Fetal Gene Therapy for Ornithine Transcarbamylase Deficiency by Intrahepatic Plasmid DNA-Micro-Bubble Injection Combined with Hepatic Ultrasound Insonation

Oishi, Yoshie; Kakimoto, Takashi; Yuan, Wenji; Kuno, Shuichi; Yamashita, Hiromasa; Chiba, Tadatoshi

doi:10.1016/j.ultrasmedbio.2015.10.007

Cited by 7 publications

(6 citation statements)

References 19 publications

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“…Several options are available to deliver the transgene expression cassette to the target cell/organ Injection of naked DNA, either as plasmids (Doenecke et al 2010;Oishi et al 2016)o rmini-circles (Viecelli et al 2014;Hou et al 2016;Wuetal2016), is a simple mode of transgene delivery which lends itself to local delivery and is relatively non-immunogenic compared to some viral vector approaches (Wolff and Budker 2005). Mini-circles are devoid of plasmid backbone DNA; this may enhance transgene expression by overcoming heterochromatin formation and avoiding inflammation triggered by bacterial DNA (Mayrhofer et al 2009).…”

Section: Design and Selection Of The Gene Transfer Vectormentioning

confidence: 99%

Gene therapy for monogenic liver diseases: clinical successes, current challenges and future prospects

Baruteau

Waddington

Alexander

et al. 2017

J of Inher Metab Disea

104

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Over the last decade, pioneering liver-directed gene therapy trials for haemophilia B have achieved sustained clinical improvement after a single systemic injection of adeno-associated virus (AAV) derived vectors encoding the human factor IX cDNA. These trials demonstrate the potential of AAV technology to provide long-lasting clinical benefit in the treatment of monogenic liver disorders. Indeed, with more than ten ongoing or planned clinical trials for haemophilia A and B and dozens of trials planned for other inherited genetic/metabolic liver diseases, clinical translation is expanding rapidly. Gene therapy is likely to become an option for routine care of a subset of severe inherited genetic/metabolic liver diseases in the relatively near term. In this review, we aim to summarise the milestones in the development of gene therapy, present the different vector tools and their clinical applications for liver-directed gene therapy. AAV-derived vectors are emerging as the leading candidates for clinical translation of gene delivery to the liver. Therefore, we focus on clinical applications of AAV vectors in providing the most recent update on clinical outcomes of completed and ongoing gene therapy trials and comment on the current challenges that the field is facing for large-scale clinical translation. There is clearly an urgent need for more efficient therapies in many severe monogenic liver disorders, which will require careful risk-benefit analysis for each indication, especially in paediatrics.

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Section: Design and Selection Of The Gene Transfer Vectormentioning

confidence: 99%

Gene therapy for monogenic liver diseases: clinical successes, current challenges and future prospects

Baruteau

Waddington

Alexander

et al. 2017

J of Inher Metab Disea

104

View full text Add to dashboard Cite

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“…To collect urine samples, mice were kept in metabolic cages for 24 hours after administration of the vehicle or allopurinol. Urinary orotic acid was measured using an established colorimetric method 20 . The absorbance was determined at 490 nm using a SpectraMax i3 Multimode microplate platform (Molecular Devices, Sunnyvale, CA).…”

Section: Methodsmentioning

confidence: 99%

“…Urinary orotic acid was measured using an established colorimetric method. 20 The absorbance was determined at 490 nm using a SpectraMax i3 Multimode microplate platform (Molecular Devices, Sunnyvale, CA). Urinary orotic acid concentration was corrected according to urinary creatinine levels determined with a model 7170 autoanalyzer (Hitachi Ltd., Tokyo, Japan).…”

Section: Allopurinol Challenge Test and Measurement Of Urinary Orotic Acidmentioning

confidence: 99%

“…OTC enzyme activity was determined by a colorimetric method based on the production of L-citrulline as described previously. 20,21 Citrulline production was determined by measuring the absorbance at 490 nm using a SpectraMax i3 Multimode microplate platform (Molecular Devices). The enzyme activity was expressed as citrulline μmol/mg protein/h.…”

Section: Otc Enzyme Activitymentioning

confidence: 99%

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Humanized liver mouse model with transplanted human hepatocytes from patients with ornithine transcarbamylase deficiency

Sugahara

Yamasaki

Yanagi

et al. 2020

J of Inher Metab Disea

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Ornithine transcarbamylase deficiency (OTCD) is a metabolic and genetic disease caused by dysfunction of the hepatocytic urea cycle. To develop new drugs or therapies for OTCD, it is ideal to use models that are more closely related to human metabolism and pathology. Primary human hepatocytes (HHs) isolated from two patients (a 6‐month‐old boy and a 5‐year‐old girl) and a healthy donor were transplanted into host mice (hemi‐, hetero‐OTCD mice, and control mice, respectively). HHs were isolated from these mice and used for serial transplantation into the next host mouse or for in vitro experiments. Histological, biochemical, and enzyme activity analyses were performed. Cultured HHs were treated with ammonium chloride or therapeutic drugs. Replacement rates exceeded 80% after serial transplantation in both OTCD mice. These highly humanized OTCD mice showed characteristics similar to OTCD patients that included increased blood ammonia levels and urine orotic acid levels enhanced by allopurinol. Hemi‐OTCD mice showed defects in OTC expression and significantly low enzymatic activities, while hetero‐OTCD mice showed residual OTC expression and activities. A reduction in ammonium metabolism was observed in cultured HHs from OTCD mice, and treatment with the therapeutic drug reduced the ammonia levels in the culture medium. In conclusion, we established in vivo OTC mouse models with hemi‐ and hetero‐patient HHs. HHs isolated from the mice were useful as an in vitro model of OTCD. These OTC models could be a source of valuable patient‐derived hepatocytes that would enable large scale and reproducible experiments using the same donor.

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“…In view of the advantages of cavitation nuclei in ultrasound stimuli, microbubbles as cavitation nuclei have been used widely in ultrasound-mediated drug/gene delivery (Huang et al, 2012;Yan et al, 2015;Oishi et al, 2016;Wang et al, 2016;Zullino et al, 2018). The commonly used microbubbles have gaseous cores and outer shells composed of phospholipids, polymers or proteins.…”

Section: Introductionmentioning

confidence: 99%

Ultrasound-Responsive Materials for Drug/Gene Delivery

et al. 2020

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Ultrasound is one of the most commonly used methods in the diagnosis and therapy of diseases due to its safety, deep penetration into tissue, and non-invasive nature. In the drug/gene delivery systems, ultrasound shows many advantages in terms of site-specific delivery and spatial release control of drugs/genes and attracts increasing attention. Microbubbles are the most well-known ultrasound-responsive delivery materials. Recently, nanobubbles, droplets, micelles, and nanoliposomes have been developed as novel carriers in this field. Herein, we review advances of novel ultrasound-responsive materials (nanobubbles, droplets, micelles and nanoliposomes) and discuss the challenges of ultrasound-responsive materials in delivery systems to boost the development of ultrasound-responsive materials as delivery carriers.

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Fetal Gene Therapy for Ornithine Transcarbamylase Deficiency by Intrahepatic Plasmid DNA-Micro-Bubble Injection Combined with Hepatic Ultrasound Insonation

Cited by 7 publications

References 19 publications

Gene therapy for monogenic liver diseases: clinical successes, current challenges and future prospects

Gene therapy for monogenic liver diseases: clinical successes, current challenges and future prospects

Humanized liver mouse model with transplanted human hepatocytes from patients with ornithine transcarbamylase deficiency

Ultrasound-Responsive Materials for Drug/Gene Delivery

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