The disclosure provides, e.g., compositions and methods for modulating a host response to a Gene Writer system. In some embodiments, modulation of the host response results in increased integration of a heterologous nucleic acid sequence of interest into a target genome. In some embodiments, modulation of the host response results in an increased stability, e.g., maintenance of an insertion or expression thereof. In some embodiments, modulation of the host response results in decreased cytotoxicity.

The present disclosure reports that pharmacological or genetic inhibition of Moloney murine leukemia virus insertion site 1 (BMI1) not only helped to eliminate BMI1+ cancer stem cells (CSCs), but can also augment PD1 blockade by strongly induced tumor cell-intrinsic immune responses by recruiting and activating CD8+ T cells. Taken together, the results indicate that in addition to purging CSCs, targeting BMI1 would enable immune checkpoint blockade to inhibit metastatic tumor growth and prevent tumor relapse by activating cell-intrinsic immunity.

Aspects of the disclosure relate to complexes comprising a muscle-targeting agent covalently linked to a molecular payload. In some embodiments, the muscle-targeting agent specifically binds to an internalizing cell surface receptor on muscle cells. In some embodiments, the molecular payload promotes the expression or activity of a functional dystrophin protein. In some embodiments, the molecular payload is an oligonucleotide, such as an antisense oligonucleotide, e.g., an oligonucleotide that causes exon skipping in a mRNA expressed from a mutant DMD allele.

Provided are a double-stranded siRNA analogue embedded with a ribavirin derivative, a conjugate containing same, and a salt and the use thereof. The provided double-stranded siRNA analogue, the conjugate containing same and the salt thereof can effectively inhibit multiple viral indicators such as hepatitis B virus DNA, pgRNA, S antigen, and E antigen, which provide an effective and feasible method for treating hepatitis B.

A modified immune cell that has attenuated expression and/or activity of YTH N6-Methyladenosine RNA Binding Protein 2 (YTHDF2), and enhanced anti-tumor activity. A composition for stimulating T cell-mediated immune response to a cancer cell and/or a tumor antigen, including an agent capable of attenuating the expression and/or activity of YTHDF2, and a pharmaceutically acceptable excipient. A composition for treating cancer, comprising an agent capable of attenuating the expression and/or activity of YTHDF2. A method for activating an immune cell. A method for generating an immune cell. A method for treating a disease, disorder or condition associated with an expression of a tumor antigen in a subject in need thereof. A method for stimulating a T cell-mediated immune response to a cancer cell and/or a tumor antigen in a subject in need thereof.

Disclosed herein are IL-34 inhibitors, including IL-34 antisense oligonucleotide sequences, and methods for treating inflammatory diseases, such as an inflammatory bowel disease, and/or fibrosis, associated with elevated activity or expression of IL-34. Also disclosed are pharmaceutical compositions containing an IL-34 inhibitor, for example, a IL-34 antisense oligonucleotide, useful for treating inflammatory diseases and/or fibrosis and manufacture of medicaments containing a disclosed IL-34 inhibitor to be used in treating inflammatory diseases and/or fibrosis.

The present invention relates to methods of inhibiting the expression of an AGT gene in a subject, as well as methods for treating subjects having an AGT-associated disorder, e.g., hypertension, using RNAi agents, e.g., double stranded RNAi agents, targeting the AGT gene. The invention also relates to methods of decreasing blood pressure levels in a subject using such RNAi agents to inhibit expression of an AGT gene.

The disclosure relates, in some aspects, to methods and compositions for production of immunomodulatory compositions. In some embodiments, the disclosure provides host cells which have been treated ex vivo with one or more oligonucleotide agents capable of controlling and/or reducing the differentiation of the host cell. In some embodiments, compositions and methods described by the disclosure are useful as immunogenic modulators for treating cancer.

Embodiments of the disclosure encompass systems, methods, and compositions related to selective advantages to somatic cells that harbor one or more particular genetic modifications. In particular embodiments, there is selective expansion of gene-targeted cells wherein the strategy involves deletion of an essential gene product that is replaced with targeted integration that also includes integration of a therapeutic transgene. The cells that harbor the replaced essential gene product, and thereby the therapeutic transgene, are selected for using pharmaceutical or nutritional agents that are linked to the function of the essential gene product.

Peptide-based systems containing hydrophobic amino acids (e.g., tryptophan), charged amino acids (e.g., arginine), and/or sulfur-containing amino acids (e.g., cysteine), which can be used either alone or in combination with nanoparticles (e.g., gold or silver nanoparticles) for siRNA delivery into living cells are disclosed.