COMPOSITIONS AND METHODS FOR THE ADMINISTRATION OF CFTR POLYPEPTIDES

Abstract

This disclosure provides recombinant nucleic acids comprising one or more polynucleotides encoding a cystic fibrosis transmembrane conductance regulator (CFTR) polypeptide (e.g., a human CFTR polynucleotide); viruses comprising the recombinant nucleic acids; compositions and formulations comprising the viruses and / or recombinant nucleic acids; methods for using them (e.g., for the treatment of a chronic lung disease, such as cystic fibrosis); and articles for the manufacture or kits thereof.

Description

COMPOSITIONS AND METHODS FOR ADMINISTRATION OF CFTR POLYPEPTIDES CROSS REFERENCE TO RELATED REQUESTS This application claims the benefit of priority to US Provisional Application Serial No. 62 / 802,871, filed February 8, 2019, which is incorporated herein in its entirety by this reference. PRESENTATION OF THE LIST OF SEQUENCES IN ASCII TEXT FILE The contents of the submitted ASCII text file are incorporated herein in their entirety by this reference: a Sequence Listing Computer Readable Form (CRF) (file name: 7613420001140SEQLIST.txt, date of record : January 17, 2020, size: 44 KB). FIELD OF THE INVENTION The present disclosure relates, in part, to recombinant nucleic acids comprising one or more polynucleotides encoding a cystic fibrosis transmembrane conductance regulator (CFTR) polypeptide, viruses comprising the same, pharmaceutical compositions, and formulations thereof, and methods of their use (eg, to provide prophylactic, palliative, or therapeutic relief of one or more signs or symptoms of chronic lung disease, such as cystic fibrosis). BACKGROUND The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-activated bicarbonate-chloride channel that is critical for pulmonary homeostasis. Reduction or loss of CFTR channel function often leads to mucus stasis, chronic bacterial infections, and accompanying chronic inflammatory responses that promote progressive lung destruction. Decreases in CFTR expression have been suggested to be a component of the lung pathology seen in patients with chronic obstructive pulmonary disease (COPD), and loss-of-function mutations in the CFTR gene cause the severe consequences associated with cystic fibrosis. (CF). 2,000+ unique mutations have been described in the CFTR gene. CF is an inherited disease characterized by a buildup of thick, sticky mucus that can damage many of the body's organs; however, the most serious pathological consequences are associated with the lungs. CF patients present with dehydrated mucus in the lungs leading to airway obstruction, chronic bacterial infections (and associated inflammatory responses), bronchiectasis, and ultimately respiratory failure. Currently, more than 70,000 people are living with cystic fibrosis around the world. Historically, children born with CF died as babies, and until 1980 the median survival was less than 20 years. Although medical advances in the past three decades have dramatically improved both the quality of life and life expectancy of CF patients (40.6 years in the United States as of 2013), there is a clear need for new treatment options that are lead to the molecular correction of CFTR deficiencies observed in CF patients, as well as patients suffering from other chronic lung diseases such as COPD. All references cited herein, including patent applications, patent publications, zcoonn / i znz / R / v non-patent literature, and NCBI / UniProtKB / Swiss-Prot accession numbers are incorporated herein at in its entirety by this reference, in the same way as if each individual reference were specifically and independently indicated as incorporated by said reference. BRIEF SUMMARY To meet these and other needs, recombinant nucleic acids (eg, recombinant herpes virus genomes) encoding one or more CFTR polypeptides for use in viruses (eg, herpes virus), compositions, and compositions are provided herein. pharmaceutical formulations, medicaments, and / or methods for treating CFTR deficiencies in a subject in need thereof and / or for providing prophylactic, palliative, or therapeutic relief of one or more signs or symptoms of chronic lung disease, such as cystic fibrosis . The present inventors have demonstrated that the recombinant viruses described herein were able to efficiently transduce airway epithelial cells derived from a CF patient and to successfully express their encoded exogenous human CFTR polypeptides (see, eg Example 2). Furthermore, the present inventors have demonstrated that the recombinant viruses described herein expressed full-length, functional human CFTR that was appropriately trafficked to the plasma membrane (see, eg, Example 2). In addition, the present inventors have shown that the recombinant viruses described herein rescued the diseased phenotype in clinically relevant 3D organotypic cultures prepared from cultured biopsies