Methods and compositions for modifying T-cells in which PD1 and/or CTLA-4 is repressed and/or inactivated using fusion proteins such as artificial transcription factors and nucleases.

A multifunctional polypeptide chain or a protein. A polypeptide chain X, comprising an antigen 1 binding domain R1, an auxiliary peptide chain linking domain R2 and an antigen 2 binding domain R3. The auxiliary peptide chain linking domain R2 is a cytokine or a cytokine binding domain in a cytokine receptor. A protein, which is a heterodimer composed of the polypeptide chain X as a main peptide chain and an auxiliary peptide chain Y. The auxiliary peptide chain Y comprises an antigen 3 binding domain R4 and a main peptide chain X linking domain R5, or the auxiliary peptide chain Y is the main peptide chain linking domain R5. The multifunctional protein mediates specific cell killing by binding to different tumor antigens with the two antigen binding domains of tumor-associated antigens therein. The multifunctional protein can function as a cytokine by introducing a cytokine or a cytokine receptor complex.

High affinity PD-1 mimic polypeptides are provided, which (i) comprise at least one amino acid change relative to a wild-type PD-1 protein; and (ii) have an increased affinity for PD-L1 relative to the wild-type protein. Compositions and methods are provided for modulating the activity of immune cells in a mammal by administering a therapeutic dose of a pharmaceutical composition comprising a high affinity PD-1 mimic polypeptide, which blocks the physiological binding interaction between PD-1 and its ligand PD-L1 and/or PD-L2.

In certain aspects, the disclosure relates to a virus engineered to comprise one or more polynucleotides that promote thanotransmission by a target cell. Thanotransmission is communication between cells that is a result of activation of a cell turnover pathway in a target cell, which signals a responding cell to undergo a biological response. Methods of promoting thanotransmission by a target cell, methods of promoting an immune response in a subject, and methods of treating cancer in a subject are also disclosed.

The disclosure provides inducible caspase polypeptides, compositions comprising inducible caspase polypeptides and sequences encoding the same, cells modified to express the polypeptides and compositions of the disclosure, as well as methods of making and methods of using same for adoptive cell therapy.

Disclosed herein are methods of treating neuronal diseases, comprising administering to a subject in need thereof a vector comprising AIMP2-DX2 and optionally a target sequence for miR-142.

In some aspects, isomyosmine or a pharmaceutically acceptable salt thereof may be administered to an individual for the treatment of diseases of the visual system.

Provided herein are compositions and methods for the stable production of bioactive small peptides of interest through delivery to target cells based on the fusion of small peptides of interest to a collagen domain of a C1qTNF protein to produce a novel scaffold protein capable of multimerization. Advantageously, the fusion proteins, compositions and methods of the present disclosure meet existing needs in the art by providing for higher stable expression and longer stability of intracellular and secretable peptides of interest. Additionally, the fusion proteins, compositions and methods of the present disclosure provide for improved binding affinity of expressed receptor peptides with ligand binding partners in the target cell. Further provided herein are polynucleotide constructs encoding the described fusion proteins and recombinant adeno-associated viral particles comprising these polynucleotides. Also provided herein are pharmaceutical compositions and nanoparticles that comprise the described fusion proteins. Further provided herein are methods of treating a subject by administering the described fusion proteins, rAAV particles, compositions and/or nanoparticles.

The invention relates generally to the THAP1 gene and mutations in this gene, as well as the THAP1 protein and mutations in this protein, that are associated with dystonia. The invention relates to the identification, isolation, cloning and characterization of the DNA sequence corresponding to the wild type and mutant THAP1 genes, as well as isolation and characterization of their transcripts and gene products. The invention further relates to methods and kits useful for detecting mutations in THAP1 that are associated with dystonia, as well as to methods and kits useful for diagnosing dystonia. The present invention also relates to therapies for treating dystonia, including gene therapeutics and protein/antibody based therapeutics.

Therapeutic proteins for inducing apoptosis in cells and method for using such proteins are described. The protein, e.g., a chimeric protein, has a host peptide fused to a more stable BH3 domain peptide. The host peptide may be Calbindin D9k, a N-terminal or C-terminal half-domain of Calmodulin, Parvalbimin (“Pa”), an amino acid sequence variant thereof, or a modified variant thereof. The BH3 domain may be Bim, Bid, Bad, Bik, Bmf, Hrk, Puma, or Noxia. Moreover, various conjugates may be attached to the chimeric protein, including a folate and polyethylene glycol.