Viral Vectors as Gene Therapy Agents for Treatment of Glioblastoma

Mozhei, Oleg; Teschemacher, Anja G.; Kasparov, Sergey

doi:10.3390/cancers12123724

Cited by 18 publications

(18 citation statements)

References 95 publications

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“…Retroviral vectors (RV) encoding HSV-TK were the first viral vectors to be evaluated in clinical trials for glioma (NCT00001328). This study showed anti-tumor activity, but only in smaller tumors (Caffery et al, 2019 ). A tumor-selective non-lytic replicating RV, Toca 511, and an extended-release formulation of 5-fluorocytosine (5-FC), Toca FC, enables highly efficient transduction of glioma cells with cytosine deaminase (CD), an enzyme that activates the conversion of 5-FC into the anticancer drug 5-fluorouracil (5-FU) directly within the infected cells (Takahashi et al, 2014 ).…”

Section: Gene Therapy and Virotherapy In Gliomamentioning

confidence: 68%

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Current Approaches for Glioma Gene Therapy and Virotherapy

Banerjee

Núñez

Haase

et al. 2021

Front. Mol. Neurosci.

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Glioblastoma (GBM) is the most common and aggressive primary brain tumor in the adult population and it carries a dismal prognosis. Inefficient drug delivery across the blood brain barrier (BBB), an immunosuppressive tumor microenvironment (TME) and development of drug resistance are key barriers to successful glioma treatment. Since gliomas occur through sequential acquisition of genetic alterations, gene therapy, which enables to modification of the genetic make-up of target cells, appears to be a promising approach to overcome the obstacles encountered by current therapeutic strategies. Gene therapy is a rapidly evolving field with the ultimate goal of achieving specific delivery of therapeutic molecules using either viral or non-viral delivery vehicles. Gene therapy can also be used to enhance immune responses to tumor antigens, reprogram the TME aiming at blocking glioma-mediated immunosuppression and normalize angiogenesis. Nano-particles-mediated gene therapy is currently being developed to overcome the BBB for glioma treatment. Another approach to enhance the anti-glioma efficacy is the implementation of viro-immunotherapy using oncolytic viruses, which are immunogenic. Oncolytic viruses kill tumor cells due to cancer cell-specific viral replication, and can also initiate an anti-tumor immunity. However, concerns still remain related to off target effects, and therapeutic and transduction efficiency. In this review, we describe the rationale and strategies as well as advantages and disadvantages of current gene therapy approaches against gliomas in clinical and preclinical studies. This includes different delivery systems comprising of viral, and non-viral delivery platforms along with suicide/prodrug, oncolytic, cytokine, and tumor suppressor-mediated gene therapy approaches. In addition, advances in glioma treatment through BBB-disruptive gene therapy and anti-EGFRvIII/VEGFR gene therapy are also discussed. Finally, we discuss the results of gene therapy-mediated human clinical trials for gliomas. In summary, we highlight the progress, prospects and remaining challenges of gene therapies aiming at broadening our understanding and highlighting the therapeutic arsenal for GBM.

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Section: Gene Therapy and Virotherapy In Gliomamentioning

confidence: 68%

“…Delivery vectors such as viral vectors, non-polymeric nanoparticles (NPs) and polymeric NPs have been used to deliver the therapeutic payload in GBM and LGG (Caffery et al, 2019 ). To elicit therapeutic effects in the brain, nucleic acids used as therapeutic moieties need to surmount several barriers.…”

Section: Introductionmentioning

confidence: 99%

Current Approaches for Glioma Gene Therapy and Virotherapy

Banerjee

Núñez

Haase

et al. 2021

Front. Mol. Neurosci.

