victoria et al. developed AAV-mediated gene editing, which effectively modified the mutant PTEN gene in GBM cells and inhibited the proliferation and growth of GBM cells. The AAV-mediated killing of GBM cells in vitro indicates the feasibility of AAV-based GBM gene therapy [60].
Anti-GBM effect of AAV through intratumoral injection
Intratumoral injection is the most generally preferred method for AAV to treat the experimental GBM mice model because of the presence of BBB. The local injection of AAV, which deliver therapeutic agents, has inhibited the growth of intracranial GBM and prolonged the survival rate of tumor-bearing mice to some extent [87]. Researchers have used multiple genetic engineering techniques to make AAV capsid have the ability to cross the BBB and search for new BBB-crossing AAV serotypes [90]. Until now, a great number of BBB-crossing AAV mutants are being developed, including the AAV-PHP.B and AAV-PHP.eB, which can transduce the entire CNS region. Peripheral toxicity, especially liver toxicity, have been addressed through some countermeasures, such as inserting CNS-specific promoters or using microRNA to suppress peripheral transgene expression [ Not applicable. Glioblastoma multiforme Adeno-associated virus Intracerebroventricular Central nervous
system Blood–brain barrier Inverted terminal
repeat Vascular endothelial
growth factor Tissue factor pathway
inhibitor-2 Human telomerase
reverse transcriptase Apoptin-derived
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The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Xu, X., Chen, W., Zhu, W. et al. Adeno‐associated virus (AAV)-based gene therapy for glioblastoma.
Cancer Cell Int 21, 76 (2021). https://doi.org/10.1186/s12935-021-01776-4 Received: Accepted: Published: DOI: https://doi.org/10.1186/s12935-021-01776-4Availability of data and materials
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