Splice-correcting oligonucleotides restore BTK function in X-linked agammaglobulinemia model

Bestas, Burcu; Moreno, Pedro M. D.; Blomberg, K. Emelie M.; Mohammad, Dara K.; Saleh, Amer F.; Sütlü, Tolga; Nordin, Joel Z.; Guterstam, Peter; Gustafsson, Manuela O.; Kharazi, Shabnam; Piątosa, Barbara; Roberts, Thomas C.; Behlke, Mark A.; Wood, Matthew; Gait, Michael J.; Lundin, Karin E.; Andaloussi, Samir El; Månsson, Robert; Berglöf, Anna; Wengel, Jesper; Smith, C. I. Edvard

doi:10.1172/jci76175

Cited by 39 publications

(41 citation statements)

References 77 publications

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“…Thus, we recently demonstrated that both locked nucleic acid (LNA) and phosphorodiamidate morpholino (PMO) oligomers correct defects in an X-linked agammaglobulinemia model [46]. Since LNA is also readily taken up in the liver, the same advantage in selectivity would apply [47].…”

Section: Discussionmentioning

confidence: 99%

RNA therapeutics inactivate PCSK9 by inducing a unique intracellular retention form

Rocha

Wiklander

Larsson

et al. 2015

Journal of Molecular and Cellular Cardiology

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Hypercholesterolemia is a medical condition often characterized by high levels of low-density lipoprotein cholesterol (LDL-C) in the blood. Despite the available therapies, not all patients show sufficient responses, especially those with very high levels of LDL-C or those with familial hypercholesterolemia. Regulation of plasma cholesterol levels is very complex and several proteins are involved (both receptors and enzymes). From these, the proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising pharmacologic target. The objective of this work is to develop a new approach to inactivate PCSK9 by splice-switching oligonucleotides (SSOs), converting the normal splice form to a natural, less abundant and inactive, splice variant. For this purpose, a new RNA therapeutic approach for hypercholesterolemia based on SSOs was developed for modulation of the splice pattern of human PCSK9 pre-mRNA. Our results show an increase of the selected splice form at both the mRNA and protein level when compared to non-treated Huh7 and HepG2 cell lines, with concomitant increase of the protein level of the low-density lipoprotein receptor (LDLR) demonstrating the specificity and efficiency of the system. In vivo, full conversion to the splice form was achieved in a reporter system when mice were treated with the specific oligonucleotide, thus further indicating the therapeutic potential of the approach. In conclusion, PCSK9 activity can be modulated by splice-switching through an RNA therapeutic approach. The tuning of the natural active to non-active isoforms represents a physiological way of regulating the cholesterol metabolism, by controlling the amount of LDL receptor available and the rate of LDL-cholesterol clearance.

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Section: Discussionmentioning

confidence: 99%

RNA therapeutics inactivate PCSK9 by inducing a unique intracellular retention form

Rocha

Wiklander

Larsson

et al. 2015

Journal of Molecular and Cellular Cardiology

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“…This paves the way for the application of this technology in other genetic diseases such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). B-PMO was also successfully used to restore the expression of Bruton´s tyrosine kinase (BTK) by splice switching in a mouse model of X-linked agammaglobulinemia [59]. As antivirals, RXR-based CPP-PMO, targeting the start of the coding region of Human respiratory syncytial virus (RSV) was shown to block viral replication in vivo both in mouse and porcine models of the virus [60,61].…”

Section: Covalent Conjugation Approach For Nucleic Acid Delivery Withmentioning

confidence: 99%

Peptides for nucleic acid delivery

Lehto

Ezzat

Wood

et al. 2016

Advanced Drug Delivery Reviews

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Nucleic acids and their synthetic oligonucleotide (ON) analogs are a group of gene therapeutic compounds which hold enormous clinical potential. Despite their undoubted potential, clinical translation of these molecules, however, has been largely held back by their limited bioavailability in the target tissues/cells. To overcome this, many different drug delivery systems have been devised. Among others, short delivery peptides, called cell-penetrating peptides (CPPs), have been demonstrated to allow for efficient delivery of nucleic acids and their ON analogs, in both cell culture and animal models. In this review, we provide brief overview of the latest advances in nucleic acid delivery with CPPs, covering the two main vectorization strategies, covalent conjugation and nanoparticle formation-based approach. In conclusion, CPP-based drug delivery systems have the capacity to overcome the hurdle of delivery and thus have the potential to facilitate the clinical translation of nucleic acid-based therapeutics.

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“…99 Because many XLA-associated mutations affect pre-mRNA splicing, attempts have also been made to model correction in a bacterial artificial chromosome (BAC)-transgenic mouse model using splice-correcting oligonucleotides with some success. 100 X-linked hyper-IgM syndrome (X-HIGM1) is a combined immunodeficiency characterized by defects in isotype switching from IgM to IgG, IgA, and IgE, as well as impaired lymphocyte and myeloid functions. X-HIGM1 is associated with mutations in the gene (TNFSF5) encoding CD40 ligand (CD40L), a member of the TNF superfamily, which is primarily expressed on activated T cells and binds the CD40 receptor on the surface of B cells and antigen-presenting cells to regulate B cell function and inflammatory responses.…”

Section: Preclinical Development Of Gene Therapy For Other Candidatementioning

confidence: 99%

Evolving Gene Therapy in Primary Immunodeficiency

Thrasher

Williams

2017

Molecular Therapy

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Splice-correcting oligonucleotides restore BTK function in X-linked agammaglobulinemia model

Cited by 39 publications

References 77 publications

RNA therapeutics inactivate PCSK9 by inducing a unique intracellular retention form

RNA therapeutics inactivate PCSK9 by inducing a unique intracellular retention form

Peptides for nucleic acid delivery

Evolving Gene Therapy in Primary Immunodeficiency

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