from multiple CF patients harboring various underlying CFTR mutations (see, for example , Example 3). Furthermore, the present inventors have shown that HSV vectors can be delivered to the lungs of immunocompetent animals via multiple routes, and furthermore, that a non-invasive inhaled route of administration expressed similar levels of an encoded transgene in the lungs, while it induces less cell invasion in these (see, for example, Example 4). Without wishing to be bound by theory, it is believed that increasing, increasing, and / or complementing CFTR polypeptide levels in one or more cells (eg, one or more airway epithelial cells and one or more submucosal gland cells) ) to an individual in need thereof by administration of one or more of the recombinant nucleic acids, viruses, medicaments and / or compositions described herein will: 1) reduce or prevent mucus buildup in one or more organs ( for example the lungs) of the individual; 2) reduce or prevent airway obstruction in the individual; 3) reduce or prevent chronic bacterial infections and / or associated chronic inflammation in the individual's lungs; 4) reduce or prevent bronchiectasis in the individual; 5) reduce, inhibit or treat progressive lung destruction in the individual; and / or 6) provide prophylactic, palliative, or therapeutic relief of one or more signs or symptoms of a chronic lung disease (eg, cystic fibrosis, COPD, etc.). Accordingly, certain aspects of the present disclosure relate to a recombinant herpes virus genome comprising one or more polynucleotides encoding a cystic fibrosis transmembrane conductance regulatory (CFTR) polypeptide. In some embodiments, the recombinant herpes virus genome is capable of replication. In some embodiments, the recombinant herpes virus genome is replication defective. In some embodiments that may be combined with any of the above embodiments, the recombinant herpesvirus genome comprises the one or more polynucleotides encoding the zcoonn / i znz / B / v CFTR polypeptide within one or more viral gene loci. In some embodiments that may be combined with any of the above embodiments, the recombinant herpes virus genome is selected from a recombinant herpes simplex virus genome, a recombinant varicella zoster virus genome, a recombinant human cytomegalovirus genome, a recombinant herpes virus 6A genome, a recombinant herpes virus 6B genome, a recombinant herpes virus 7 genome, a recombinant Kaposi sarcoma-associated herpes virus genome, and any combinations or derivatives thereof. In some embodiments that may be combined with any of the above embodiments, the CFTR polypeptide is a human CFTR polypeptide. In some embodiments that may be combined with any of the above embodiments, the CFTR polypeptide comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93% , at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 5 or SEQ ID NO: 6. In some embodiments that may be combined with any of the above embodiments, the CFTR polypeptide comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of amino acids of SEQ ID NO: 5. In some embodiments, the CFTR polypeptide comprises the amino acid sequence of SEQ ID NO: 5. In some embodiments that may be combined with any of the above embodiments, the recombinant herpes virus genome is a recombinant herpes simplex virus genome. In some embodiments, the recombinant herpes simplex virus genome is a recombinant herpes simplex virus type 1 (HSV1) genome, a recombinant herpes simplex virus type 2 (HSV-2) genome, or any derivative thereof. In some embodiments, the recombinant herpes simplex virus genome is a recombinant HSV-1 genome. In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation. In some embodiments, the inactivating mutation is in a herpes simplex virus gene. In some embodiments, the inactivating mutation is a deletion of the herpes simplex virus gene coding sequence. In some embodiments, the herpes simplex virus gene is selected from infected cell protein (ICP) 0, ICP4 one or both copies), ICP22, ICP27, ICP47, thymidine kinase (tk), Long Unique Region (UL) 41 and UL55. In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in one or both copies of the ICP4 gene. In some embodiments that may be combined with any of the above embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP22 gene. In some embodiments that may be combined with any of the above embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the UL41 gene. In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in one or both copies of the ICP0 gene. In some embodiments that may be combined with any of the above embodiments, the recombinant herpes simplex virus genome comprises a zcoonn / i znz / R / v knockout mutation in the ICP27 gene. In some embodiments that may be combined with any of the above embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP47 gene. In some embodiments that may be combined