Safe and Efficient Silencing with a Pol II, but Not a Pol lII, Promoter Expressing an Artificial miRNA Targeting Human Huntingtin

Pfister, Edith L.; Chase, Kathryn; Sun, Huaming; Kennington, Lori; Conroy, Faith; Johnson, Emily; Miller, Rachael; Borel, Florie; Aronin, Neil; Mueller, Christian

doi:10.1016/j.omtn.2017.04.011

Cited by 26 publications

(30 citation statements)

References 37 publications

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“…Similarly, shRNA expression that is driven by the strong U6 promoter is associated with toxicity owing to saturation of the endogenous microRNA (miRNA) biogenesis pathway 137 , which can be ameliorated by using a weaker H1 promoter. Alternatively, new platforms based on the expression of artificial microrNAs (amiRs) by Pol II promoters provide a more versatile solution for RNA interference (RNAi) 138–142 .…”

Section: Vector Designmentioning

confidence: 99%

Adeno-associated virus vector as a platform for gene therapy delivery

Wang

Tai

Gao

2019

Nat Rev Drug Discov

1,681

1,347

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Adeno-associated virus (AAV) vectors are the leading platform for gene delivery for the treatment of a variety of human diseases. Recent advances in developing clinically desirable AAV capsids, optimizing genome designs and harnessing revolutionary biotechnologies have contributed substantially to the growth of the gene therapy field. Preclinical and clinical successes in AAVmediated gene replacement, gene silencing and gene editing have helped AAV gain popularity as the ideal therapeutic vector, with two AAV-based therapeutics gaining regulatory approval in Europe or the United States. Continued study of AAV biology and increased understanding of the associated therapeutic challenges and limitations will build the foundation for future clinical success.

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Section: Vector Designmentioning

confidence: 99%

Adeno-associated virus vector as a platform for gene therapy delivery

Wang

Tai

Gao

2019

Nat Rev Drug Discov

1,681

1,347

View full text Add to dashboard Cite

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“…However, evidence of side effects prompted new studies using artificial miRNAs for gene silencing. This approach improved the therapeutic effect in the absence of any detectable detrimental effect up to 9 months after treatment (Boudreau et al, 2009; Drouet et al, 2009), and has been employed in many subsequent preclinical studies not only on HD (Miniarikova et al, 2016; Pfister et al, 2017; Pfister et al, 2018) but also on superoxide dismutase 1-linked amyotrophic lateral sclerosis (Foust et al, 2013; Borel et al, 2018).…”

Section: Regulation Of Gene Expressionmentioning

confidence: 99%

Gene Therapy Tools for Brain Diseases

et al. 2019

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Neurological disorders affecting the central nervous system (CNS) are still incompletely understood. Many of these disorders lack a cure and are seeking more specific and effective treatments. In fact, in spite of advancements in knowledge of the CNS function, the treatment of neurological disorders with modern medical and surgical approaches remains difficult for many reasons, such as the complexity of the CNS, the limited regenerative capacity of the tissue, and the difficulty in conveying conventional drugs to the organ due to the blood–brain barrier. Gene therapy, allowing the delivery of genetic materials that encodes potential therapeutic molecules, represents an attractive option. Gene therapy can result in a stable or inducible expression of transgene(s), and can allow a nearly specific expression in target cells. In this review, we will discuss the most commonly used tools for the delivery of genetic material in the CNS, including viral and non-viral vectors; their main applications; their advantages and disadvantages. We will discuss mechanisms of genetic regulation through cell-specific and inducible promoters, which allow to express gene products only in specific cells and to control their transcriptional activation. In addition, we will describe the applications to CNS diseases of post-transcriptional regulation systems (RNA interference); of systems allowing spatial or temporal control of expression [optogenetics and Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)]; and of gene editing technologies (CRISPR/Cas9, Zinc finger proteins). Particular attention will be reserved to viral vectors derived from herpes simplex type 1, a potential tool for the delivery and expression of multiple transgene cassettes simultaneously.

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“…AAV-mediated delivery of therapeutic ASOs may represent a means to produce sustained drug delivery at a more reasonable cost. AAV delivery of shRNA and miRNA has been successfully used to decrease in vivo expression of DNM2 (myotubular myopathy) [ 78 ] and mutant huntingtin [ 79 ] in mice. SOD1 was successfully targeted for reduction with an AAV-delivered exon skipping ASO in a murine model of amyotrophic lateral sclerosis [ 80 ].…”

Section: Gene Therapy: Brain Tropic Adenoviral Vectorsmentioning

confidence: 99%

Emerging Technologies for Delivery of Biotherapeutics and Gene Therapy Across the Blood–Brain Barrier

2018

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Antibody, immuno- and gene therapies developed for neurological indications face a delivery challenge posed by various anatomical and physiological barriers within the central nervous system (CNS); most notably, the blood–brain barrier (BBB). Emerging delivery technologies for biotherapeutics have focused on trans-cellular pathways across the BBB utilizing receptor-mediated transcytosis (RMT). ‘Traditionally’ targeted RMT receptors, transferrin receptor (TfR) and insulin receptor (IR), are ubiquitously expressed and pose numerous translational challenges during development, including species differences and safety risks. Recent advances in antibody engineering technologies and discoveries of RMT targets and BBB-crossing antibodies that are more BBB-selective have combined to create a new preclinical pipeline of BBB-crossing biotherapeutics with improved efficacy and safety. Novel BBB-selective RMT targets and carrier antibodies have exposed additional opportunities for re-targeting gene delivery vectors or nanocarriers for more efficient brain delivery. Emergence and refinement of core technologies of genetic engineering and editing as well as biomanufacturing of viral vectors and cell-derived products have de-risked the path to the development of systemic gene therapy approaches for the CNS. In particular, brain-tropic viral vectors and extracellular vesicles have recently expanded the repertoire of brain delivery strategies for biotherapeutics. Whereas protein biotherapeutics and bispecific antibodies enabled for BBB transcytosis are rapidly heading towards clinical trials, systemic gene therapy approaches for CNS will likely remain in research phase for the foreseeable future. The promise and limitations of these emerging cross-BBB delivery technologies are further discussed in this article.

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Safe and Efficient Silencing with a Pol II, but Not a Pol lII, Promoter Expressing an Artificial miRNA Targeting Human Huntingtin

Cited by 26 publications

References 37 publications

Adeno-associated virus vector as a platform for gene therapy delivery

Adeno-associated virus vector as a platform for gene therapy delivery

Gene Therapy Tools for Brain Diseases

Emerging Technologies for Delivery of Biotherapeutics and Gene Therapy Across the Blood–Brain Barrier

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