Adeno‐associated virus (AAV)-based gene therapy for glioblastoma

Xu, Xin; Chen, Wenli; Zhu, Wenjun; Chen, Jing; Ma, Bin; Ding, Jianxia; Wang, Zaichuan; Li, Yifei; Wang, Yeming; Zhang, Xiaochun

doi:10.1186/s12935-021-01776-4

Cited by 16 publications

(11 citation statements)

References 90 publications

(78 reference statements)

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“…We then investigated the in vivo effect of diosmin on NEP expression after knocking down AhR in the brain. The AAV delivery into the CSF through ICV injection has been shown to achieve efficient gene transfer to a broad area of the brain in adult mice 37 , 38 . Furthermore, AAV9 has been reported to effectively targets neurons in adult mice through single stereotaxic or intracardiac injection 39 , 40 .…”

Section: Resultsmentioning

confidence: 99%

Activating AhR alleviates cognitive deficits of Alzheimer's disease model mice by upregulating endogenous Aβ catabolic enzyme Neprilysin

Qian

Yang

et al. 2021

Theranostics

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Rationale: Neprilysin (NEP) is a major endogenous catabolic enzyme of amyloid β (Aβ). Previous studies have suggested that increasing NEP expression in animal models of Alzheimer's disease had an ameliorative effect. However, the underlying signaling pathway that regulates NEP expression remains unclear. The aryl hydrocarbon receptor (AhR) is a ligand-activated cytoplasmic receptor and transcription factor. Recent studies have shown that AhR plays essential roles in the central nervous system (CNS), but its physiological and pathological roles in regulating NEP are not entirely known. Methods: Western blotting, immunofluorescence, quantitative RT-PCR and enzyme activity assay were used to verify the effects of AhR agonists on NEP in a cell model (N2a) and a mouse model (APP/PS1). Luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay were conducted to investigate the roles of AhR in regulating NEP transcription. Object recognition test and the Morris water maze task were performed to assess the cognitive capacity of the mice. Results: Activating AhR by the endogenous ligand L-Kynurenine (L-KN) or FICZ, or by the exogenous ligand diosmin or indole-3-carbinol (I3C) significantly increases NEP expression and enzyme activity in N2a cells and APP/PS1 mice. We also found that AhR is a direct transcription factor of NEP. Diosmin treatment effectively ameliorated the cognitive disorder and memory deficit of APP/PS1 transgenic mice. By knocking down AhR or using a small molecular inhibitor targeting AhR or NEP, we found that diosmin enhanced Aβ degradation through activated AhR and increased NEP expression. Conclusions: These results indicate a novel pathway for regulating NEP expression in neurons and that AhR may be a potential therapeutic target for the treatment of Alzheimer's disease.

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Section: Resultsmentioning

confidence: 99%

Activating AhR alleviates cognitive deficits of Alzheimer's disease model mice by upregulating endogenous Aβ catabolic enzyme Neprilysin

Qian

Yang

et al. 2021

Theranostics

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“…AAV is a single-stranded linear DNA-deficient virus widely used as a non-replicating viral vector for GBM gene therapy. AAV vectors possess the characteristics of relatively low cytotoxicity, poor immunogenicity, broad tissue tropism, and long-term stable transgene expression (Xu et al, 2021). AAV is widely applied in the treatment of GBM by carrying effective therapeutic genes, including anti-angiogenic genes, cytotoxicity or suicide genes, and immune-stimulating genes (Mormino and Garofalo, 2022).…”

Section: Exploration Of the Oncolytic Potential Of Aav In Gbm Therapymentioning

confidence: 99%

Glioblastoma microenvironment and its reprogramming by oncolytic virotherapy

Long

Liu

et al. 2022

Front. Cell. Neurosci.

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Glioblastoma (GBM), a highly aggressive form of brain tumor, responds poorly to current conventional therapies, including surgery, radiation therapy, and systemic chemotherapy. The reason is that the delicate location of the primary tumor and the existence of the blood-brain barrier limit the effectiveness of traditional local and systemic therapies. The immunosuppressive status and multiple carcinogenic pathways in the complex GBM microenvironment also pose challenges for immunotherapy and single-targeted therapy. With an improving understanding of the GBM microenvironment, it has become possible to consider the immunosuppressive and highly angiogenic GBM microenvironment as an excellent opportunity to improve the existing therapeutic efficacy. Oncolytic virus therapy can exert antitumor effects on various components of the GBM microenvironment. In this review, we have focused on the current status of oncolytic virus therapy for GBM and the related literature on antitumor mechanisms. Moreover, the limitations of oncolytic virus therapy as a monotherapy and future directions that may enhance the field have also been discussed.

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“…38 For instance, AAVs that cross the blood-brain barrier and are specific for central nervous system could be used for treatment of invasive glioblastoma. 39 To improve cancer specificity, wild-type AAV capsids can also be engineered to target cell surface tumour antigens. 40,41 For example, AAV2 was modified to bind HER2 receptor by inserting designed ankyrin repeat proteins (DARPins) into the AAV capsid.…”

Section: Adeno-associated Virus Vectorsmentioning

confidence: 99%

Cancer gene therapy goes viral: viral vector platforms come of age

Bezeljak

2022

Radiology and Oncology

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Background Since the advent of viral vector gene therapy in 1990s, cancer treatment with viral vectors promised to revolutionize the field of oncology. Notably, viral vectors offer a unique combination of efficient gene delivery and engagement of the immune system for anti-tumour response. Despite the early potential, viral vector-based cancer treatments are only recently making a big impact, most prominently as gene delivery devices in approved CAR-T cell therapies, cancer vaccines and targeted oncolytic therapeutics. To reach this broad spectrum of applications, a number of challenges have been overcome – from our understanding of cancer biology to vector design, manufacture and engineering. Here, we take an overview of viral vector usage in cancer therapy and discuss the latest advancements. We also consider production platforms that enable mainstream adoption of viral vectors for cancer gene therapy. Conclusions Viral vectors offer numerous opportunities in cancer therapy. Recent advances in vector production platforms open new avenues in safe and efficient viral therapeutic strategies, streamlining the transition from lab bench to bedside. As viral vectors come of age, they could become a standard tool in the cancer treatment arsenal.

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Adeno‐associated virus (AAV)-based gene therapy for glioblastoma

Cited by 16 publications

References 90 publications

Activating AhR alleviates cognitive deficits of Alzheimer's disease model mice by upregulating endogenous Aβ catabolic enzyme Neprilysin

Activating AhR alleviates cognitive deficits of Alzheimer's disease model mice by upregulating endogenous Aβ catabolic enzyme Neprilysin

Glioblastoma microenvironment and its reprogramming by oncolytic virotherapy

Cancer gene therapy goes viral: viral vector platforms come of age

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