Splicing modulation therapy in the treatment of genetic diseases

Virginia Arechavala-Gomeza,¹ Bernard Khoo,² Annemieke Aartsma-Rus<sup>3

1</sup>Neuromuscular Disorders Group, BioCruces Health Research Institute, Barakaldo, Bizkaia, Spain; ²Endocrinology, Division of Medicine, University College London, London, UK; ³Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands

All authors contributed equally to this manuscript

Abstract: Antisense-mediated splicing modulation is a tool that can be exploited in several ways to provide a potential therapy for rare genetic diseases. This approach is currently being tested in clinical trials for Duchenne muscular dystrophy and spinal muscular atrophy. The present review outlines the versatility of the approach to correct cryptic splicing, modulate alternative splicing, restore the open reading frame, and induce protein knockdown, providing examples of each. Finally, we outline a possible path forward toward the clinical application of this approach for a wide variety of inherited rare diseases.

Keywords: splicing, therapy, antisense oligonucleotides, cryptic splicing, alternative splicing

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