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

Baruteau, Julien; Waddington, Simon N.; Alexander, Ian E.; Gissen, Paul

doi:10.1007/s10545-017-0053-3

Cited by 89 publications

(105 citation statements)

References 236 publications

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“…[61][62][63][64] According to recent surveys, liver diseases account for 2 million deaths annually. 65) Most liver diseases are considered incurable with only palliative treatment available, while the others have limited therapeutic approaches. Gene therapy has resuscitated the hope of providing effective treatments for these diseases.…”

Section: Lnps For Gene Delivery To Hepatocytesmentioning

confidence: 99%

Lipid Nanoparticles for Cell-Specific <i>in Vivo</i> Targeted Delivery of Nucleic Acids

Khalil

Younis

Kimura

et al. 2020

Biological & Pharmaceutical Bulletin

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The last few years have witnessed a great advance in the development of nonviral systems for in vivo targeted delivery of nucleic acids. Lipid nanoparticles (LNPs) are the most promising carriers for producing clinically approved products in the future. Compared with other systems used for nonviral gene delivery, LNPs provide several advantages including higher stability, low toxicity, and greater efficiency. Additionally, systems based on LNPs can be modified with ligands and devices for controlled biodistribution and internalization into specific cells. Efforts are ongoing to improve the efficiency of lipid-based gene vectors. These efforts depend on the appropriate design of nanocarriers as well as the development of new lipids with improved gene delivery ability. Several ionizable lipids have recently been developed and have shown dramatically improved efficiency. However, enhancing the ability of nanocarriers to target specific cells in the body remains the most difficult challenge. Systemically administered LNPs can access organs in which the capillaries are characterized by the presence of fenestrations, such as the liver and spleen. The liver has received the most attention to date, although targeted delivery to the spleen has recently emerged as a promising tool for modulating the immune system. In this review, we discuss recent advances in the use of LNPs for cellspecific targeted delivery of nucleic acids. We focus mainly on targeting liver hepatocytes and spleen immune cells as excellent targets for gene therapy. We also discuss the potential of endothelial cells as an alternate approach for targeting organs with a continuous endothelium.

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Section: Lnps For Gene Delivery To Hepatocytesmentioning

confidence: 99%

Lipid Nanoparticles for Cell-Specific <i>in Vivo</i> Targeted Delivery of Nucleic Acids

Khalil

Younis

Kimura

et al. 2020

Biological & Pharmaceutical Bulletin

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“…Adeno-associated virus (AAV) vector mediated gene therapy has achieved promising results in recent clinical trials in liver 1 and neurodegenerative 2 inherited diseases, and led to the market approval of the first gene therapy product in the western world to treat lipoprotein lipase deficiency 3 . These successes underpin the current interest in this technology as illustrated by the rapidly expanding number of gene therapy based clinical trials 4 .…”

Section: Main Textmentioning

confidence: 99%

Argininosuccinic aciduria fosters neuronal nitrosative stress reversed by Asl gene transfer

Baruteau

Perocheau

Hanley

et al. 2018

Preprint

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Argininosuccinate lyase (ASL) belongs to the liver-based urea cycle detoxifying ammonia, and the citrulline-nitric oxide cycle synthesising nitric oxide (NO). ASL-deficient patients present argininosuccinic aciduria characterised by hyperammonaemia and a multi-organ disease with neurocognitive impairment. Current therapeutic guidelines aim to control ammonaemia without considering the systemic NO imbalance. Here, we observed a neuronal disease with oxidative/nitrosative stress in ASL-deficient mouse brains. A single systemic injection of gene therapy mediated by an adeno-associated viral vector serotype 8 (AAV8) in adult or neonatal mice demonstrated the long-term correction of the urea cycle and the citrulline-NO cycle in the brain, respectively. The neuronal disease persisted if ammonaemia only was normalised but was dramatically reduced after correction of both ammonaemia and neuronal ASL activity. This was correlated with behavioural improvement and a decrease of the cortical cell death rate. Thus, the cerebral disease in argininosuccinic aciduria involves neuronal oxidative/nitrosative stress not mediated by hyperammonaemia, which is reversed by AAV gene transfer targeting the brain and the liver, acting on two different metabolic pathways via a single vector delivered systemically. This approach provides new hope for hepatocerebral metabolic diseases.

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“…Among the AAV serotypes, AAVs 2 and 8 have been shown to be the most efficient for liver-directed gene therapy. Pioneering liver-directed gene therapy trials for hemophilia B have achieved sustained clinical improvement after a single systemic injection of adeno-associated virus (AAV 2/8) derived vectors encoding the human factor IX cDNA [22].…”

Section: Gene Therapies For Cps1 Deficiencymentioning

confidence: 99%

Cell and Gene Therapy for Carbamoyl Phosphate Synthetase 1 Deficiency

Zhang¹,

Li²

2017

JPNC

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Carbamoyl phosphate synthetase 1 (CPS1) is the first and rate-limiting enzyme in the urea cycle. CPS1 deficiency is a devastating condition, which is clinically characterized by periodic episodes of life-threatening hyperammonemia. Currently, there is no cure for CPS1 deficiency except for liver transplantation, which is limited by a severe shortage of donors and significant risk of mortality and morbidity. Based on the progress to date, cell-based therapies-including hepatocyte or stem cell transplantation-and new approaches for gene therapy have become the promising curative treatments for CPS1 deficiency. This review outlines the current progress and challenges of cell and gene therapies for CPS1 deficiency.

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

Cited by 89 publications

References 236 publications

Lipid Nanoparticles for Cell-Specific <i>in Vivo</i> Targeted Delivery of Nucleic Acids

Lipid Nanoparticles for Cell-Specific <i>in Vivo</i> Targeted Delivery of Nucleic Acids

Argininosuccinic aciduria fosters neuronal nitrosative stress reversed by Asl gene transfer

Cell and Gene Therapy for Carbamoyl Phosphate Synthetase 1 Deficiency

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