Although mRNA vaccines have become widely used, there are many issues remaining with them, such as temperature stability and anaphylaxis. Viral vector vaccines are highly stable because they are based on DNA, the genetic information forming the basis of antigenic proteins. Adenovirus vector vaccines were approved during the COVID-19 pandemic, however, quality issues subsequently led to declining demand. Alternatively, adeno-associated virus（AAV） vectors have low pathogenicity, immunogenicity, and cytotoxicity and are currently one of the most widely studied vectors for gene therapy. In this article, we will explain the standards for AAV vectors to be used as a new modality to compensate for the disadvantages of mRNA vaccines, including efforts to improve purification technology and quality.

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Replication-defective adenovirus（Ad） vectors played a pivotal role in the advancement of in vivo cancer gene therapy research during the 1990s. The development of conditionally replicated Ad （CRA）, i.e. the representative oncolytic virus（OV）, commenced during the 2000s, and research and clinical applications of CRAs armed with immune genes have been active in recent years. We developed a platform technology that can efficiently generate diverse types of “CRAs that can specifically target tumors with multiple factors”（m-CRAs） and survivin-responsive m-CRAs（Surv.m-CRAs） as innovative anticancer agents. Surv.m-CRA-1, which does not carry a therapeutic gene, is currently undergoing a multicenter, Phase II investigator-initiated clinical trial for early approval for malignant bone tumors. Moreover, we have recently identified a novel concept, “the need for optimal expression levels of immune transgene by optimal promoters,” in OVs armed with immune genes, to achieve both maximal therapeutic effects and the highest level of safety. In this review, we show Ad virology, the aforementioned points and discuss the potential for the next generation of CRAs.

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Oncolytic virotherapy is an area of cancer treatment that has garnered significant attention, with various oncolytic viruses evaluated in clinical trials. In the past decade, three oncolytic viruses have received regulatory approval. The advantage of oncolytic virotherapy lie not only in the direct destruction of tumor cells by the virus but also in the stimulation of an antitumor immune response. However, there are issues in terms of application, particularly regarding the use of viruses in treatment and the fact that these therapies are primarily localized treatments. In terms of antitumor efficacy, the challenges include limited efficiency of virus delivery and dissemination, as well as the elimination of viruses by the host’s immune system. Many researchers are conducting various studies to overcome these challenges. I introduce the advancements and challenges in oncolytic virotherapy.

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Gene therapy for hematopoietic stem cells （HSCs） holds promise as a treatment for various genetic diseases. HSCs constitute peripheral blood throughout life, and thus, repairing pathogenic mutations and deletions in HSCs can allow for the lifelong treatment of genetic diseases. Autologous HSC gene therapy has been developed through lentiviral gene addition and gene editing in patient HSCs, and no requirement of a compatible donor makes this therapy applicable to most patients. The efficacy of HSC gene therapy using lentiviral vectors and gene editing has been proven in recent clinical trials; however, the complexity and high cost due to ex vivo culture have hindered widespread use. Therefore, the development of in vivo HSC gene therapy, which can directly deliver gene therapy tools to bone marrow HSCs by systemic administration, is a desirable solution.

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Messenger RNA-encapsulated lipid nanoparticles, referred to as LNP-mRNA, are a novel modality that has been approved as mRNA vaccines against SARS-CoV-2. mRNA composed of unmodified nucleic acids can induce inflammatory reactions, leading to adverse reactions when administered to the body. However, it has been discovered that using mRNA composed of modified nucleic acids can reduce excessive inflammatory reactions, expanding the potential for the application of mRNA in pharmaceuticals. On the other hand, it has become clear that the pH-responsive lipid used in LNPs also exhibits adjuvant activity associated with innate immune activation. This article provides an overview of LNP-mRNA and its natural immune effects.

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Regarding viral vector products as gene therapy products, several points to consider were summarized from the perspectives of quality, non-clinical efficacy, non-clinical safety, non-clinical biodistribution, clinical evaluation, and Cartagena Act compliance. In addition, the timing and reliability of the nonclinical studies and the consistency of the quality of the test article used were summarized as points to be noted in the evaluation. When developing viral vector products, it is necessary to consider quality, non-clinical, and clinical evaluation methods depending on the product and disease characteristics. Utilizing PMDA consultation services is encouraged in order to develop products efficiently.

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