Human AAT gene transfer to pig liver improved by using a perfusion isolated organ endovascular procedure

Sendra, Luis; Pérez, Daniel; Miguel, Antonio; Herrero, Marí­a José; Noguera, Inmaculada; Díaz, Ana; Barettino, Domingo; Martí‐Bonmatí, Luis; Aliño, Salvador F.

doi:10.1007/s00330-015-3792-2

Cited by 9 publications

(14 citation statements)

References 22 publications

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“…Metabolic and genetic diseases, which show lower level of normal functional protein, are so far good candidates for this type of procedure. Although there is evidence showing transgene expression and that the procedure was safely performed in pigs [54][55][56][57], dogs [58,59], and baboons [60,61], further preclinical studies are necessary prior to human therapy application.…”

Section: Resultsmentioning

confidence: 99%

“…For its application in human, safety and efficacy of this approach have been extensively studied and improved. To date, various types of nucleic acid have been delivered by this approach in rodents as well as pigs [54][55][56][57], dogs [58,59], and rhesus monkeys [60,61]. Functional analyses of therapeutic gene were reported in nonalcoholic steatohepatitis [62], hepatitis B and C [63], fulminant hepatitis [64,65], liver fibrosis [66,67], liver regeneration [68], Fabry's disease [64], and colon cancer [69].…”

Section: Hydrodynamic Gene Delivery (Hgd)mentioning

confidence: 99%

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Nucleic Acid-Based Therapy: Development of a Nonviral-Based Delivery Approach

Yokoo¹,

Kamimura²,

Kanefuji³

et al. 2019

In Vivo and Ex Vivo Gene Therapy for Inherited and Non-Inherited Disorders

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Gene therapy returns to the center stage of medicine to treat patients with diseases that are unable to be cured with the conventional therapeutic strategies. This development is due to various reasons, including vector development and significant achievement in nextgeneration sequencing. Among the various methodologies of gene therapy, nucleic acidbased therapy has been considered to be promising in various diseases. The development of delivery methods to target cells in vivo, however, remains critical. These include viral vector-based and nonviral vector-based gene delivery methods as well as physical approaches such as hydrodynamic gene delivery (HGD). HGD is a simple and effective in vivo gene transfer method for the functional analysis of therapeutic genes and regulatory elements in small animals. Moreover, this chapter outlines the principle of HGD, gene expression studies in rodents, and recent advances in clinical application of HGD and provides future perspectives in developing a safe and efficient method for nucleic acidbased therapy.

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Section: Resultsmentioning

confidence: 99%

Section: Hydrodynamic Gene Delivery (Hgd)mentioning

confidence: 99%

Nucleic Acid-Based Therapy: Development of a Nonviral-Based Delivery Approach

Yokoo¹,

Kamimura²,

Kanefuji³

et al. 2019

In Vivo and Ex Vivo Gene Therapy for Inherited and Non-Inherited Disorders

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“…However, hepatic delivery remains the Achilles heel in non-viral gene therapy studies aiming at clinical trials. [42][43][44] It remains to be seen whether the SB transposons can be used in the in vivo approach as successfully as they are being used to treat blood cancers in human patients. 71 …”

Section: Discussionmentioning

confidence: 99%

“…4,41,42 Until recently, the efficacy of non-viral DNA delivery to treat large animals has been discouraging. 4,[42][43][44] The authors developed and examined the potential of catheter-mediated infusion via the hepatic veins wherein targeted liver tissues are isolated from the blood flow by balloon occlusion of blood vessels. In dogs aged ‡3 months, 41 detectable expression of the reporter enzyme canine serum alkaline phosphatase (cSEAP) was achieved for up to 6 weeks, a duration that is too short for clinical application, which requires extended gene expression.…”

Section: Introductionmentioning

confidence: 99%

Prolonged Expression of Secreted Enzymes in Dogs After Liver-Directed Delivery ofSleeping BeautyTransposons: Implications for Non-Viral Gene Therapy of Systemic Disease

et al. 2017

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The non-viral, integrating Sleeping Beauty (SB) transposon system is efficient in treating systemic monogenic disease in mice, including hemophilia A and B caused by deficiency of blood clotting factors and mucopolysaccharidosis types I and VII caused by a-L-iduronidase (IDUA) and b-glucuronidase (GUSB) deficiency, respectively. Modified approaches of the hydrodynamics-based procedure to deliver transposons to the liver in dogs were recently reported. Using the transgenic canine reporter secreted alkaline phosphatase (cSEAP), transgenic protein in the plasma was demonstrated for up to 6 weeks post infusion. This study reports that immunosuppression of dogs with gadolinium chloride (GdCl 3 ) prolonged the presence of cSEAP in the circulation up to 5.5 months after a single vector infusion. Transgene expression declined gradually but appeared to stabilize after about 2 months at approximately fourfold baseline level. Durability of transgenic protein expression in the plasma was inversely associated with transient increase of liver enzymes alanine transaminase and aspartate transaminase in response to the plasmid delivery procedure, which suggests a deleterious effect of hepatocellular toxicity on transgene expression. GdCl 3 treatment was ineffective for repeat vector infusions. In parallel studies, dogs were infused with potentially therapeutic transposons. Activities of transgenic IDUA and GUSB in plasma peaked at 50-350% of wildtype, but in the absence of immunosuppression lasted only a few days. Transposition was detectable by excision assay only when the most efficient transposase, SB100X, was used. Dogs infused with transposons encoding canine clotting factor IX (cFIX) were treated with GdCl 3 and showed expression profiles similar to those in cSEAP-infused dogs, with expression peaking at 40% wt (2 lg/mL). It is concluded that GdCl 3 can support extended transgene expression after hydrodynamic introduction of SB transposons in dogs, but that alternative regimens will be required to achieve therapeutic levels of transgene products.

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“…The gene solution is injected through hepatic veins. The backflow is blocked by inflated balloon[54].…”

mentioning

confidence: 99%

Liver Gene Therapy: Employing Surgery and Radiology for Translational Research

Sendra¹,

Herrero²,

Martí‐Bonmatí³

et al. 2018

Liver Research and Clinical Management

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Gene therapy is a therapeutic strategy that aims to employ nucleic acids as drugs for the transient or permanent treatment of inherited or acquired pathologies. Based on the type of vector employed for the gene transfer, gene therapy can be classified as viral gene therapy and nonviral gene therapy. Nonviral gene therapy is less efficient but safer than viral gene therapy. Hydrodynamic naked DNA transfer has shown great translational potential, achieving therapeutic levels of a human protein in the murine model. The translational process of the procedure has already been performed. Different radiologic and surgical approaches permitted pressurizing the liver in vivo by excluding its vascularization partially or totally. These approaches mediated a tissue rate of human alpha-1-antitrypsin protein translation (100-1000 copies per cell) close to those obtained with the mouse gold standard model in a safe mode that could be translated to human settings.

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Human AAT gene transfer to pig liver improved by using a perfusion isolated organ endovascular procedure

Cited by 9 publications

References 22 publications

Nucleic Acid-Based Therapy: Development of a Nonviral-Based Delivery Approach

Nucleic Acid-Based Therapy: Development of a Nonviral-Based Delivery Approach

Prolonged Expression of Secreted Enzymes in Dogs After Liver-Directed Delivery ofSleeping BeautyTransposons: Implications for Non-Viral Gene Therapy of Systemic Disease

Liver Gene Therapy: Employing Surgery and Radiology for Translational Research

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