Hiroyuki Abe

Safety Assessment of Liver-Targeted Hydrodynamic Gene Delivery in Dogs

Evidence in support of safety of a gene delivery procedure is essential toward gene therapy. Previous studies using the hydrodynamics-based procedure primarily focus on gene delivery efficiency or gene function analysis in mice. The current study focuses on an assessment of the safety of computer-controlled and liver-targeted hydrodynamic gene delivery in dogs as the first step toward hydrodynamic gene therapy in clinic. We demonstrate that the impacts of the hydrodynamic procedure were limited in the injected region and the influences were transient. Histological examination and the hepatic microcirculation measurement using reflectance spectrophotometry reveal that the liver-specific impact of the procedure involves a transient expansion of the liver sinusoids. No systemic damage or toxicity was observed. Physiological parameters, including electrocardiogram, heart rate, blood pressure, oxygen saturation, and body temperature, remained in normal ranges during and after hydrodynamic injection. Body weight was also examined to assess the long-term effects of the procedure in animals who underwent 3 hydrodynamic injections in 6 weeks with 2-week time interval in between. Serum biochemistry analysis showed a transient increase in liver enzymes and a few cytokines upon injection. These results demonstrate that image-guided, liver-specific hydrodynamic gene delivery is safe.

Image-Guided Hydrodynamic Gene Delivery: Current Status and Future Directions

Hydrodynamics-based delivery has been used as an experimental tool to express transgene in small animals. This in vivo gene transfer method is useful for functional analysis of genetic elements, therapeutic effect of oligonucleotides, and cancer cells to establish the metastatic cancer animal model for experimental research. Recent progress in the development of image-guided procedure for hydrodynamics-based gene delivery in large animals directly supports the clinical applicability of this technique. This review summarizes the current status and recent progress in the development of hydrodynamics-based gene delivery and discusses the future directions for its clinical application.

Late Onset Post-Transfusion Hepatitis E Developing during Chemotherapy for Acute Promyelocytic Leukemia

We herein report the case of a leukemia patient who developed hepatitis E seven months after undergoing a transfusion with contaminated blood products. The latency period in this case was significantly longer than that of typical hepatitis E. Recently, chronic infection with hepatitis E virus (HEV) genotype 3 has been reported in immunocompromised patients. There is a possibility that our patient was unable to eliminate the virus due to immunosuppression following chemotherapy and the administration of steroids. The prevalence of HEV in healthy Japanese individuals is relatively high and constitutes a critical source of infection via transfusion. Hepatitis E is an important post-transfusion infection, and immunocompromised patients may exhibit a long latency period before developing the disease.

Effective Prevention of Liver Fibrosis by Liver-targeted Hydrodynamic Gene Delivery of Matrix Metalloproteinase-13 in a Rat Liver Fibrosis Model

Liver fibrosis is the final stage of liver diseases that lead to liver failure and cancer. While various diagnostic methods, including the use of serum marker, have been established, no standard therapy has been developed. The objective of this study was to assess the approach of overexpressing matrix metalloproteinase-13 gene (MMP13) in rat liver to prevent liver fibrosis progression. A rat liver fibrosis model was established by ligating the bile duct, followed by liver-targeted hydrodynamic gene delivery of a MMP13 expression vector, containing a CAG promoter-MMP13-IRES-tdTomato-polyA cassette. After 14 days, the serum level of MMP13 peaked at 71.7 pg/ml in MMP13-treated group, whereas the nontreated group only showed a level of ~5 pg/ml (P < 0.001). These levels were sustained for the next 60 days. The statistically lower level of the hyaluronic acids in treated group versus the nontreated group (P < 0.05) reveals the therapeutic effect of MMP13 overexpression. Quantitative analysis of tissue stained with sirius red showed a statistically larger volume of fibrotic tissue in the nontreated group compared to that of MMP13-treated rats (P < 0.05). These results suggest that the liver-targeted hydrodynamic delivery of MMP13 gene could be effective in the prevention of liver fibrosis.

Liver-targeted hydrodynamic gene therapy: Recent advances in the technique

One of the major research focuses in the field of gene therapy is the development of clinically applicable, safe, and effective gene-delivery methods. Since the first case of human gene therapy was performed in 1990, a number of gene-delivery methods have been developed, evaluated for efficacy and safety, and modified for human application. To date, viral-vector-mediated deliveries have shown effective therapeutic results. However, the risk of lethal immune response and carcinogenesis have been reported, and it is still controversial to be applied as a standard therapeutic option. On the other hand, delivery methods for nonviral vector systems have been developed, extensively studied, and utilized in in vivo gene-transfer studies. Compared to viral-vector mediated gene transfer, nonviral systems have less risk of biological reactions. However, the lower gene-transfer efficiency was a critical hurdle for applying them to human gene therapy. Among a number of nonviral vector systems, our studies focus on hydrodynamic gene delivery to utilize physical force to deliver naked DNA into the cells in the living animals. This method achieves a high gene-transfer level by DNA solution injections into the tail vein of rodents, especially in the liver. With the development of genome editing methods, in vivo gene-transfer therapy using this method is currently the focus in this research field. This review explains the method principle, efficiency, safety, and procedural modifications to achieve a high level of reproducibility in large-animal models.