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“…Therefore, gene or nucleic acid carriers that are able to successfully penetrate into the tumour tissue have been extensively studied. Although several clinical trials have evaluated the use of viral vectors for GBM gene therapy, none achieved FDA approval, mainly due to inefficient viral delivery, lack of tumour penetration and insufficient efficacy (138,139). However, a number of non-viral vectors have shown promising results in pre-clinical trials and have entered clinical trial testing (140).…”

Section: Pharmaceutical Products Tested In Clinical Trialsmentioning

confidence: 99%

Glioblastoma pharmacotherapy: A multifaceted perspective of conventional and emerging treatments (Review)

et al. 2021

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Due to its localisation, rapid onset, high relapse rate and resistance to most currently available treatment methods, glioblastoma multiforme (GBM) is considered to be the deadliest type of all gliomas. Although surgical resection, chemotherapy and radiotherapy are among the therapeutic strategies used for the treatment of GBM, the survival rates achieved are not satisfactory, and there is an urgent need for novel effective therapeutic options. In addition to single-target therapy, multi-target therapies are currently under development. Furthermore, drugs are being optimised to improve their ability to cross the blood-brain barrier. In the present review, the main strategies applied for GBM treatment in terms of the most recent therapeutic agents and approaches that are currently under pre-clinical and clinical testing were discussed. In addition, the most recently reported experimental data following the testing of novel therapies, including stem cell therapy, immunotherapy, gene therapy, genomic correction and precision medicine, were reviewed, and their advantages and drawbacks were also summarised.

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“…Despite the significant advancement with the use of viral vectors as cytotoxic agents and/or for gene therapy, clinical trials have failed (149)(150)(151). None of the proposed viral vectors against GBM have been approved clinically (152,153).…”

Section: Viral-based Deliverymentioning

confidence: 99%

Targeting Non-coding RNA for Glioblastoma Therapy: The Challenge of Overcomes the Blood-Brain Barrier

Sharma

Calderón

Vivas‐Mejía

2021

Front. Med. Technol.

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Glioblastoma (GBM) is the most malignant form of all primary brain tumors, and it is responsible for around 200,000 deaths each year worldwide. The standard therapy for GBM treatment includes surgical resection followed by temozolomide-based chemotherapy and/or radiotherapy. With this treatment, the median survival rate of GBM patients is only 15 months after its initial diagnosis. Therefore, novel and better treatment modalities for GBM treatment are urgently needed. Mounting evidence indicates that non-coding RNAs (ncRNAs) have critical roles as regulators of gene expression. Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are among the most studied ncRNAs in health and disease. Dysregulation of ncRNAs is observed in virtually all tumor types, including GBMs. Several dysregulated miRNAs and lncRNAs have been identified in GBM cell lines and GBM tumor samples. Some of them have been proposed as diagnostic and prognostic markers, and as targets for GBM treatment. Most ncRNA-based therapies use oligonucleotide RNA molecules which are normally of short life in circulation. Nanoparticles (NPs) have been designed to increase the half-life of oligonucleotide RNAs. An additional challenge faced not only by RNA oligonucleotides but for therapies designed for brain-related conditions, is the presence of the blood-brain barrier (BBB). The BBB is the anatomical barrier that protects the brain from undesirable agents. Although some NPs have been derivatized at their surface to cross the BBB, optimal NPs to deliver oligonucleotide RNA into GBM cells in the brain are currently unavailable. In this review, we describe first the current treatments for GBM therapy. Next, we discuss the most relevant miRNAs and lncRNAs suggested as targets for GBM therapy. Then, we compare the current drug delivery systems (nanocarriers/NPs) for RNA oligonucleotide delivery, the challenges faced to send drugs through the BBB, and the strategies to overcome this barrier. Finally, we categorize the critical points where research should be the focus in order to design optimal NPs for drug delivery into the brain; and thus move the Oligonucleotide RNA-based therapies from the bench to the clinical setting.

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Viral Vectors as Gene Therapy Agents for Treatment of Glioblastoma

Cited by 18 publications

References 95 publications

Current Approaches for Glioma Gene Therapy and Virotherapy

Current Approaches for Glioma Gene Therapy and Virotherapy

Glioblastoma pharmacotherapy: A multifaceted perspective of conventional and emerging treatments (Review)

Targeting Non-coding RNA for Glioblastoma Therapy: The Challenge of Overcomes the Blood-Brain Barrier

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