KR-20260066185-A - PRE-MRNA SPLICE SWITCHING OR MODULATING OLIGONUCLEOTIDES COMPRISING BICYCLIC SCAFFOLD MOIETIES, WITH IMPROVED CHARACTERISTICS FOR THE TREATMENT OF GENETIC DISORDERS

Abstract

The present invention provides an antisense splice-switching oligonucleotide with improved features that enhance clinical applicability for treating,/or improving,/or preventing, or delaying neuromuscular disorders, e.g., DMD.

Inventors

• 반 되테콤 유디트 크리스티나 테오도라
• 드 비서 피터 크리스티안

Assignees

• 바이오마린 테크놀로지스 비.브이.

Dates

Publication Date

20260512

Application Date

20170705

Priority Date

20160705

Claims (1)

1. An object or method disclosed in the description or drawings of the invention.

Description

Pre-MRNA splice switching or modulating oligonucleotides comprising biotic scaffold moieties, with improved characteristics for the treatment of genetic disorders field The present invention relates to the field of antisense oligonucleotides, more specifically splice-switching oligonucleotides, for the treatment of genetic disorders, more specifically, neuromuscular disorders. The present invention relates particularly to the use of oligonucleotides with improved features that enhance clinical applicability, as further defined herein. Background of the present invention Antisense oligonucleotides (AONs) are currently in clinical (pre) development for a number of diseases and conditions, including cancer, inflammatory conditions, cardiovascular diseases, and neurodegenerative and neuromuscular disorders. Their mechanism of action targets various targets, such as RNaseH-mediated degradation of target RNA in the nucleus or cytoplasm, splice coordination (exon inclusion or skipping) in the nucleus, or translation inhibition by steric hindrance of ribosomal subunit binding in the cytoplasm. Splice-adjusting or splice-switching oligonucleotides (SSOs) were first described for the correction of abnormal splicing in human β-globin-free mRNA (Dominski and Kole, 1993), and are currently used in cystic fibrosis (CFTR gene, Friedman et al., 1999), breast cancer (BRCA1 gene, Uchikawa et al., 2007), prostate cancer (FOLH1 gene, Williams et al., 2006), inflammatory diseases (IL-5R alpha and MyD88 genes, Karras et al., 2001, Vickers et al., 2006), ocular albinism type 1 (OA1 gene, Vetrini et al., 2006), and ataxia telangiectasia (ATM gene, Du et al., 2007]), nevus-like basal cell carcinoma syndrome (PTCH1 gene, literature [Uchikawa et al., 2007]), methylmalonic acidemia (MUT gene, literature [Rincon et al., 2007]), premature birth (COX-2 gene, literature [Tyson-Capper et al., 2006]), atherosclerosis (APOB gene, literature [Khoo et al., 2007]), propionic acidemia (PCCA, PCCB genes, literature [Rincon et al., 2007]), leukemia (c-myc and WT1 genes, literature [Renshaw et al., 2004], [Giles et al., 1999]), dystrophic epidermolysis bullosa (COL7A1 gene, literature [Goto et al., 2006]), familial hypercholesterolemia (APOB gene, literature [Disterer et al., 2013]), laser-induced choroidal angiogenesis and corneal transplant rejection (KDR gene, literature [Uehara et al., 2013]), hypertrophic cardiomyopathy (MYBPC3 gene, literature [Gedicke-Hornung et al., 2013]), Usher syndrome (USH1C gene, literature [Lentz et al., 2013]), Fukuyama-type congenital muscular dystrophy (FKTN gene, literature [Taniguchi-lkeda et al., 2011]), laser-induced choroidal angiogenesis (FLT1 gene, literature [Owen et al., 2012]), cancer (STAT3 and bcl-X genes, literature [Zammarchi et al., 2011], [Mercatante et al., 2002]), and Hughkinson-Gilford Research is underway for various genetic disorders, including but not limited to progeria (Hutchinson-Gilford progeria) (LMNA gene, [Osorio et al., 2011]), Miyoshi myopathy (DYSF gene, [Wein et al., 2010]), spinocerebellar ataxia type 1 (ATXN1 gene, [Gao et al., 2008]), Alzheimer's disease/FTDP-17 tauopathy (MAPT gene, [Peacey et al., 2012]), myotonic dystrophy (CLC1 gene, [Wheeler et al., 2007]), and Huntington's disease ([Evers et al., 2014]). However, splice-switching AONs have made the greatest progress in the treatment of neuromuscular disorders such as Duchenne muscular dystrophy (DMD) and spinal muscular dystrophy (SMA type). Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are the most common juvenile forms of muscular dystrophy. DMD is a severe, fatal neuromuscular disorder that requires wheelchair support before the age of 12, and patients typically die before the age of 30 due to respiratory or cardiac failure. It is caused by the absence of functional dystrophin due to reading frame-shift deletions (~67%) or duplications (~7%) in one or more exons, or point mutations (~25%) in the 2.24 Mb DMD gene. BMD is also caused by mutations in the DMD gene, but it maintains an open reading frame and results in the acquisition of semi-functional dystrophin protein, typically leading to a much milder phenotype and a longer lifespan. Over the past decade, modifying splicing in a specific manner to restore the disrupted reading frame of the transcript has emerged as a promising therapy for DMD (see [van Ommen et al., 2008]; [Yokota et al., 2007]; [van Deutekom et al., 2007]; [Goemans et al., 2011]; [Voit et al., 2014; Cirak et al., 2011]). By using highly sequence-specific splice-switching antisense oligonucleotides (AONs) that are located on the mutational side or bind to the exon containing it and disrupt its splicing signal, the skipping of said exon can be induced during the processing of DMD-free mRNA. Despite the resulting truncated transcript, the open reading frame is restored, and a protein similar to that found in BMD patients is produced. AON-induced exon skipping is mutation-specific a