The present disclosure provides oligomeric compound comprising a modified oligonucleotide having a central region comprising one or more modifications. In certain embodiments, the present disclosure provides oligomeric compounds having an improved therapeutic index or an increased maximum tolerated dose.

Compositions and methods for enhancing targeted gene editing and methods of use thereof are disclosed. In the most preferred embodiments, gene editing is carried out utilizing a gene editing composition such as triplex-forming oligonucleotides, CRISPR, zinc finger nucleases, TALENS, or others, in combination with a gene modification potentiating agent such as stem cell factor (SCF), a CHK1 or ATR inhibitor, or a combination thereof. A particular preferred gene editing composition is triplex-forming peptide nucleic acids (PNAs) substituted at the γ position for increased DNA binding affinity. Nanoparticle compositions for intracellular delivery of the gene editing composition are also provided and particular advantageous for use with in vivo applications.

The present disclosure provides oligomeric compound comprising a modified oligonucleotide having a central region comprising one or more modifications. In certain embodiments, the present disclosure provides oligomeric compounds having an improved therapeutic index or an increased maximum tolerated dose.

An aptamer-based switch technology is provided that enhances control of the use of chimeric antigen receptor (CAR)-related immunotherapies. The aptamer-based switch utilizes a synthetic bridge molecule containing a target-binding aptamer bound through a linker to a CAR-binding aptamer. A system containing a CAR and a corresponding aptameric bridge provides an immunotherapy platform that: (i) can be targeted to any desired antigen by choosing the target-binding aptamer of the bridge, (ii) can be redirected from one target to another by changing the target-binding aptamer; (iii) can be dosed according to the changing needs of an individual patient overtime by altering the administration protocol for the bridge; (iv) can be switched on or off quickly or gradually; (v) can be used as a companion diagnostic for a specific CAR therapy; (vi) can be integrated with either in vivo or ex vivo CAR expression; (vii) is non-immunogenic; and (viii) has low production costs.

The application discloses methods and compositions for inhibiting functions associated with Interleukin-8 (IL8). The methods and compositions may involve the use of aptamers for binding to IL8 and preventing or reducing association of IL8 with CXCR1, CXCR2, or both. The methods and compositions may include one or more aptamers that bind to an N-terminal domain of IL8. The methods and compositions may include one or more aptamers that bind to a hydrophobic pocket of IL8. The methods and compositions may include one or more aptamers that bind to an N-loop of IL8. The methods and compositions may include one or more aptamers that bind to a GAG binding site of IL8. The application further provides anti-IL8 aptamers for the treatment of ocular diseases or disorders. In some cases, the anti-IL8 aptamers may have a stem-loop secondary structure.

One aspect of the present invention relates to double-stranded RNA (dsRNA) agent capable of inhibiting the expression of a target gene. The antisense strand of the dsRNA molecule comprises at least one thermally destabilizing nucleotide occurring at a seed region; the dsRNA comprises at least four 2′-fluoro modifications, and the sense strand of the dsRNA molecule comprises ligand, wherein the ligand is an ASGPR ligand. Other aspects of the invention relate to pharmaceutical compositions comprising these dsRNA molecules suitable for therapeutic use, and methods of inhibiting the expression of a target gene by administering these dsRNA molecules, e.g., for the treatment of various disease conditions.

The application discloses a functional nucleic acid having nucleoside analog drug integrated into skeleton, a derivative, and preparation methods thereof wherein the derivative is obtained by conjugating or self-assembling the functional nucleic acid having nucleoside analog drug integrated into skeleton with one of a polymer, a hydrophobic molecule, and a transfection reagent. Compared with the prior art, the functional nucleic acid having nucleoside analog drug integrated into skeleton and the derivative thereof can efficiently enter cells and be used to regulate genes; subsequently, the functional nucleic acid having nucleoside analog drug integrated into skeleton can be degraded by nuclease and release active ingredient of the nucleoside analog drug, thus playing a role in chemotherapy. Hence, the functional nucleic acid having nucleoside analog drug integrated into skeleton and the derivative thereof can simply and efficiently realize a combination therapy of gene therapy and chemotherapy, and a complex synthesis procedure is avoided.

The present invention provides a natural type miRNA, which is a single-stranded nucleic acid containing X region and Y region, wherein the 3′-terminus of said X region and the 5′-terminus of said Y region are linked via a linker region of a non-nucleotide structure, the X region contains (a) a guide strand sequence or (b) a passenger strand sequence of a mature miRNA, when the X region contains (a), the Y region contains a passenger strand sequence of the mature miRNA, when the X region contains (b), the Y region contains a guide strand sequence of the mature miRNA, and the guide strand sequence and the passenger strand sequence form a double-stranded structure.

The present invention provides, for example, an oligonucleotide derivative or a salt thereof comprising a circular oligonucleotide and a linear oligonucleotide, wherein the circular oligonucleotide and the linear oligonucleotide have base sequences complementary to each other, and form a complex via a hydrogen bond between the complementary base sequences, and a method for producing the same.

The invention provides an artificial match-type miRNA utilizing miRNA. In particular, the invention provides a single strand nucleic acid containing an X region and a Y region, wherein the 3-terminal of the X region and the 5-terminal of the Y region are linked via a linker region of a non-nucleotide structure, the X region contains a guide strand sequence of a mature miRNA, and the Y region contains a sequence completely complementary to the X region is an artificial match-type miRNA. The artificial match-type miRNA can suppress expression of the target gene.