Correction of a Splicing Mutation Affecting an Unverricht-Lundborg Disease Patient by Antisense Therapy

Published on Sep 11, 2018in Genes3.331
· DOI :10.3390/genes9090455
Liliana Matos7
Estimated H-index: 7
Ana Joana Duarte3
Estimated H-index: 3
+ 3 AuthorsSandra Alves17
Estimated H-index: 17
Unverricht-Lundborg disease (ULD) is a common form of progressive myoclonic epilepsy caused by mutations in the cystatin B gene (CSTB) that encodes an inhibitor of several lysosomal cathepsins. Presently, only pharmacological treatment and psychosocial support are available for ULD patients. To overcome the pathogenic effect of the ULD splicing mutation c.66G>A (exon 1), we investigated whether an antisense oligonucleotide therapeutic strategy could correct the defect in patient cells. A specific locked nucleic acid (LNA) antisense oligonucleotide was designed to block a cryptic 5′ss in intron 1. Overall, this approach allowed the restoration of the normal splicing pattern. Furthermore, the recovery was both sequence and dose-specific. In general, this work provides a proof of principle on the correction of a CSTB gene defect causing ULD through a mutation-specific antisense therapy. It adds evidence to the feasibility of this approach, joining the many studies that are paving the way for translating antisense technology into the clinical practice. The insights detailed herein make mutation-based therapy a clear candidate for personalized treatment of ULD patients, encouraging similar investigations into other genetic diseases.
  • References (41)
  • Citations (2)
📖 Papers frequently viewed together
7 Citations
6 Citations
1 Author (Niccolò Bacchi)
78% of Scinapse members use related papers. After signing in, all features are FREE.
Two decades after antisense oligonucleotides (ASOs) were initially identified as agents capable of modulating RNA processing and protein expression, the first antisense oligonucleotide (ASO) therapies have now been approved for the treatment of neurological disease. Here, Rinaldi and Wood discuss our current understanding of ASO pharmacology, and the future prospects for ASO-mediated treatment of neurological disease
59 CitationsSource
#1Kathleen M. Schoch (WashU: Washington University in St. Louis)H-Index: 6
#2Timothy M. Miller (WashU: Washington University in St. Louis)H-Index: 45
Multiple neurodegenerative diseases are characterized by single-protein dysfunction and aggregation. Treatment strategies for these diseases have often targeted downstream pathways to ameliorate consequences of protein dysfunction; however, targeting the source of that dysfunction, the affected protein itself, seems most judicious to achieve a highly effective therapeutic outcome. Antisense oligonucleotides (ASOs) are small sequences of DNA able to target RNA transcripts, resulting in reduced or...
52 CitationsSource
#1Marc Suñé-PouH-Index: 3
Last. Carlos SuñéH-Index: 19
view all 8 authors...
The tightly regulated process of precursor messenger RNA (pre-mRNA) alternative splicing (AS) is a key mechanism in the regulation of gene expression. Defects in this regulatory process affect cellular functions and are the cause of many human diseases. Recent advances in our understanding of splicing regulation have led to the development of new tools for manipulating splicing for therapeutic purposes. Several tools, including antisense oligonucleotides and trans-splicing, have been developed t...
12 CitationsSource
#1Giovanni Assenza (Sapienza University of Rome)H-Index: 17
#2A. Benvenga (Sapienza University of Rome)H-Index: 5
Last. Vincenzo Di Lazzaro (Sapienza University of Rome)H-Index: 62
view all 8 authors...
Summary Unverricht-Lundborg disease or progressive myoclonic epilepsy type 1 (EPM1) is an autosomal recessive disease caused by mutation of the cystatin B gene (CSTB), located on chromosome 21q22.3. The most common mutation is an expansion of unstable dodecamer repetition (CCCCGCCCCGCG), whereas other types of mutations are rare. Among these, heterozygous compound mutations are described to induce a more severe phenotype than that of homozygous dodecameric repetition. We report two siblings affe...
