The present disclosure relates, in some embodiments, to isolated nucleic acids (also referred to as cap guides) and methods of use thereof for RNA mapping. The disclosure is based, in part, on guide RNAs that bind to a position that is at least 7 nucleotides downstream of the first nucleotide of an mRNA molecule.

The invention provides compounds, methods, and pharmaceutical compositions for reducing the amount or activity of Apolipoprotein E (ApoE) mRNA, and in certain embodiments reducing the amount of ApoE protein in a cell or animal, wherein reducing the amount or activity of ApoE would be beneficial.

The invention provides compounds, methods, and pharmaceutical compositions for reducing the amount or activity of N-acylsphingosine amidohydrolase (acid ceramidase) 1 (ASAH1) mRNA, and in certain embodiments reducing the amount of ASAH1 protein in a cell or animal, wherein reducing the amount or activity of ASAH1 would be beneficial.

The present invention provides an antisense oligonucleotide for inhibiting biosynthesis of chondroitin sulfate. The antisense oligonucleotide comprises at least one modified nucleotide, wherein the antisense oligonucleotide suppresses expression of one or both of the chondroitin sulfate N-acetylgalactosaminyltransferase-1 (CSGalNAcT1) gene and the chondroitin sulfate N-acetylgalactosaminyltransferase-2 (CSGalNAcT2) gene.

Among the various aspects of the present disclosure is the provision of compositions and methods for selectively reducing pathogenic isoforms (e.g., DNAJB6) in a subject having a neuromuscular disorder. An aspect of the present disclosure provides for selectively reducing DNAJB6 in a subject having a neuromuscular disorder (e.g., limb-girdle muscular dystrophy D1 (LGMD-D1)) comprising administering an amount of a DNAJB6-targeting antisense oligonucleotide (ASO) sufficient to reduce the expression of DNAJB6 compared to the subject prior to being administered the DNAJB6-targeting ASO.

Disclosed herein are antisense oligonucleotide sequences, and methods of use for treating neurological diseases. Described herein are oligonucleotide inhibitors. In various embodiments, the oligonucleotide targets a transcript for the treatment of neurological diseases, including motor neuron diseases, and/or neuropathies. For example, inhibitors of the transcript can be used to treat PD, ALS, FTD, and ALS with FTD.

The invention provides an antisense oligonucleotide capable of controlling ATN1 gene expression and treating dentatorubral-pallidoluysian atrophy. An inventive compound comprises a modified oligonucleotide consisting of 8 to 80 linked nucleosides and having a nucleobase sequence including at least 8 contiguous nucleobases that are complementary to a transcript of ATN1, or a pharmacologically acceptable salt thereof.

Provided herein are compositions and methods for decreasing tau mRNA and protein expression. These compositions and methods are useful in treating tau-related diseases and disorders.

Methods of inhibiting a respiratory virus, (i.e., a virus associated with a respiratory condition, e.g., influenza A, influenza B, RSV, etc.) in a sample are provided. Aspects of the methods include contacting a sample comprising viral RNA (vRNA) having a target motif with an effective amount of an agent that specifically binds the target motif to inhibit the respiratory virus. Also provided are methods of treating or preventing respiratory virus infection in a subject. Also provided are compounds and pharmaceutical compositions comprising an oligonucleotide sequence complementary to a target vRNA region that find use in the subject methods.

Among other things, the present disclosure relates to designed oligonucleotides, compositions, and methods thereof. In some embodiments, provided oligonucleotide compositions provide altered splicing of a transcript. In some embodiments, provided oligonucleotide compositions have low toxicity. In some embodiments, provided oligonucleotide compositions provide improved protein binding profiles. In some embodiments, provided oligonucleotide compositions have improved delivery. In some embodiments, provided oligonucleotide compositions have improved uptake. In some embodiments, the present disclosure provides methods for treatment of diseases using provided oligonucleotide compositions.