Liver‐targeted gene therapy: Approaches and challenges

Aravalli, Rajagopal N.; Belcher, John D.; Steer, Clifford J.

doi:10.1002/lt.24122

Cited by 29 publications

(30 citation statements)

References 203 publications

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“…Two decades ago, there was considerable interest in liver gene therapy (31). In most trials, a vector, usually an Adenovirus, carrying a wild-type copy of the defective gene was introduced into hepatocytes.…”

Section: Liver-based Gene Therapiesmentioning

confidence: 99%

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Hereditary Angioedema as a Metabolic Liver Disorder: Novel Therapeutic Options and Prospects for Cure

et al. 2016

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Hereditary angioedema (HAE) is a rare autosomal dominant disorder caused by mutations of the SERPING1 or the Factor 12 genes. It is potentially fatal, particularly if not identified at an early stage. Apart from androgens, which are contraindicated in children and in pregnant women, a range of effective, albeit very expensive treatments have recently become available for HAE patients. The cost of these new treatments is beyond the reach of most developing countries. At this time, there is no cure for the disorder. In spite of mutations of the SERPING1 gene, autoimmunity and infections are not prominent features of the condition. Here, we present the argument that HAE should be viewed primarily as a metabolic liver disorder. This conceptual paradigm shift will stimulate basic research and may facilitate new therapeutic approaches to HAE outlined in this paper. We suggest several novel potential treatment options for HAE from the perspectives of clinical immunology, molecular biology, and liver transplantation. Many of these offer the prospect of curing the disorder. The effectiveness of these options is rapidly improving in many cases, and their risks are decreasing. Given the very high costs of treating HAE, some of these curative options may become feasible in the next decade.

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Section: Liver-based Gene Therapiesmentioning

confidence: 99%

“…There is considerable interest in other new viral and non-viral approaches for gene therapy in liver disease (31). Most human studies are at a proof-of-concept stage.…”

Section: Liver-based Gene Therapiesmentioning

confidence: 99%

Hereditary Angioedema as a Metabolic Liver Disorder: Novel Therapeutic Options and Prospects for Cure

et al. 2016

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“…Recently, efficient tools for genome engineering, particularly as CRISPR/Cas9, have become available providing an alternative possibility for stable genome modifications. 35 However, efficient delivery of the required designer nucleases remains a challenge. Nonintegrating lentiviral vectors have been suggested as an efficient delivery vehicle for CRISPR/Cas9.…”

Section: Discussionmentioning

confidence: 99%

Primary Human Hepatocytes Repopulate Livers of Mice AfterIn VitroCulturing and Lentiviral-Mediated Gene Transfer

Bierwolf¹,

Volz

Lütgehetmann

et al. 2016

Tissue Engineering Part A

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Cell-based therapies represent a promising alternative to orthotopic liver transplantation. However, therapeutic effects are limited by low cell engraftment rates. We recently introduced a technique creating human hepatocyte spheroids for potential therapeutic application. The aim of this study was to evaluate whether these spheroids are suitable for engraftment in diseased liver tissues. Intrasplenic spheroid transplantation into immunodeficient uPA/SCID/beige mice was performed. Hepatocyte transduction ability prior to transplantation was tested by lentiviral labeling using red-green-blue (RGB) marking. Eight weeks after transplantation, animals were sacrificed and livers were analyzed by immunohistochemistry and immunofluorescence. To investigate human hepatocyte-specific gene expression profiles in mice, quantitative real-time-PCR was applied. Human albumin and alpha-1-antitrypsin concentrations in mouse serum were quantified to assess the levels of human chimerism. Precultured human hepatocytes reestablished their physiological liver tissue architecture and function upon transplantation in mice. Positive immunohistochemical labeling of the proliferating cell nuclear antigen revealed that human hepatocytes retained their in vivo proliferation capacity. Expression profiles of human genes analyzed in chimeric mouse livers resembled levels determined in native human tissue. Extensive vascularization of human cell clusters was detected by demonstration of von Willebrand factor activity. To model gene therapy approaches, lentiviral transduction was performed ex vivo and fluorescent microscopic imaging revealed maintenance of RGB marking in vivo. Altogether, this is the first report demonstrating that cultured and retroviral transduced human hepatocyte spheroids are able to engraft and maintain their regenerative potential in vivo.

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“…In the liver the AAV-induced immune response has been blunted by inhibition of expression of toll-like receptor 9 [44]. A big advantage of AAV vectors is the that they can target dividing and nondividing cells with a high efficiency [45]. More recently gene therapy using adeno associated viral vectors (AAV) has shown promising results in hemophilia B patients.…”

Section: Transducing Atp7b To Correct the Wd Phenotypementioning

confidence: 99%

“…As noted above, here the liver may be advantaged compared to other organs due to some already available vectors that target hepatocytes. However there can be a shortened viability of the virus due to neutralizing antibodies that have been pre-formed when the individual has been previously exposed to the wild type virus [45]. This can theoretically result in a sub-therapeutic dose of the vector being administered to treat the disease.…”

Section: Limitations To Use Of Viral Vectors For Gene Therapymentioning

confidence: 99%

Prospects for Cure in Wilson Disease

Camarata¹,

To²,

Schilsky³

2018

obm genet

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Wilson Disease is a monogenetic disorder of copper metabolism affecting the ATP7B gene. Treatment is lifelong and focuses on removal of copper to arrest disease progression and improve the clinical manifestations of copper toxicity. Currently the only cure is liver transplantation, however, lifelong monitoring and immunosuppressive medications are still needed afterwards. The possibility of introducing functional ATP7B gene through gene therapy provides an exciting potential option for achieving a more permanent cure without the need for additional therapy and medical monitoring.

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Liver‐targeted gene therapy: Approaches and challenges

Cited by 29 publications

References 203 publications

Hereditary Angioedema as a Metabolic Liver Disorder: Novel Therapeutic Options and Prospects for Cure

Hereditary Angioedema as a Metabolic Liver Disorder: Novel Therapeutic Options and Prospects for Cure

Primary Human Hepatocytes Repopulate Livers of Mice AfterIn VitroCulturing and Lentiviral-Mediated Gene Transfer

Prospects for Cure in Wilson Disease

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