Compared to the number of drug candidates that have successfully made it to the clinical trial phase, there are many more lead compounds which have been tested in vivo using various animal models. Much of the current work that has progressed to in vivo testing has been directed to the RNA repeat expansions implicated in genetic neuromuscular diseases. In myotonic dystrophy type 1 (DM1), r(CUG)exp mRNAs sequester proteins including the alternative splicing regulator MBNL1 into the nucleus causing missplicing. Several groups have developed compounds which bind the toxic RNA and dissolve nuclear foci. In 2011, Artero and coworkers discovered that a peptide could reduce the toxicity associated with r(CUG) repeats in Drosophila and mouse models. [https://scholar.google.com/citations?user=sYLAwlMAAAAJ&hl=en Disney] and colleagues provided the first small molecules that targeted r(CUG) repeats in animals models by using rational designing to identify many small molecules directly targeting this toxic RNA and the compounds improved disease defects in a DM1 mouse model.
Other works by the Disney group has shown that in cellular models of various RNA-mediated diseases that are causes by RNA repeats such as r(CAG) in Huntingtons disease and r(CCUG) repeats in Myotonic Dystrophy Types 2  could also be targeted with small molecules. Nakamori and colleagues also reported in 2012 that erythromycin could be orally dosed in DM1 mouse models to restore missplicing defects and inhibit the complex formed between r(CUG) and MBNL1. In that same year, Miller and coworkers screened a library of compounds to find a small molecule drug that could improve splicing defects in a mouse model. The Zimmerman group has taken a rational design approach to discovering small molecule drugs that target r(CUG). One such compound contains a selective triaminotriazine recognition motif which binds to the UU mismatches in r(CUG) selectively most likely in a base triplet combined with an amidinium RNA groove binding unit. Studies using a Drosophila' model for DM1 showed an influence on related phenotypic outcomes such as eye morphology and climbing distance.
Aside from studies involved r(CUG) repeats, other complex RNA structures have also been targeted. Pearson and coworkers discovered that a cationic porphyrin (TMPyP4) bound a G-quadruplex r(GC) and inhibited the binding of proteins to r(GC). Work by Disney and Petrucelli rationally identified small molecules that can target this repeat and affect disease biology in model cellular systems and also in patient-derive iNeurons. Further studies by Rothstein and colleagues determined that TMPyP4 could suppress r(GC)-mediated neurodegeneration in a Drosophila model. Additionally targets have been rationally identified by using a powerful seqecune-based design approach termed informal to identify dozens of bioactive small molecules that target disease causing non-coding RNA termed INFORNA. This study important showed for the first time that small molecules appear to have selectivities that are competitive with oligonucleotides with cell-permeable and medicinally optimizable small molecules. Additionally, compounds have been shown to be bioactive in diverse disease settings that ranged from breast cancer. and hepatocellular carcinoma. More recently, the Disney group further used their prediction database INFORNA to design Targaprimir-96 to target miRNA precursors in animal models of cancer, the first small molecules to do so. This compound has a nanomolar affinity for the miRNA hairpin precursor selectively over other sequences. Targaprimir-96 was further tested in cells and in mice, inhibiting tumor growth in a xenograft mouse model of triple negative breast cancer upon i.p. injection.