Language：Japanese   Publisher：International Journal of Molecular Sciences  

Omega-3 (ω-3) polyunsaturated fatty acids in fish oil have been shown to prevent diet-induced obesity in lean mice and to promote heat production in adipose tissue. However, the effects of fish oil on obese animals remain unclear. This study investigated the effects of fish oil in obese mice. C57BL/6J mice were fed a lard-based high-fat diet (LD) for 8 weeks and then assigned to either a fish oil-based high-fat diet (FOD) or continued the LD for additional 8 weeks. A control group was fed a standard diet for 16 weeks. Mice fed the FOD showed weight loss, reduced adipose tissue mass, and lower plasma insulin and leptin levels compared to those fed the LD. Rectal temperatures were higher in the FOD and LD groups compared to the control group. Energy intake was lower in the FOD group than the LD group but similar to the control group. The FOD and LD groups exhibited increased expression of heat-producing genes such as Ppargc1a, Ucp1, Adrb3, and Ppara in brown adipose tissue but not in white adipose tissue. The FOD reduced food consumption and increased rectal temperature and heat-producing genes in brown adipose tissue. Fish oil may therefore be a potential therapeutic approach to obesity.

DOI： 10.3390/ijms26010302

Scopus

PubMed

Language：Japanese   Publisher：Biochemical and Biophysical Research Communications  

There is no effective therapy for peritoneal carcinomatosis derived from gastric cancer. An ideal conditionally replicating adenovirus (CRA) that selectively replicates in and kills cancer cells has not been developed for gastric cancer-derived peritoneal carcinomatosis. Using our platform technology of CRA regulated and treating tumors with multiple factors (m-CRA), we generated two types of survivin-responsive m-CRAs, Surv.m-CRA-CMVp and Surv.m-CRA-CEAp, consisting of E1A downstream of the survivin promoter, and the mutated E1B gene downstream of the human cytomegalovirus immediate early gene enhancer/promoter and carcinoembryonic antigen promoter, respectively. Survivin mRNA was expressed at high and undetectable levels in two gastric cancer cells and eleven normal cells, respectively. Carcinoembryonic antigen was expressed at high and very low levels in MKN-45 gastric cancer and normal PrEC cells, respectively, and was not detected in other cell types. While both Surv.m-CRA-CEAp and Surv.m-CRA-CMVp exhibited potent cytotoxic effects on MKN-45 cells in vitro, Surv.m-CRA-CEAp significantly reduced cytotoxicity to normal cells compared to Surv.m-CRA-CMVp. Control mice that received an intraperitoneal injection of MKN-45 cells gradually lost body weight and died of peritoneal carcinomatosis within 98 days. In contrast, all mice receiving Surv.m-CRA-CEAp or Surv.m-CRA-CMVp-infected MKN-45 cells increased their body weight and survived 120 days. In conclusion, the triple-regulated Surv.m-CRA-CEAp enhances cancer specificity (i.e., safety) without reducing the potent therapeutic effect for carcinoembryonic antigen-positive gastric cancer-derived peritoneal carcinomatosis. The modified E1B promoter strategy of CRA facilitates the development of novel CRAs for the effective and safe treatment of a variety of refractory cancers.

DOI： 10.1016/j.bbrc.2024.150894

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PubMed

Language：Japanese   Publisher：THE JAPAN SOCIETY OF DRUG DELIVERY SYSTEM  

Replication-defective adenovirus（Ad） vectors played a pivotal role in the advancement of <i>in vivo</i> cancer gene therapy research during the 1990s. The development of conditionally replicated Ad （CRA）, <i>i.e</i>. 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.

