Recombinant herpes simplex virus 2 (HSV-2) vaccine vectors, compositions and vaccines comprising such, and methods of use thereof are each provided.

Aspects of the present disclosure provide synthetic promoters that are differentially modulated between certain diseased cells (e.g., cancer cells) and normal cells (e.g., non-cancer cells). These synthetic promoters are useful, for example, for targeted expression of therapeutic molecules in diseased cells.

Provided is a recombinant virus comprising a fragment of exogenous polynucleotides encoding suppressor of cytokine signaling 4 (SOCS4) or a functional fragment thereof, wherein the recombinant vims expresses SOCS4 or the functional fragment once replication in a cell. Also provided are use of a recombinant oncolytic virus for preparation of therapeutic drugs of cancer and side effects of virus infection.

The present disclosure provides recombinant nucleic acids comprising one or more polynucleotides encoding a polypeptide (e.g., an inhaled therapeutic polypeptide, such as a human alpha-1-antitrypsin polypeptide); viruses comprising the recombinant nucleic acids; compositions and formulations comprising the recombinant nucleic acids and/or viruses; methods of their use (e.g., for delivering the polypeptide to one or more cells of the respiratory tract and/or for the treatment of a disease affecting the lungs, such as alpha-1-antitrypsin deficiency); and articles of manufacture or kits thereof.

The present invention provides a recombinant oncolytic Herpes Simplex Virus (oHSV) comprising a non-HSV ligand specific for a molecule (protein, lipid, or carbohydrate determinant) present on the surface of a cell (such as a cancer cell) and one or more copies of one or more microRNA target sequences inserted into one or more HSV gene loci, preferably one or more HSV gene(s) required for replication of HSV in normal (i.e., non-cancerous) cells. The invention further provides stocks and pharmaceutical compositions comprising the inventive oHSV and methods for killing tumor cells employing the inventive oHSV.

Aspects of the disclosure relate to synthetic regulatory systems comprising a multifunctional Cas nuclease and at least two guide RNAs (gRNAs) including a truncated gRNA and an multilayered regulatory control element. The synthetic regulatory system modulates endogenous gene expression, including transcriptional repression and transcriptional activation of one or more endogenous genes of a mammalian inner ear cell with multiple safety switches. Also provided herein are methods for modulating hearing sensitivity in damaged cells of the organ of corti.

Provided is a recombinant oncolytic virus composition, comprising a first recombinant oncolytic virus and a second recombinant oncolytic virus. Both the first and second recombinant oncolytic viruses comprise a herpes simplex virus vector and an exogenous gene, the exogenous gene is encoded from one of cytokine, a monoclonal antibody having a tumor preventative and/or treatment function, tumor antigens, prodrug invertase, tumor suppressor polypeptide, antisense RNA or small RNA, wherein the exogenous genes in the first and the second recombinant oncolytic viruses are different. Also provided is an application of the recombinant oncolytic virus composition in preparation of a medicament drug for treating tumors.

The present invention is directed to Herpes simplex-2 viruses that may be used in vaccines to immunize patients against genital herpes.

Provided herein are methods for enhancing gene therapy in an individual by administering an IRAK degrader with the gene therapy to suppress innate immunity to the gene therapy. In some embodiments, the gene therapy uses an adeno-associated virus (AAV) vector, an adenovirus vector, a lentivirus vector, a Herpes simplex virus (HSV) vector or a lipid nanoparticle. Also provided herein are methods for selecting an individual for treatment with an IRAK degrader in combination with a gene therapy agent.

The invention provides a method of modulating electrophysiological activity of an excitable cell. The method involves causing exogenous expression of a glycine receptor (GlyR) protein in an excitable cell of a subject. Thereafter, the excitable cell is exposed to an allosteric modulator of the GlyR protein. Modulation of the exogenous GlyR protein (an ion channel) in response to the allosteric modulator modulates the electrophysiological activity of the excitable cell. The method can be used to control pain in a subject. The invention further provides a replication-defective HSV vector comprising an expression cassette encoding a GlyR protein, stocks and pharmaceutical compositions containing such vectors, and a transgenic animal.