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 relates in some aspects to methods, compositions and uses involving immunotherapies, such as adoptive cell therapy, e.g., T cell therapy, and an immunomodulatory compound, such as a structural or functional analog or derivative of thalidomide and/or an inhibitor of E3-ubiquitin ligase. The provided methods, compositions and uses include those for combination therapies involving the administration or use of one or more immunomodulatory compounds in conjunction with a T cell therapy, such as a genetically engineered T cell therapy involving cells engineered with a recombinant receptor, such as chimeric antigen receptor (CAR)-expressing T cells. Also provided are compositions, methods of administration to subjects, articles of manufacture and kits for use in the methods. In some aspects, features of the methods and cells provide for increased or improved activity, efficacy, persistence, expansion and/or proliferation of T cells for adoptive cell therapy or endogenous T cells recruited by immunotherapeutic agents.

The present invention provides a linear multimeric biomolecule polymer wherein a biomolecule is bonded to a polyubiquitin scaffold formed of two or more covalently bonded ubiquitins, by obtaining, from a host cell, a biomolecule bonded with a ubiquitin C-terminal tag through recombinant expression, and polyubiquitinating the biomolecule in vitro in the presence of proteins involved in ubiquitination, E1 (activation enzyme), E2 (conjugation enzyme), and E3 (ligase), and a substrate. The polymer according to the present invention may be used in the separation and purification of a biomolecule, the separation of a target material that binds to the biomolecule, etc.

The present invention relates to cell-penetrating effector proteins of type III secretion system (T3SS)-containing bacteria of the genus Salmonella or Shigella and variants, fragments and immunomodulatory domains thereof, for use in immunotherapy. The present invention further relates to cell-penetrating effector proteins of type III secretion system (T3SS)-containing bacteria of the genus Salmonella or Shigella and variants, fragments and immunomodulatory domains thereof, for delivering cargo molecules into eukaryotic cells.

A CRISPR/Cas system and method for editing or regulating transcription of a genome of a cell are provided, wherein the system includes a Cas endonuclease fused with one or more degron sequences and at least one activatable cognate single guide RNA harboring an inactivation sequence in a non-essential region of the cognate sgRNA, wherein said inactivation sequence comprises one or more endonuclease recognition sites of, e.g., a ribozyme.

Angelman Syndrome (AS) is a genetic disorder occurring in approximately one in every 15,000 births. It is characterized by severe mental retardation, seizures, difficulty speaking and ataxia. The gene responsible for AS was discovered to be UBE3A and encodes for E6-AP, a ubiquitin ligase. A unique feature of this gene is that it undergoes maternal imprinting in a neuron-specific manner. In the majority of AS cases, there is a mutation or deletion in the maternally inherited UBE3A gene, although other cases are the result of uniparental disomy or mismethylation of the maternal gene. While most human disorders characterized by severe mental retardation involve abnormalities in brain structure, no gross anatomical changes are associated with AS. We have generated a Ube3a protein with additional sequences that should allow the secretion from cells and uptake by neighboring neuronal cells. This would confer a functional E6-AP protein into the neurons and rescue disease pathology.

The disclosure relates to methods and compositions for reactivating a silenced FMR1 gene. In some aspects, methods described by the disclosure are useful for treating a FMR1-inactivation-associated disorder (e.g., fragile X syndrome).

The present disclosure provides compositions and methods for treating subjects at risk for or with sensorineural hearing loss by modulating the rate of Atoh1 protein degradation to increase levels of Atoh1 protein.

Methods of treating and preventing fibrosis and pathological inflammation through inhibition of WWP2 are disclosed, as well as agents for use in such methods.

The present disclosure relates to compounds for activating the enzymatic activity of an E3 ubiquitin ligase and methods for treating a disease or disorder in a subject with diminished E3 ubiquitin ligase enzymatic activity. In some embodiments, the present disclosure provides a compound of Formula (I) or a compound of Formula (II) or pharmaceutically acceptable salts thereof. ##STR00001##