The present invention relates to an isolated chimeric molecule comprising a degradation domain including a eukaryotic U-box motif and a targeting domain capable of immunospecifically directing the degradation domain to a substrate where the targeting domain is heterologous to the degradation domain. A linker couples the degradation domain to the targeting domain. Also disclosed are compositions as well as methods of treating a disease, substrate silencing, screening agents for therapeutic efficacy against a disease, and methods of screening for disease biomarkers.

The present disclosure is related to compositions and methods for the regulated and controlled expression of proteins.

Provided herein are methods for treating or preventing, or ameliorating at least one symptom of, a neurodegenerative disease associated with TDP-43 pathology, comprising administering to a subject an effective amount of a peptide comprising or consisting of the amino acid sequence of SEQ ID NO:1 or a conservative variant thereof, optionally linked to a protein destabilization domain sequence, or a nucleic acid molecule encoding said peptide. Also provided is a peptide comprising or consisting of the amino acid sequence of SEQ ID NO:1 or a conservative variant thereof, a chimeric molecule comprising said peptide linked to a protein destabilization domain sequence, and a polynucleotide encoding said peptide or chimeric molecule.

The present disclosure provides drug responsive domains derived from human carbonic anhydrase 2 that can modulate protein stability for human interleukin 15 (EL15) payloads, as well as compositions and methods of use thereof.

The preset disclosure provides chimeric polypeptides comprising a cage polypeptide comprising a degron, wherein the degron is sequestered or caged. Upon activation by a key polypeptide, the degron becomes active. The degron can recruit an ubiquitin ligase and a lysine in the degron or surrounding sequence be ubiquitinated. The ubiquitinated chimeric polypeptide is marked for degradation, together with any biologically active molecule attached to the chimeric polypeptide. The chimeric polypeptides of the present disclosure can be incorporated, for example, to chimeric antigen receptors (CAR). Accordingly, in response to the administration of a key polypeptide or endogenous expression of a key polypeptide mediated, for example, by an inducible promoter, the amount of CAR expressed on the surface of an immune cell can be modulated.

Provided herein are fusion proteins including two protein domains separated by a heterologous protease cleavage site, wherein a first of the protein domains is a conditional expression domain. Thus, the fusion proteins comprise three essential elements: a conditional expression domain, a domain containing the protein of interest, and a protease cleavage domain separating the two. Also provided herein are methods for treating autoantibody and alloantibody-mediated diseases or conditions in a subject by targeting B cells with anti-B cell modified T cells. In one embodiment, a chimeric antigen receptor (CAR) modified T cell is selectively ablated in a subject after adoptive transfer. Pharmaceutical compositions comprising the temporally regulated CAR modified T cell are also described herein.

The present invention relates to compositions and methods for the regulated and controlled expression of proteins. Methods for inducing anti-cancer immune responses in a subject are also provided.

The disclosure provides methods, base editors, vectors encoding base editors and cognate gRNAs, and compositions and kits comprise said components, for installing nucleobase edits to the SMN2 locus to increase the activity and/or amount and/or stability of SMN2 protein in a cell, thereby treating Spinal Muscular Atrophy. In certain aspect, the disclosure provides compositions and methods to edit C840T of exon 7 of the SMN2 gene, or installing another one or more nucleobase edits which have the effect of removing or inactivating a degron, such as the C-terminal portion of the region encoded by exon 6 or the 4-amino acid region encoded by exon 8 (i.e., the EMLA (SEQ ID NO: 466)-tail) so as to remove or limit their degron activity to reduce, mitigate, or eliminate the intracellular degradation of the SMN2 protein.

The disclosure includes compositions comprising synthetic zinc finger degrons, and their use with non-naturally occurring or engineered programmable nucleases. Compositions specifically targeting the engineered programmable nucleases for control of gene editing outcomes, and compositions, systems and method of use are further detailed.

Disclosed herein are compositions comprising use of compositions comprising a live attenuated recombinant Listeria strain comprising a fusion protein of a truncated listeriolysin O (LLO) protein, a truncated ActA protein, or a PEST amino acid sequence fused to a heterologous antigen, including a tumor-associated antigen, wherein the compositions further comprise or are co-administered with an antibody or fragment thereof. Also disclosed are combination therapies comprising use of these compositions comprising live attenuated recombinant Listeria strains, in conjunction with an antibody or fragment thereof for use in treating, protecting against, and/or inducing an immune response against a tumor, especially wherein the treating, protection against and/or inducing an immune response increases percent survival in a subject.