Targeted Gene Delivery: Importance of Administration Routes

Fumoto, Shintaro; Kawakami, Shigeru; Hashida, Mitsuru; Nishida, Koyo

doi:10.5772/54741

Cited by 16 publications

(15 citation statements)

References 175 publications

(164 reference statements)

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“…Conversely an intravenous injection allows a broad distribution balanced by non-specificity. Injections in the hepatic artery or the portal vein improve the selectivity but require cannulation with its associated risks (Fumoto et al 2013). Peripheral intravenous delivery provides similar transduction compared to intrahepatic or intraportal routes for AAV vectors (Sarkar et al 2006;Nathwani et al 2007); ii) higher doses of vector achieve greater transduction, but may generate more severe immune responses (Raper et al 2003;Mingozzi and High 2013).…”

Section: Parameters Of Vector Deliverymentioning

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: Parameters Of Vector Deliverymentioning

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

show abstract

“…16 Immune responses to vectors or transgenes represent a serious concern during systemic treatment, particularly when a nonspecific promoter, such as the CMV promoter, is used. Although we observed hepatocyte transduction in the current study, an immune response was not observed in the liver.…”

Section: Risks Of Systemic Gene Therapymentioning

confidence: 99%

Benefits of Neuronal Preferential Systemic Gene Therapy for Neurotransmitter Deficiency

et al. 2015

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Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive disease that impairs synthesis of dopamine and serotonin. Children with AADC deficiency exhibit severe motor, behavioral, and autonomic dysfunctions. We previously generated an IVS6+4A>T knock-in mouse model of AADC deficiency (Ddc(KI) mice) and showed that gene therapy at the neonatal stage can rescue this phenotype. In the present study, we extended this treatment to systemic therapy on young mice. After intraperitoneal injection of AADC viral vectors into 7-day-old Ddc(KI) mice, the treated mice exhibited improvements in weight gain, survival, motor function, autonomic function, and behavior. The yfAAV9/3-Syn-I-mAADC-treated mice showed greater neuronal transduction and higher brain dopamine levels than AAV9-CMV-hAADC-treated mice, whereas AAV9-CMV-hAADC-treated mice exhibited hyperactivity. Therefore, neurotransmitter-deficient animals can be rescued at a young age using systemic gene therapy, although a vector for preferential neuronal expression may be necessary to avoid hyperactivity caused by this treatment.

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“…The route of vector administration often determines the pharmacokinetics of the vector, and the choice of the route of administration plays an important role in vector development [ 228 ]. When administered intravenously, naked plasmid DNA undergoes degradation in the blood and transfers to non-parenchymal cells of the liver, and rarely results in gene expression [ 229 ].…”

Section: Rational Designmentioning

confidence: 99%

Understanding In Vivo Fate of Nucleic Acid and Gene Medicines for the Rational Design of Drugs

et al. 2021

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Nucleic acid and genetic medicines are increasingly being developed, owing to their potential to treat a variety of intractable diseases. A comprehensive understanding of the in vivo fate of these agents is vital for the rational design, discovery, and fast and straightforward development of the drugs. In case of intravascular administration of nucleic acids and genetic medicines, interaction with blood components, especially plasma proteins, is unavoidable. However, on the flip side, such interaction can be utilized wisely to manipulate the pharmacokinetics of the agents. In other words, plasma protein binding can help in suppressing the elimination of nucleic acids from the blood stream and deliver naked oligonucleotides and gene carriers into target cells. To control the distribution of these agents in the body, the ligand conjugation method is widely applied. It is also important to understand intracellular localization. In this context, endocytosis pathway, endosomal escape, and nuclear transport should be considered and discussed. Encapsulated nucleic acids and genes must be dissociated from the carriers to exert their activity. In this review, we summarize the in vivo fate of nucleic acid and gene medicines and provide guidelines for the rational design of drugs.

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Targeted Gene Delivery: Importance of Administration Routes

Cited by 16 publications

References 175 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

Benefits of Neuronal Preferential Systemic Gene Therapy for Neurotransmitter Deficiency

Understanding In Vivo Fate of Nucleic Acid and Gene Medicines for the Rational Design of Drugs

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