Polynucleotide repeat disorders are a set of genetic disorders caused by polynucleotide repeat expansions (typically trinucleotide repeat expansions). The expanded polynucleotide/trinucleotide repeats have been shown to cause the retention of transcripts in the nucleus, where it accumulates in numerous foci (RNA aggregates). More and more RNA aggregates or foci have been identified in different pathologies, for example Myotonic Dystrophy type 1 (DM1) (Davis et al., 1997) and type 2 (DM2) (Liquori et al., 2001), Fragile X-associated tremor/ataxia syndrome (FXTAS) (Tassone et al., 2004), Spinocerebellar ataxia type 8 (SCA8) (Daughters et al., 2009) and Huntington's disease-like 2 (HDL2) (Rudnicki et al., 2007). All these diseases are characterized by microsatellite expansions of CNG or CCTG repeats in specific genes, leading to the accumulation of their transcripts as nuclear RNA foci (Ranum and Cooper, 2006).
Myotonic dystrophy is a chronic, slowly progressing, highly variable, inherited multisystemic disease. Two types of myotonic dystrophy exist. Type 1 (DM1), also known as Steinert disease, has a severe congenital form and a milder childhood-onset form. Type 2 (DM2), also known as proximal myotonic myopathy (PROMM), is rarer and generally manifests with milder signs and symptoms than DM1. DM1 is the most common adult form of muscular dystrophy with a prevalence of up to 1 in 7,000 worldwide. DM1 is highly prevalent in the Saguenay region of Quebec where its carrier rate reaches 1 in 550, making DM1 a Canadian-specific disease. There is no current treatment for the progressive myopathy, which eventually kills the patients, highlighting the urgent medical need for therapeutics. It is a multisystemic disorder (FIG. 1), caused by an expansion of CUG trinucleotide repeats in the 3′ untranslated region (UTR) of the protein kinase DMPK mRNA (Brook et al. 1992, Buxton et al. 1992, Fu et al. 1992, Mahadevan et al. 1992). The expanded CUG repeats have been shown to cause the retention of this transcript in the nucleus, where it accumulates in numerous foci (FIG. 2; Taneja et al. 1995, Davis et al. 1997). The current toxic RNA hypothesis posits that the retention of mutant DMPK (dystrophia myotonica protein kinase) mRNAs in the nucleus alters the function of RNA-binding proteins, such as the alternative splicing factors MBNL1 and CUGBP1. As a consequence, mRNA mis-splicing has been reported for several genes in DM1 (reviewed in Wheeler and Thornton 2007). One of the mechanisms proposed is that these nuclear RNA foci sequester essential proteins that normally interact with CUG nucleotides in mRNAs and interfere with their normal function in the cell. Disrupting these nuclear RNA foci and promoting the nuclear export of the CUG-rich transcripts should reduce the alteration of splicing factor function and prevent the development of symptoms in patients with DM1 (Wheeler 2008).
There is thus a need for the development of novel strategies to inhibit the aggregation of RNA with expanded tracts of triplet repeats, for the treatment of diseases associated with the presence of triplet repeats
The present description refers to a number of documents, the content of which is herein incorporated by reference in their entirety.
USPTO Backgrounds
USPTO Backgrounds