with any of the above embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the UL55 gene. In some embodiments that may be combined with any of the above embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the joint region. In some embodiments, the recombinant herpes simplex virus genome comprises a gap region deletion. In some embodiments that may be combined with any of the above embodiments, the recombinant herpes simplex virus genome comprises the one or more polynucleotides encoding the CFTR polypeptide within one or more viral gene loci. In some embodiments that may be combined with any of the above embodiments, the recombinant herpes simplex virus genome comprises the one or more polynucleotides encoding the CFTR polypeptide within one or both loci of the ICP4 viral gene. In some embodiments that may be combined with any of the above embodiments, the recombinant herpes simplex virus genome comprises the one or more polynucleotides encoding the CFTR polypeptide within the ICP22 viral gene locus. In some embodiments that may be combined with any of the above embodiments, the recombinant herpes simplex virus genome comprises the one or more polynucleotides encoding the CFTR polypeptide within the UL41 viral gene locus. In some embodiments that may be combined with any of the above embodiments, the recombinant herpes simplex virus genome comprises the one or more polynucleotides encoding the CFTR polypeptide within one or both loci of the ICPO viral gene. In some embodiments that may be combined with any of the above embodiments, the recombinant herpes simplex virus genome comprises the one or more polynucleotides encoding the CFTR polypeptide within the ICP27 viral gene locus. In some embodiments that may be combined with any of the above embodiments, the recombinant herpes simplex virus genome comprises the one or more polynucleotides encoding the CFTR polypeptide within the ICP47 viral gene locus. In some embodiments that may be combined with any of the above embodiments, the recombinant herpes simplex virus genome comprises the one or more polynucleotides encoding the CFTR polypeptide within the UL55 viral gene locus. In some embodiments that may be combined with any of the above embodiments, the recombinant herpesvirus genome has reduced cytotoxicity when introduced into a target cell, compared to a corresponding wild-type herpesvirus genome. In some embodiments, the target cell is a human cell. In some modalities that can be combined with any of the above modalities, the target cell is a respiratory tract cell. In some modalities that can be combined with any of the above modalities, the target cell is an airway epithelial cell or a submucosal gland cell. Other aspects of the present disclosure relate to a herpes virus comprising any of the recombinant herpes virus genomes described herein. In some forms, the herpes virus is capable of replication. In some embodiments, the herpes virus is replication defective. In some modalities that can be combined with any of the above modalities, zcoonn / i znz / R / v herpes virus has reduced cytotoxicity compared to a corresponding wild-type herpes virus. In some embodiments, the herpes virus has reduced cytotoxicity when introduced into a target cell compared to a corresponding wild-type herpes virus. In some embodiments, the target cell is a human cell. In some modalities that can be combined with any of the above modalities, the target cell is a respiratory tract cell. In some modalities that can be combined with any of the above modalities, the target cell is an airway epithelial cell or a submucosal gland cell. In some modalities that can be combined with any of the above modalities, the herpes virus is selected from a herpes simplex virus, a varicella zoster virus, a human cytomegalovirus, a herpes virus 6A, a herpes virus 6B, a virus of herpes 7, a herpes virus associated with Kaposi's sarcoma, and any combinations or derivatives thereof. In some modalities that can be combined with any of the above modalities, the herpes virus is a herpes simplex virus. In some embodiments, the herpes simplex virus is HSV-1, HSV-2, or any of their derivatives. In some embodiments, the herpes simplex virus is an HSV-1. Other aspects of the present disclosure relate to a pharmaceutical composition comprising any of the recombinant herpes virus genomes described herein and / or any of the herpes viruses described herein and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is suitable for topical, transdermal, subcutaneous, intradermal, oral, intranasal, intratracheal, sublingual, buccal, rectal, vaginal, inhaled, intravenous, intraarterial, intramuscular, intracardiac administration; intraosseous, intraperitoneal, transmucosal, intravitreal, subretinal, intraarticular, periarticular, local and / or epicutaneous. In some embodiments, the pharmaceutical composition is suitable for