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Targeting DM1 with a Multivalent Ligand

RNA: A Popular Target in DM1

Given the novel disease mechanisms that are operative for myotonic dystrophy (DM), “drugging the RNA World” is a very popular theme in drug discovery and development for this disease. Small and large molecule approaches based on this strategy are in preclinical development for DM. Companies such as Expansion Therapeutics are moving toward interventional clinical trials to test the strategy. Dr. Steven Zimmerman (University of Illinois at Urbana–Champaign) and colleagues have recently published data in a model organism in support of a multivalent candidate therapeutic targeting both expanded repeat DNA and RNA in addressing the RNA gain-of-function in DM1 (Lee et al., 2019).

Multivalent Targeting of DM1 Expanded Repeats in DNA and RNA

Dr. Zimmerman and his colleagues have exploited their expertise in bioorganic, synthetic organic, and physical organic chemistry to design and evaluate multivalent ligands targeted to expanded CTG DNA and expanded CUG RNA in a preclinical discovery and development effort for DM1 therapeutics. The Zimmerman team describes the approach as exploiting “smart molecules designed to enter the cell nucleus, bind the target DNA or RNA specifically and operate to reverse the deleterious effects of the expanded repeats.” The efficacy of this strategy lies in the use of a single ligand that targets both transcription of expanded CTG repeat DNA and interactions of expanded CUG repeat RNA with Muscleblind to mitigate the consequences of DM1.

The research team first focused on rational optimization of their existing small molecule inhibitor that targets DM1 expanded repeat RNA. Dimerization of the inhibitor markedly improved its efficacy, but vastly reduced cell permeability—thus necessitating a strategy change to ensure drug-like properties of the candidate therapeutic. Utilization of a linker sequence improved cell permeability and allowed oligomerization of the original monomer to further enhance binding to CUG expansions. Moreover, optimization of their synthetic and purification procedures provided a means to move forward with further testing of the molecule.

Studies in HeLa cells transfected with 960 CTG-repeat DMPK showed the ability of the multivalent compound to disrupt the nuclear foci and rescue the mis-splicing characteristic of DM1 in a dose-dependent manner. Activity in suppressing nuclear foci in the HeLa cell model was 1000-fold greater than with the original monomeric compound. The oligomer also showed promising activity in DM1 patient-derived myoblasts.

A surprising finding with the oligomeric compound tested here was that it also targeted expanded CTG DNA—this dual mechanism capability in targeting both transcription of the expanded repeat DMPK gene and its toxic transcript could potentiate the activity of the compound. Finally, in initial model organism efficacy testing, the oligomer showed activity in a DM1 Drosophila climbing assay and in a liver-specific DM1 mouse model—supporting both the bioavailability and activity of the compound. Preliminary toxicity studies showed no liabilities.

Synthesis and Next Steps

Taken together, a multivalent, cell-penetrating compound with potential to knock down both production of toxic DMPK RNA transcript and its interactions with MBNL represents an attractive opportunity for therapy development in DM1. The model organisms that this compound has been tested in thus far, a DM1 fly and liver-specific DM1 mouse, are not ‘traditional’ models for therapy development in the disease, but establish an initial level of proof of concept. The strength of the Zimmerman group lies in bioorganic chemistry expertise and partnership with groups with strengths in DM1 disease mechanisms and preclinical models should help ascertain the value in moving forward with the novel compounds developed here.


Intrinsically cell-penetrating multivalent and multitargeting ligands for myotonic dystrophy type 1.
Lee J, Bai Y, Chembazhi UV, Peng S, Yum K, Luu LM, Hagler LD, Serrano JF, Chan HYE, Kalsotra A, Zimmerman SC.
Proc Natl Acad Sci U S A. 2019 Apr 11. pii: 201820827. doi: 10.1073/pnas.1820827116. [Epub ahead of print]






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