RNA Trans-Splicing Modulation via Antisense Molecule Interference

Liemberger, Bernadette; Hofbauer, Josefina Piñón; Wally, Verena; Arzt, Claudia; Hainzl, Stefan; Köcher, Thomas; Murauer, Eva M.; Bauer, Johann; Reichelt, Julia; Koller, Ulrich

doi:10.3390/ijms19030762

Cited by 16 publications

(8 citation statements)

References 38 publications

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“…One possibility was suggested from previous studies showing that splicing events can be experimentally induced in vivo by exposing primary transcripts to antisense RNAs that pair with known splice sites in the primary transcript [71,72]. Indeed, there is growing evidence that de novo expression of antisense RNAs may play a significant role in the induction of alternate-splice variants [73] and that this may be a significant factor in cancer onset/ progression. Our results are generally consistent with this hypothesis and suggest that allele-specific alternative splicing, possibly mediated by changes in the expression of antisense RNAs, may play a significant role in the induction of changes in ASE patterns in cancer.…”

Section: Discussionmentioning

confidence: 99%

Tumor suppressor genes and allele-specific expression: mechanisms and significance

et al. 2020

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Recent findings indicate that allele-specific expression (ASE) at specific cancer driver gene loci may be of importance in onset/progression of the disease. Of particular interest are loss-of-function (LOF) of tumor suppressor gene (TSGs) alleles. While LOF tumor suppressor mutations are typically considered to be recessive, if these mutant alleles can be significantly differentially expressed relative to wild-type alleles in heterozygotes, the clinical consequences could be significant.LOF TSG alleles are shown to be segregating at high frequencies in world-wide populations of normal/healthy individuals. Matched sets of normal and tumor tissues isolated from 233 cancer patients representing four diverse tumor types demonstrate functionally important changes in patterns of ASE in individuals heterozygous for LOF TSG alleles associated with cancer onset/progression. While a variety of molecular mechanisms were identified as potentially contributing to changes in ASE patterns in cancer, changes in DNA copy number and allele-specific alternative splicing possibly mediated by antisense RNA emerged as predominant factors.In conclusion, LOF TSGs are segregating in human populations at significant frequencies indicating that many otherwise healthy individuals are at elevated risk of developing cancer. Changes in ASE between normal and cancer tissues indicates that LOF TSG alleles may contribute to cancer onset/progression even when heterozygous with wild-type functional alleles.

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Section: Discussionmentioning

confidence: 99%

Tumor suppressor genes and allele-specific expression: mechanisms and significance

et al. 2020

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“…This approach has been applied to accurately restore gene function in a variety of human genetic diseases, including hemophilia A [60], muscular dystrophy [61,62] or Alzheimer's disease [63]. In EB, SMaRT-mediated RNA editing was first achieved for the PLEC gene [12], but has more recently, been used to correct the EB-associated genes KRT14 [10,11,13] and COL7A1 [37][38][39][40] in vitro and in pre-clinical animal models. However, while these studies indicated a potential clinical applicability of SMaRT technology in gene therapy for EB, the efficiency of this RNA-based method needs to be significantly improved if it is to move forward towards clinical translation.…”

Section: Rna-based Therapies For Epidermolysis Bullosamentioning

confidence: 99%

Therapy Development for Epidermolysis Bullosa

Hofbauer¹,

Wally²,

Guttmann‐Gruber³

et al. 2021

Rare Diseases - Diagnostic and Therapeutic Odyssey

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Although rare genodermatoses such as Epidermolysis bullosa have received more attention over the last years, no approved treatment options targeting causal mutations are currently available. Still, such diseases can be devastating, in some cases even associated with life-threatening secondary manifestations. Therefore, developing treatments that target disease-associated complications along with causal therapies remains the focus of current research efforts, in order to increase patient’s quality of life and potentially their life expectancy. Epidermolysis bullosa is a genodermatosis that is caused by mutations in either one of 16 genes, predominantly encoding structural components of the skin and mucosal epithelia that are crucial to give these barrier organs physical and mechanical resilience to stress. The genetic heterogeneity of the disease is recapitulated in the high variability of phenotypic expressivity observed, ranging from minor and localized blistering to generalized erosions and wound chronification, rendering certain subtypes a systemic disease that is complicated by a plethora of secondary manifestations. During the last decades, several studies have focused on developing treatments for EB patients and significant progress has been made, as reflected by numerous publications, patents, and registered trials available. Overall, strategies range from causal to symptom-relieving approaches, and include gene, RNA and cell therapies, as well as drug developments based on biologics and small molecules. In this chapter, we highlight the most recent and promising approaches that are currently being investigated in order to provide effective treatments for patients with epidermolysis bullosa in the future.

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“…Within COL7A1, exons 79, 73 and 80 are dispensable and can, in the presence of specifically designed antisense oligonucleotides (ASOs), be skipped during pre‐mRNA splicing . Furthermore, ASOs can be employed to modulate and improve SMaRT efficiency . With approximately 21 nucleotides in length, ASOs are relatively small and can be chemically modified to increase their stability.…”

Section: From Replacement Gene Therapy To Precision Medicinementioning

confidence: 99%

Epidermolysis bullosa: Advances in research and treatment

Prodinger

Reichelt

Bauer

et al. 2019

Experimental Dermatology

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Epidermolysis bullosa (EB) is the umbrella term for a group of rare inherited skin fragility disorders caused by mutations in at least 20 different genes. There is no cure for any of the subtypes of EB resulting from different mutations, and current therapy only focuses on the management of wounds and pain. Novel effective therapeutic approaches are therefore urgently required. Strategies include gene‐, protein‐ and cell‐based therapies. This review discusses molecular procedures currently under investigation at the EB House Austria, a designated Centre of Expertise implemented in the European Reference Network for Rare and Undiagnosed Skin Diseases. Current clinical research activities at the EB House Austria include newly developed candidate substances that have emerged out of our translational research initiatives as well as already commercially available medications that are applied in off‐licensed indications. Squamous cell carcinoma is the major cause of death in severe forms of EB. We are evaluating immunotherapy using an anti‐PD1 monoclonal antibody as a palliative treatment option for locally advanced or metastatic squamous cell carcinoma of the skin unresponsive to previous systemic therapy. In addition, we are evaluating topical calcipotriol and topical diacerein as potential agents to improve the healing of skin wounds in EBS patients. Finally, the review will highlight the recent advancements of gene therapy development for EB.

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RNA Trans-Splicing Modulation via Antisense Molecule Interference

Cited by 16 publications

References 38 publications

Tumor suppressor genes and allele-specific expression: mechanisms and significance

Tumor suppressor genes and allele-specific expression: mechanisms and significance

Therapy Development for Epidermolysis Bullosa

Epidermolysis bullosa: Advances in research and treatment

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