Advances in understanding and treating liver diseases during pregnancy: A review.

Liver disease in pregnancy is rare but pregnancy-related liver diseases may cause threat to fetal and maternal survival. It includes pre-eclampsia; eclampsia; haemolysis, elevated liver enzymes, and low platelets syndrome; acute fatty liver of pregnancy; hyperemesis gravidarum; and intrahepatic cholestasis of pregnancy. Recent basic researches have shown the various etiologies involved in this disease entity. With these advances, rapid diagnosis is essential for severe cases since the decision of immediate delivery is important for maternal and fetal survival. The other therapeutic options have also been shown in recent reports based on the clinical trials and cooperation and information sharing between hepatologist and gynecologist is important for timely therapeutic intervention. Therefore, correct understandings of diseases and differential diagnosis from the pre-existing and co-incidental liver diseases during the pregnancy will help to achieve better prognosis. Therefore, here we review and summarized recent advances in understanding the etiologies, clinical courses and management of liver disease in pregnancy. This information will contribute to physicians for diagnosis of disease and optimum management of patients.

Hemodynamics of a hydrodynamic injection

The hemodynamics during a hydrodynamic injection were evaluated using cone beam computed tomography (CBCT) and fluoroscopic imaging. The impacts of hydrodynamic (5 seconds) and slow (60 seconds) injections into the tail veins of mice were compared using 9% body weight of a phase-contrast medium. Hydrodynamically injected solution traveled to the heart and drew back to the hepatic veins (HV), which led to liver expansion and a trace amount of spillover into the portal vein (PV). The liver volumes peaked at 165.6 ± 13.3% and 165.5 ± 11.9% of the original liver volumes in the hydrodynamic and slow injections, respectively. Judging by the intensity of the CBCT images at the PV, HV, right atrium, liver parenchyma (LP), and the inferior vena cava (IVC) distal to the HV conjunction, the slow injection resulted in the higher intensity at PV than at LP. In contrast, a significantly higher intensity was observed in LP after hydrodynamic injection in comparison with that of PV, suggesting that the liver took up the iodine from the blood flow. These results suggest that the enlargement speed of the liver, rather than the expanded volume, primarily determines the efficiency of hydrodynamic delivery to the liver.

Diagnostic imaging of hepatic lymphoma.

Hepatic lymphoma is a rare disease with poor prognosis because of delayed diagnosis. The disease comprises primary, metastatic, and intravascular hepatic lymphomas. The pathological characteristics of lymphomas differ contributing to difficulty in early diagnosis. Early diagnosis and appropriate treatment result in improved prognosis; therefore, diagnostic radiology and its development with various contrast agents are critical for improving disease outcomes. Herein, we review hepatic lymphomas and summarize the results of imaging studies in correlation with pathological characteristics. The information provided will help physicians in early diagnosis and thereby improving prognosis.

Efficacy of the regimen using twice-daily β-interferon followed by the standard of care for chronic hepatitis C genotype 1b with high viral load.

Aim:  In patients with refractory genotype 1b chronic hepatitis C with high viral loads, we retrospectively compared the efficacy of standard of care treatment (SOC: combined PEG‐IFN‐α‐2b/ribavirin for 48 weeks) and a regimen in which 2 weeks of SOC induction was replaced by twice‐daily β‐interferon alone (IFN‐β induction therapy).

The Combination Therapy of Dissolution Using Carbonated Liquid and Endoscopic Procedure for Bezoars: Pragmatical and Clinical Review

Bezoars are relatively rare foreign bodies of gastrointestinal tract and often cause ileus and ulcerative lesions in the stomach and subsequent bleeding and perforation due to their size and stiffness. Therefore, the removal of bezoars is essential and recent development of devices, the endoscopic removal procedure, is often applied. However, due to their stiffness, simple endoscopic removal failed in not a few cases, and surgical removal has also been used. Recently, the efficacy of a combination therapy of endoscopic procedure and dissolution using carbonated liquid has been reported. To develop the safe and effective removal procedure, we carefully reviewed a total of 55 reported cases in this study including our 3 additional cases, successfully treated with dissolution with endoscopic fragmentation. In summary, the data showed the efficiency in the combination therapy, treating the larger size of bezoar and reducing the length of hospital stay. To the best of our knowledge, this is the largest pragmatical and clinical review for the combination therapy of dissolution and endoscopic treatment for bezoars. This review should help physicians to manage bezoars more efficiently.