5 CitationsSource
105 CitationsSource
50 CitationsSource
#1Arielle CrespelH-Index: 21
#2Edoardo FerlazzoH-Index: 22
Last. Annika Vaarmann (UT: University of Tartu)H-Index: 9
view all 11 authors...
We first review the clinical presentation and current therapeutic approaches available for treating Unverricht-Lundborg disease (ULD), a progressive myoclonus epilepsy. Next, we describe the identification of disease causing mutations in the gene encoding cystatin B (CSTB). A Cstb-deficient mouse model, which recapitulates the key features of ULD including myoclonic seizures, ataxia, and neuronal loss, was generated to shed light on the mechanisms contributing to disease pathophysiology. Studies...
15 CitationsSource
#1Rudolph L. Juliano (UNC: University of North Carolina at Chapel Hill)H-Index: 38
The oligonucleotide therapeutics field has seen remarkable progress over the last few years with the approval of the first antisense drug and with promising developments in late stage clinical trials using siRNA or splice switching oligonucleotides. However, effective delivery of oligonucleotides to their intracellular sites of action remains a major issue. This review will describe the biological basis of oligonucleotide delivery including the nature of various tissue barriers and the mechanism...
211 CitationsSource
#1John M. LeeH-Index: 17
#2Chika NobumoriH-Index: 12
Last. Loren G. FongH-Index: 46
view all 11 authors...
The alternatively spliced products of LMNA, lamin C and prelamin A (the precursor to lamin A), are produced in similar amounts in most tissues and have largely redundant functions. This redundancy suggests that diseases, such as Hutchinson-Gilford progeria syndrome (HGPS), that are caused by prelamin A–specific mutations could be treated by shifting the output of LMNA more toward lamin C. Here, we investigated mechanisms that regulate LMNA mRNA alternative splicing and assessed the feasibility o...
33 CitationsSource
#1Claudia A. Chiriboga (Columbia University)H-Index: 20
#2Kathryn J. Swoboda (UofU: University of Utah)H-Index: 47
Last. Kathie M. Bishop (Isis Pharmaceuticals)H-Index: 16
view all 9 authors...
Objective: To examine safety, tolerability, pharmacokinetics, and preliminary clinical efficacy of intrathecal nusinersen (previously ISIS-SMN Rx ), an antisense oligonucleotide designed to alter splicing of SMN2 mRNA, in patients with childhood spinal muscular atrophy (SMA). Methods: Nusinersen was delivered by intrathecal injection to medically stable patients with type 2 and type 3 SMA aged 2–14 years in an open-label phase 1 study and its long-term extension. Four ascending single-dose level...
237 CitationsSource
Cited By2
Last. Pasquale Striano (UniGe: University of Genoa)H-Index: 40
view all 9 authors...
AbstractIntroduction: Progressive myoclonus epilepsies (PMEs) are a group of neurodegenerative diseases, invariably leading to severe disability or fatal outcome in a few years or decades. Nowadays...
#1Alessandro Orsini (UniPi: University of Pisa)H-Index: 5
#2Angelo Valetto (UniPi: University of Pisa)H-Index: 14
Last. Pasquale StrianoH-Index: 40
view all 10 authors...
Abstract Progressive Myoclonus Epilepsies (PMEs) are a group of uncommon clinically and genetically heterogeneous disorders characterised by myoclonus, generalized epilepsy, and neurological deterioration, including dementia and ataxia. PMEs may have infancy, childhood, juvenile or adult onset, but usually present in late childhood or adolescence, at variance from epileptic encephalopathies, which start with polymorphic seizures in early infancy. Neurophysiologic recordings are suited to describ...
4 CitationsSource
In order to delineate a better approach to functional studies, we have selected 23 missense mutations distributed in different domains of two lysosomal enzymes, to be studied by in silico analysis. In silico analysis of mutations relies on computational modeling to predict their effects. Various computational platforms are currently available to check the probable causality of mutations encountered in patients at the protein and at the RNA levels. In this work we used four different platforms fr...