Methods of treating hepatic steatosis involve administering to a subject a DENND5B inhibitor, thereby reducing the expression of and/or activity of DENND5B in liver of the subject. The DENND5B inhibitor can include antisense oligonucleotide (ASO), CRISPR interference (CRISPRi), miRNA, siRNA, locked nucleic acid (LNA) nucleotides, or a combination thereof.

Compositions, non-viral vectors, recombinant viruses, and recombinant viral vectors for inhibiting ΔFosB expression or activity in a cell and for treating dyskinesia in a subject (e.g., a human patient having Parkinson's disease and Levodopa-induced dyskinesia) include a nucleic acid sequence encoding a shRNA specific for ΔFosB. Methods of using these compositions, non-viral vectors, recombinant viruses, and recombinant viral vectors are also described herein. These compositions, non-viral vectors, recombinant viruses, and recombinant viral vectors and methods of use provide novel therapies for dyskinesia based on the reduction of ΔFosB expression and/or activity.

Methods for treating cancer with a stabilized BCL9 peptide are encompassed, wherein the stabilized peptide comprises a portion of the HD2 domain of the BCL9 protein containing a hydrocarbon crosslinker generated using α, α-disubstituted amino acids.

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 inhibits expression or activity of DUX4. In some embodiments, the molecular payload is an oligonucleotide, such as an antisense oligonucleotide or RNAi oligonucleotide.

Embodiments of the disclosure concern methods and compositions related to cancer treatment for an individual utilizing recombinant fibroblast cells that comprise one or more activities that are endothelial cell-like. The cells are delivered to a tumor microenvironment following which their death results in destabilization of the tumor vasculature. In particular embodiments, the fibroblast cells recombinantly express one or more of ETV2, FOXC2, and FLI1.

The present disclosure relates to engineered polypeptides comprising degradation domains, compounds, compositions, and methods for their preparation and use as for degrading engineered proteins in cells.

The present disclosure provides gene edited modified immune cells or precursors thereof (e.g., gene edited modified T cells) comprising an exogenous T cell receptor (TCR) and/or a chimeric antigen receptor (CAR) having specificity for a target antigen, and an insertion and/or deletion in one or more endogenous gene loci, wherein the endogenous gene loci encode regulators of T cell function, thereby resulting in immune cells having enhanced function. Compositions and methods of treatment are also provided. The present invention provides methods of screening for TCR- or CAR-T cells with enhanced immune function (e.g., T cell efficacy, T cell memory, and/or T cell persistence).

Provided herein are novel blocking chimeric antigen receptors (“bCARs”) and immune cells (e.g., effector and regulatory immune cells) that express such bCARs. Such blocking CARs prevent undesired activation of the immune cells, particularly undesired activation of the immune cells against normal tissue in therapeutic applications. Thus, such bCARs advantageously allow for selective immune cell activation only upon interaction with specific target cells (e.g., tumor cell).

The present invention relates to peptides, proteins, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated T-cell peptide epitopes, alone or in combination with other tumor-associated peptides that can for example serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses, or to stimulate T cells ex vivo and transfer into patients. Peptides bound to molecules of the major histocompatibility complex (MHC), or peptides as such, can also be targets of antibodies, soluble T-cell receptors, and other binding molecules.

Disclosed are methods of determining activity of mTOR variants upon exposure to mTOR inhibitors, such a rapamycin or rapalogs thereof, methods for determining kinase activity of a mTOR variant, and methods for determining tumor cell response to treatment with rapamycin or rapalogs thereof. A method for determining whether a compound inhibits mTOR activity in a cell is also disclosed.