Gene therapies targeting the liver

Cozmescu, Andrei Claudiu; Counsell, John R.; Gissen, Paul

doi:10.1016/j.jhep.2020.08.003

Cited by 12 publications

(26 citation statements)

References 9 publications

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“…Anyway, these studies showed that long-term liver transduction using AAV is possible and have paved the way for the use of rAAVs in the treatment of IMLD. [9][10][11]66,67 The first IMLD experimentally treated with an AAV vector was FH via infusion of an AAV vector carrying very-low-density lipoprotein receptor (VLDLR) into the portal circulation of FH mice resulting in a 40% reduction in serum cholesterol and triglyceride. Importantly, the reduction was stable for the duration of the study.…”

Section: Vectors Based On Adeno-associated Virus (Aav)mentioning

confidence: 99%

“…Albeit using different AAV serotypes, promoters and delivery routes, in general, all studies showed long-term therapeutic efficacy in the absence of major safety issues. [9][10][11]66,67 J o u r n a l P r e -p r o o f…”

Section: Vectors Based On Adeno-associated Virus (Aav)mentioning

confidence: 99%

“…Anyway, these studies showed that long-term liver transduction using AAV is possible and have paved the way for the use of rAAVs in the treatment of IMLD. [9] , [10] , [11] , 66 , 67 …”

Section: Viral Vectorsmentioning

confidence: 99%

“…Thus, liver-directed gene therapy and gene editing strategies have emerged as promising alternatives to OLT for IMLD. [9][10][11] Furthermore, substrate reduction therapy (SRT) or metabolic pathway reprograming (MPR) are attractive strategies for several metabolic disorders associated with the accumulation of toxic metabolic products. 12,13 Taking advantage of small interfering RNA (siRNA) technology or target-specific gene editing with the goal J o u r n a l P r e -p r o o f of inhibiting key metabolic enzymes, new molecular-based approaches such as genetically based next-generation SRT or MPR are under development.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Novel vectors and approaches for gene therapy in liver diseases

Maestro

Weber²,

Zabaleta

et al. 2021

JHEP Reports

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Section: Vectors Based On Adeno-associated Virus (Aav)mentioning

confidence: 99%

Section: Vectors Based On Adeno-associated Virus (Aav)mentioning

confidence: 99%

“…Anyway, these studies showed that long-term liver transduction using AAV is possible and have paved the way for the use of rAAVs in the treatment of IMLD. [9] , [10] , [11] , 66 , 67 …”

Section: Viral Vectorsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Novel vectors and approaches for gene therapy in liver diseases

Maestro

Weber²,

Zabaleta

et al. 2021

JHEP Reports

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“…In recent years, in addition to conventional gene therapy based on gene supplementation using adeno‐associated viral vectors (AAVs), [ 3–5 ] two different therapeutic strategies have emerged as a new class of genetic medicine with great potential to treat inherited disorders: encapsulated therapeutic mRNA and gene editing. [ 4–8 ] Several clinical development milestones were achieved with these approaches in 2021.…”

Section: Introductionmentioning

confidence: 99%

mRNA and gene editing: Late breaking therapies in liver diseases

Zabaleta

Torella

Weber³

et al. 2022

Hepatology

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The efficient delivery of RNA molecules to restore the expression of a missing or inadequately functioning protein in a target cell and the intentional specific modification of the host genome using engineered nucleases represent therapeutic concepts that are revolutionizing modern medicine. The initiation of several clinical trials using these approaches to treat metabolic liver disorders as well as the recently reported remarkable results obtained by patients with transthyretin amyloidosis highlight the advances in this field and show the potential of these therapies to treat these diseases safely and efficaciously. These advances have been possible due, firstly, to significant improvements made in RNA chemistry that increase its stability and prevent activation of the innate immune response and, secondly, to the development of very efficient liver‐targeted RNA delivery systems. In parallel, the breakout of CRISPR/CRISPR‐associated 9–based technology in the gene editing field has marked a turning point in in vivo modification of the cellular genome with therapeutic purposes, which can be based on gene supplementation, correction, or silencing. In the coming years we are likely to witness the therapeutic potential of these two strategies both separately and in combination. In this review we summarize the preclinical data obtained in animal models treated with mRNA as a therapeutic agent and discuss the different gene editing strategies applied to the treatment of liver diseases, highlighting both their therapeutic efficacy as well as safety concerns.

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Carboxymethyl chitosan prolongs adenovirus‐mediated expression of IL‐10 and ameliorates hepatic fibrosis in a mouse model

Gou

Weng

Chen

et al. 2022

Bioengineering & Transla Med

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Effective and safe liver‐directed gene therapy has great promise in treating a broad range of liver diseases. While adenoviral (Ad) vectors have been widely used for efficacious in vivo gene delivery, their translational utilities are severely limited due to the short duration of transgene expression and solicitation of host immune response. Used as a promising polymeric vehicle for drug release and nucleic acid delivery, carboxymethyl chitosan (CMC) is biocompatible, biodegradable, anti‐microbial, inexpensive, and easy accessible. Here, by exploiting its biocompatibility, controlled release capability and anti‐inflammatory activity, we investigated whether CMC can overcome the shortcomings of Ad‐mediated gene delivery, hence improving the prospect of Ad applications in gene therapy. We demonstrated that in the presence of optimal concentrations of CMC, Ad‐mediated transgene expression lasted up to 50 days after subcutaneous injection, and at least 7 days after intrahepatic injection. Histologic evaluation and immunohistochemical analysis revealed that CMC effectively alleviated Ad‐induced host immune response. In our proof‐of‐principle experiment using the CCl4‐induced experimental mouse model of chronic liver damage, we demonstrated that repeated intrahepatic administrations of Ad‐IL10 mixed with CMC effectively mitigated the development of hepatic fibrosis. Collectively, these results indicate that CMC can improve the prospect of Ad‐mediated gene therapy by diminishing the host immune response while allowing readministration and sustained transgene expression.

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Gene therapies targeting the liver

Cited by 12 publications

References 9 publications

Novel vectors and approaches for gene therapy in liver diseases

Novel vectors and approaches for gene therapy in liver diseases

mRNA and gene editing: Late breaking therapies in liver diseases

Carboxymethyl chitosan prolongs adenovirus‐mediated expression of IL‐10 and ameliorates hepatic fibrosis in a mouse model

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