A method for making a change in an endogenous chromosomal DNA sequence of a mammalian cell, comprising steps of: (i) introducing into said cell an oligonucleotide having a sequence that is complementary to the chromosomal DNA sequence and that includes the change; (ii) allowing sufficient time for the cell to incorporate the change into the endogenous chromosomal DNA sequence through endogenous nucleic acid modifying pathways; and (iii) identifying the presence of the change in the chromosomal DNA sequence. The invention is particularly useful for correcting mutations in the CFTR gene.

Compositions, systems, and methods are described herein to modulate (reduce/inhibit) expression/activity of FNIP1 and/or FNIP2 (“FNIP1/FNIP2”) in a cell, animal or human subject, which can prevent, ameliorate, or treat diseases (neuromuscular or neurodegenerative diseases). Methods are described for modulating (reducing/inhibiting) FNIP1/FNIP2 expression/activity via a modulator to regulate FNIP1/FNIP2 expression/activity. Also included are compositions containing modulators that regulate FNIP1/FNIP2 expression/activity. Pharmaceutical compositions, kits, and methods of delivering compositions used in modulating, reducing, or inhibiting FNIP1/FNIP2 expression/activity are described. Methods to develop, synthesize, or produce modulators, and treat ALS and related disorders (TDP-43 proteinopathies, oxidative stress, obesity, anemia, or ischemic diseases) are provided. Also provided are compositions, systems, and methods to modulate (increase) FNIP1/FNIP2 expression/activity in a cell, an animal or human subject, which can treat, prevent, or ameliorate diseases. Furthermore, described are diagnostic and testing methods to detect FNIP1/FNIP2 associated variants or expression/activity levels, and compositions comprising diagnostic or testing kits.

Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of UBE3A-ATS, the endogenous antisense transcript of ubiquitin protein ligase E3A (UBE3A) in a cell or subject, and in certain instances increasing the expression of paternal UBE3A and the amount of UBE3A protein in a cell or subject. Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom or hallmark of a neurogenetic disorder. Such symptoms and hallmarks include developmental delays, ataxia, speech impairment, sleep problems, seizures, and EEG abnormalities. Such neurogenetic disorders include Angelman Syndrome.

The present disclosure relates to RNAi agents, e.g., double stranded RNAi agents, able to inhibit 17P-hydroxy steroid dehydrogenase type 13 (HSD17B13 or 17β-H8013) gene expression. Also disclosed are pharmaceutical compositions that include HSD17B13 RNAi agents and methods of use thereof. The HSD17B13 RNAi agents disclosed herein may be conjugated to targeting ligands to facilitate the delivery′ to cells, including to hepatocytes. Delivery 7 of the HSD17B13 RNAi agents in vivo provides for inhibition of HSD17B13 gene expression. The RNAi agents can be used in methods of treatment of HSD17B13-related diseases and disorders, including non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hepatic fibrosis, and alcoholic or non-alcoholic liver diseases, including cirrhosis.

Herein is disclosed synthetic oligonucleotides comprising 2′F-ANA nucleosides that can be utilized to control plant-chewing and phloem-feeding insects, bacteria present in such insects, and bacteria present in plants. The novel approaches and materials provided herein allow for reduction of pesticide and antibiotic use without the need to create genetically modified plants.

The present invention relates to antisense oligonucleotides that modulate the expression of and/or function of PAR4, in particular, by targeting natural antisense polynucleotides of PAR4. The invention also relates to the identification of these antisense oligonucleotides and their use in treating diseases and disorders associated with the expression of PAR4.

Novel oligonucleotide pairs which can form a duplex comprising one or more DNA-like nucleotides (e.g., 2′-substituted arabinonucleotides (ANA)); in combination with one or more RNA-like nucleotides (e.g., 2′-substituted ribonucleotides (RNA) and/or locked nucleic acid nucleotides (LNA)), are disclosed. The use of such oligonucleotide duplexes, such as for silencing the expression of a nucleic acid or gene of interest using small interfering RNA (siRNA) technologies, is also disclosed.

The present invention provides stable, nuclease-resistant TNA and TNA-DNA oligonucleotides, wherein the oligonucleotides are completely resistant to enzymatic degradation for at least 24-72 hours. Methods of synthesis and use in diagnostic and therapeutic applications are also provided. Specifically, in one embodiment, we describe the chemical and biological stability of TNA and mixed-backbone (mosaic) TNA-DNA oligonucleotides under a variety of conditions and sequence contexts.

Disclosed herein are compounds, compositions and methods for modulating the expression of huntingtin in a cell, tissue or animal. Further provided are methods of slowing or preventing Huntington's Disease (HD) progression using an antisense compound targeted to huntingtin. Additionally provided are methods of delaying or preventing the onset of Huntington's Disease (HD) in an individual susceptible to Huntington's Disease (HD). Also provided are uses of disclosed compounds and compositions in the manufacture of a medicament for treatment of diseases and disorders.

The present invention provides a modified nucleic acid monomer compound having a specific backbone such as 2-ethylglycerol or methoxymethyl-1,3-propanediol backbone instead of a ribose or deoxyribose backbone of a nucleoside, and an oligonucleic acid analogue containing the monomer compound as at least one of building blocks. The oligonucleic acid analogue containing the nucleic acid monomer compound of the present invention allows provision of an oligonucleic acid analogue having excellent biological stability and/or target gene silencing activity.