The present disclosure provides recombinant nucleic acids comprising one or more polynucleotides encoding a cystic fibrosis transmembrane conductance regulator (CFTR) polypeptide (e.g., a human CFTR 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 the treatment of a chronic lung disease, such as cystic fibrosis); and articles of manufacture or kits thereof.

An oncolytic virus for use in a method of treating or preventing cutaneous squamous cell carcinoma (CSCC), renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), small cell lung cancer (SCLC), advanced recurrent head and neck cancer, squamous cell carcinoma of the head and neck (SCCHN), nasopharyngeal carcinoma (NPC), hepatocellular carcinoma (HCC), anal cancer, colorectal cancer (CRC), basal cell carcinoma (BCC), Merkel cell carcinoma, appendiceal carcinoma, sarcoma of the skin, recurrent melanoma after surgery, advanced or metastatic urothelialcarcinoma, liver metastases, microsatellite instability high cancer (MSI-H), mixed advanced solid tumors, virally caused cancer, locoregionally advanced cancer, pediatric cancer, cancer in patients with no or minimal pre-existing anti-cancer immunity, cancer as first line therapy, cancer in previously treated patients, cancer in patients who have not received checkpoint blockade therapy, and/or cancer in patients who have received checkpoint blockade therapy, wherein the oncolytic virus: is, or is derived from, a clinical isolate which has been selected by comparing the abilities of a panel of three or more clinical isolates of the same viral species to kill tumor cells of two or more tumor cell lines in vitro and selecting a clinical isolate which is capable of killing cells of two or more tumor cell lines more rapidly and/or at a lower dose in vitro than one or more of the other clinical isolates in the panel; comprises (i) a fusogenic protein-encoding gene; and (ii) an immune stimulatory molecule or an immune stimulatory molecule-encoding gene; comprises (i) a GM-CSF-encoding gene; and (ii) an immune co-stimulatory pathway activating molecule or an immune co-stimulatory pathway activating molecule-encoding gene; and/or comprises a gene encoding a CTLA-4 inhibitor.

Provided is a composition comprising a mutant Q209L-GNAQ DNA vaccine encoding, in a N-terminal to C-terminal direction, a fusion protein comprising VP22 or an HLA-binding sequence thereof, a mutant GNAQ sequence comprising a Q209L mutation, and a PADRE epitope. Also provided are methods of treatment and methods of vaccination comprising administering to a patient the composition. Also provided is a method of generating mutant GNAQ-specific T cells comprising priming T cells with ex vivo cultured dendritic cells transduced or electroplated with the composition.

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.

Provided are antigenic compositions and uses thereof that include at least two human herpesvirus (HHV) polypeptides involved in mediating HHV binding, fusion, and entry into host cells, such as gp350, gH, gL, and gB, or nucleic acids encoding the polypeptides. The two HHV polypeptides comprise any combination of: a gB polypeptide; a gp350 polypeptide; a gL polypeptide; and a gH polypeptide, and optionally any one or more of the following polypeptides: gp42, gM, gN, gl, gC, gE, gD, ORF68, BMRF-2, BDLF2, UL128, UL130, UL131A, and gpK8.1. Also disclosed are methods of inducing an immune response or treating or preventing an HHV infection in a subject by administering to the subject at least two of the HHV polypeptides or nucleic acid(s) encoding the same. Methods of passively transferring immunity using high-titer anti-HHV antibodies or immune cells are also disclosed.

The present disclosure is in the field of genome engineering, particularly targeted integration of a functional SCID-related genes (e.g., IL2RG, RAG1 and/or RAG2 gene) into an IL2RG gene of a cell for provision of proteins lacking or deficient in SCID.

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

The present disclosure provides recombinant nucleic acids comprising one or more polynucleotides encoding a cystic fibrosis transmembrane conductance regulator (CFTR) polypeptide (e.g., a human CFTR 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 the treatment of a chronic lung disease, such as cystic fibrosis); and articles of manufacture or kits thereof.

Persistence of HIV in anatomic sanctuary sites such as the brain prevents viral eradication. Although combination antiretroviral therapy (cART) inhibits viral replication to undetectable level by standard clinical assay, it does not selectively eliminate virus reservoirs. To target HIV reservoirs, the present inventor developed an HIV Rev-dependent lentiviral vector carrying a series of therapeutic genes, such as diphtheria toxin, anthrolysin O from Bacillus anthracis, human TRAF6, or the herpes simplex 1 virus thymidine kinase gene (HSV-tk). The present disclosure provides the Rev-dependent vectors for targeting viral reservoir in a SIV/rhesus macaque model. SIV-infected rhesus macaques were first treated with cART for over 6 months starting 12 weeks post infection, followed by injections with viral particles assembled from a SIV Rev-dependent vector carrying HSV-tk. Following particle injection, animals were further treated briefly (two weeks) with ganciclovir (GCV), which induces the killing of SIV+, HSV-tk expressing cells. cART was terminated following the GCV treatment, and there was observed a partial control of viral rebound over a period of 4 months after cART cessation. The animal was further treated with additional Rev-dependent vector particles, and viral load was diminished to the undetectable level for over 1 year in the absence of any treatment. These results suggest that the Rev-dependent vector, with or without a functional gene, has the potential to diminish viral reservoirs in vivo and can offer a cure of functional cure of HIV/SIV infection.

The present invention relates to methods of enhancing the translation ability and stability of an RNA molecule. The methods involve providing a cell-free composition comprising an RNA molecule to be translated, where the RNA molecule lacks an N.sup.6,2O-dimethyladenosine (m.sup.6A.sub.m) residue. Also disclosed are methods of making RNA molecules and treatment methods using an RNA molecule comprising a 7-methylguanosine (m.sup.7G), a 5 triphosphate linker (-ppp-), and an N.sup.6,2-0-dimethyladenosine (m.sup.6A.sub.m).