DOI： 10.2745/dds.39.248

Scopus

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

In general, ensuring safety is the top priority of a new modality. Although oncolytic virus armed with an immune stimulatory transgene (OVI) showed some promise, the strategic concept of simultaneously achieving maximum effectiveness and minimizing side effects has not been fully explored. We generated a variety of survivin-responsive "conditionally replicating adenoviruses that can target and treat cancer cells with multiple factors (m-CRAs)" (Surv.m-CRAs) armed with the granulocyte-macrophage colony-stimulating factor (GM-CSF) transgene downstream of various promoters using our m-CRA platform technology. We carefully analyzed both therapeutic and adverse effects of them in the in vivo syngeneic Syrian hamster cancer models. Surprisingly, an intratumor injection of a conventional OVI, which expresses the GM-CSF gene under the constitutively and strongly active "cytomegalovirus enhancer and β-actin promoter", provoked systemic and lethal GM-CSF circulation and shortened overall survival (OS). In contrast, a new conceptual type of OVI, which expressed GM-CSF under the cancer-predominant and mildly active E2F promoter or the moderately active "Rous sarcoma virus long terminal repeat", not only abolished lethal adverse events but also prolonged OS and systemic anti-cancer immunity. Our study revealed a novel concept that optimal expression levels of an immune stimulatory transgene regulated by a suitable upstream promoter is crucial for achieving high safety and maximal therapeutic effects simultaneously in OVI therapy. These results pave the way for successful development of the next-generation OVI and alert researchers about possible problems with ongoing clinical trials.

DOI： 10.1016/j.trsl.2024.07.002

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PubMed

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

AIMS: Hepatocyte growth factor (HGF) is a multifunctional cytokine that plays important roles in pancreatic physiology. Approvals of gene therapy drugs have highlighted gene therapy as an innovative new drug modality, but the very recent reports of deaths in clinical trials have provided a warning that high-dose gene therapy can cause dangerous liver toxicity. The present study aimed to develop a safe and low-dose but therapeutically effective adenovirus-mediated HGF gene therapy for streptozotocin (STZ)-induced type 1 diabetes (T1D) in mice. MAIN METHODS: A single intravenous injection of a low dose (3 × 108 plaque forming units) of adenoviral vector expressing the HGF gene under the transcriptional control of a strong promoter, i.e., the cytomegalovirus immediate-early enhancer and a modified chicken β-actin promoter (Ad.CA-HGF), was given to T1D mice. KEY FINDINGS: Low-dose HGF gene therapy significantly attenuated the elevation of blood glucose concentrations at the acute phase of T1D, and this effect persisted for several weeks. Temporal upregulation of plasma insulin at the acute phase was maintained at a normal level in Ad.CA-HGF-treated mice, suggesting that the therapeutic mechanism may involve protection of the remaining β-cells by HGF. Liver enzymes in plasma were not elevated in any of the mice, including the Ad.CA-HGF-treated animals, all of which looked healthy, suggesting the absence of lethal adverse effects observed in patients receiving high intravenous doses of viral vectors. SIGNIFICANCE: A low dose of intravenous Ad-mediated HGF gene therapy is clinically feasible and safe, and thus represents a new therapeutic strategy for treating T1D.

DOI： 10.1016/j.lfs.2020.119014

Scopus

PubMed

Language：Japanese   Publisher：日本DDS学会  

非増殖型アデノウイルス(Ad)ベクターが1990年代のin vivoがん遺伝子治療の研究を牽引し、2000年代より腫瘍溶解性ウイルス(OV)の制限増殖型Ad(CRA)の開発が本格化し、近年は免疫遺伝子搭載型CRAの研究と臨床応用が盛んである。筆者らは、複雑に遺伝子改変したCRA(多因子増殖制御型CRA;m-CRA)を多種多様・効率的に作製できるプラットフォーム技術を開発し、サバイビン反応性m-CRA(Surv.m-CRA)を創出した。治療遺伝子未搭載のSurv.m-CRA-1は、治療抵抗性の悪性骨腫瘍への早期承認を目指した多施設共同・第II相医師主導治験を現在進めている。さらに最近、安全かつ最大の治療効果を得るための、免疫遺伝子搭載OVにおける「至適プロモーターによる至適発現の必要性」という新概念を見出した。本稿ではAdのウイルス学に続いて上記を概説し、次世代CRAの展望について述べる。(著者抄録)

Event date： 2023.5

Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

Venue：鹿児島   Country：Japan  

Event date： 2025.7

Language：English   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2025.3

Language：Japanese   Presentation type：Poster presentation  

Venue：横浜   Country：Japan  

Event date： 2023.11

Language：Japanese  

Venue：東京   Country：Japan  

Event date： 2023.7

Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Venue：京都   Country：Japan