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

Abstract

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.

Neuroinflammation and progressive myoclonus epilepsies: from basic science to therapeutic opportunities

“…This adds evidence to the feasibility of ASO therapies and highlights the importance of personalised treatment of ULD patients (Ref. 54). As one of the pathological determinants of ULD is the presence of oxidative stress (see above), some reports have recently indicated that ULD patients treated with high doses of N-acetyl-cysteine showed marked improvement in seizures, ataxia and blockade of symptoms progression (reviewed in Ref.…”

Emerging treatments for progressive myoclonus epilepsies

“…As expected, patient's treated fibroblast expressed only the normal spliced transcript, with normal CSTB protein levels. Moreover, the recovery was LNA dose-specific, without evidences of increased cell death [75].…”

New Trends and Most Promising Therapeutic Strategies for Epilepsy Treatment

“…Hence, the use of ASOs in clinical practice requires overcoming problems related to the design, bioavailability, and targeted delivery ( 78 ). To date, few in-human studies have been conducted that primarily addressed invariably progressive and fatal diseases such as PMEs ( 79 , 80 ). The authors proved the feasibility of the ASOs-based approach by specifically customizing oligonucleotides over the genetic defect of patients.…”