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Oligonucleotides are a promising class of genetic medicine for myotonic dystrophy type 1 (DM1), the most common adult-onset muscular dystrophy. However, poor muscle distribution of nucleic acid drugs following systemic administration has hindered drug development, and no curative treatment currently exists. DM1 pathology requires drug localization to the nucleus, where pathogenic mutant RNA is sequestered, posing additional challenges after cellular internalization regarding endosomal escape and nuclear uptake. Here, we show that a locked nucleic acid oligonucleotide targeting mutant CUG repeat RNA tracts, conjugated to a bottlebrush polymer, exhibits improved muscle distribution and potent correction of DM1-associated splicing dysregulation in a DM1 mouse model. Significant improvements in myotonia, body weight, and grip strength were observed. The conjugate was well tolerated following 12 weeks of weekly intravenous administration. These findings suggest that bottlebrush polymer conjugates may overcome key limitations of conventional oligonucleotide therapeutics for neuromuscular conditions, with potential to become a potent and cost-effective DM1 therapy. 

Continuum  GY91_combined_cont_selfcal_7a_pbcor.fits - Spectral Setting 7a continuum image  GY91_combined_cont_selfcal_7b_pbcor.fits - Spectral Setting 7b continuum image   GY91_hirescontinuum.image.fits - high resolution B6 continuum image from observations originally published in Cieza et al. 2021  Image cubes -  CS_channelmap_pbcor.fits - pb-corrected CS image cubes N2Hp_channelmap_taper1_pbcor.fits - tapered pb-corrected N2H+ image cubes H2CO_290_channelmap_pbcor.fits - pb-corrected H2CO 4(0,4)-3(0,3) image cubes H2CO_291_channelmap_taper1_pbcor.fits - tapered pb-corrected H2CO 4(2,3)-3(2,2) image cubes H2CS_channelmap_taper1_pbcor.fits - tapered pb-corrected H2CS image cubes C18O_channelmap_pbcor.fits - pb-corrected C18O image cubes 13C18O_channelmap_taper1_pbcor.fits - tapered pb-corrected 13C18O image cubes Moment Maps CS_moment0.fits - CS moment 0 map N2Hp_moment0_taper1.fits - tapered N2H+ moment 0 map H2CO_290_masked_moment0.fits - masked H2CO 4(0,4)-3(0,3) moment 0 map H2CO_291_moment0_taper1.fits - tapered H2CO 4(2,3)-3(2,2) moment 0 map H2CS_moment0_taper1.fits - tapered H2CS moment 0 map C18O_masked_moment0.fits - masked C18O moment 0 map 13C18O_moment0_taper1.fits - tapered 13C18O moment 0 map -------------------- CS_moment1.fits - CS moment 1 map N2Hp_moment1_taper1.fits - tapered N2H+ moment 1 map H2CO_290_moment1_taper1.fits - tapered H2CO 4(0,4)-3(0,3) moment 1 map H2CS_moment1_taper1.fits - tapered H2CS moment 0 map C18O_moment1.fits - C18O moment 1 map Measurement sets GY91_7a_combined_obs_LINE.ms.tar - measurement sets for each LINE in spectral setting 7a (lines are all binned by 30s)  GY91_7b_combined_obs_LINE.ms.tar - measurement sets for each LINE in spectral setting 7b (C18O and 13C18O binned by 30s; only a subset of channels from the SPWs are included due to large data volume) GY91_7a_combined_cont_obs_datacorr_a1.ms.tar - self-calibrated continuum measurement set for the 7a spectral setting continuum  GY91_7b_combined_cont_obs_datacorr_a1.ms.tar - self-calibrated continuum measurement set for the 7b spectral setting continuum  GY91_hirescontinuum.ms.tar - high resolution B6 continuum measurement set from from observations originally published in Cieza et al. 2021  Keplerian Masks H2CO_290_KeplerianMask.fits - Keplerian mask used to generate moment 0 map for H2CO 4(0,4)-3(0,3)  C18O_KeplerianMask.fits - Keplerian mask used to generate moment 0 map for C18O MCFOST Parameter Files/Outputs  OpticalConstants.tar - optical constants used in MCFOST models  M_mass.tar - input and output files for MCFOST model with mass (39, 44, 49 earth masses)  Scripts Band7a_reduction.py - reduction scripts for continuum and line in spectral setting 7a Band7b_reduction.py - reduction scripts for continuum and line in spectral setting 7b GY91hirescontinuumselfcal.py - CASA script for generating high-resolution B6 continuum image from observations originally published in Cieza et al. 2021 

GY 91, commonly categorized as a Class I young stellar object, is notable for disk dust substructures that have been hypothesized to trace early planet formation. Using the Atacama Large Millimeter/submillimeter Array 12 m and Atacama Compact Array, we present new Band 7 dust continuum and molecular line observations of GY 91 at an angular resolution of 0.3 (40 au). We report detections of CS J = 6–5, N2H+ J = 3–2, C18O3 , as well as a tentative detection of 13C18O J = 3–2. We observe azimuthal asymmetry in CS and H2CS emission, as well as radially structured H2CO 4(0,4)–3(0,3) emission outside the dust continuum. C18O and H2CO 4(0,4)–3(0,3) show significant cloud contamination, while CS and N2H+ are good tracers of Keplerian rotation originating from the disk. Envelope emission does not appear to contribute significantly either to the continuum or molecular line observations. GY 91’s chemical properties appear in large part to resemble those of Class II disks, although observations of additional molecular probes should be obtained for a fuller comparison. With CS, we estimated a dynamical stellar mass of 0.58 M⊙, which is higher than previous estimates from stellar evolutionary models (0.25 M⊙). Using both radiative transfer modeling of the dust continuum and comparison of the C18O and N2H+ fluxes to literature thermochemical models, we estimate a disk mass of ∼0.01 M⊙.