oral, intranasal, intratracheal, and / or inhaled administration. In some embodiments, the pharmaceutical composition is suitable for inhaled administration. In some embodiments, the pharmaceutical composition is suitable for non-invasive inhaled administration. In some embodiments, the pharmaceutical composition is suitable for use in a dry powder inhaler, a pressurized metered dose inhaler, a fine mist inhaler, a nebulizer, an electrohydrodynamic aerosol device, or any combination of these. In some embodiments, the pharmaceutical composition is suitable for nebulization (eg, through the use of a vibrating mesh nebulizer). In some embodiments that can be combined with any of the above embodiments, the pharmaceutical composition comprises a phosphate buffer. In some modalities that can be combined with any of the preceding modalities, the pharmaceutical composition comprises glycerol. In some embodiments that can be combined with any of the above embodiments, the pharmaceutical composition comprises a lipid carrier. In some embodiments that can be combined with any of the above embodiments, the pharmaceutical composition comprises a nanoparticle carrier. Other aspects of the present disclosure relate to the use of any of the recombinant nucleic acids, herpes viruses, and / or pharmaceutical compositions described herein as a medicament. Other aspects of the present disclosure relate to the use of any of the recombinant nucleic acids, herpes viruses, and / or pharmaceutical compositions described herein in a therapy. zcoonn / i znz / R / v Other aspects of the present description refer to the use of any of the recombinant nucleic acids, herpes virus, and / or pharmaceutical composition described herein in the production or manufacture of a medicament to treat one or more signs or symptoms of a deficiency. of CFTR and / or a chronic lung disease (for example, cystic fibrosis, COPD, etc.). Other aspects of the present disclosure relate to a method of potentiating, increasing, increasing, and / or supplementing the levels of a CFTR polypeptide in one or more cells of a subject, the method comprising administering to the subject an effective amount of any of the genomes of the recombinant herpes virus described herein, any of the herpes viruses described herein, and / or any of the compositions described herein. In some embodiments, the one or more cells are one or more cells of the respiratory tract. In some embodiments, the one or more cells are one or more airway epithelial cells and / or one or more submucosal gland cells. In some modalities that can be combined with any of the above modalities, the subject suffers from a chronic lung disease. In some modalities, the chronic lung disease is cystic fibrosis or chronic obstructive pulmonary disease (COPD). In some modalities that can be combined with any of the above modalities, the subject is a human being. In some embodiments that may be combined with any of the above embodiments, the subject's genome comprises a loss-of-function mutation in a CFTR gene. In some modalities that may be combined with any of the above modalities, the recombinant herpes virus genome, herpes virus, and / or pharmaceutical composition are administered orally, intranasally, intratracheally, sublingually, buccally, topically, rectally, by inhalation, transdermal, subcutaneous, intravenous intradermal, intraarterial, intramuscular, intracardiac, intraosseous, intraperitoneal, transmucosal, vaginal, intravitreal, intraorbital, subretinal, intraarticular, periarticular, local and / or epicutaneous to the subject. In some embodiments, the recombinant herpes virus genome, herpes virus, and / or pharmaceutical composition are administered orally, intranasally, intratracheally, or by inhalation to the subject. In some embodiments, the recombinant herpes virus genome, herpes virus, and / or pharmaceutical composition are administered by inhalation to the subject. In some embodiments, the recombinant herpes virus genome, herpes virus, and / or the pharmaceutical composition are administered by non-invasive inhalation to the subject. In some embodiments, the recombinant herpes virus genome, herpes virus, and / or pharmaceutical composition are administered using a dry powder inhaler, pressurized metered-dose inhaler, fine mist inhaler, nebulizer, or electrohydrodynamic aerosol device. . In some embodiments, the recombinant herpes virus genome, herpes virus, and / or the pharmaceutical composition are administered via a nebulizer (eg, a vibrating mesh nebulizer). Other aspects of the present disclosure relate to a method of reducing or inhibiting progressive lung destruction in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the recombinant herpes virus genomes described herein. , any of the herpes viruses described herein and / or any of the compositions described herein. In some embodiments, the subject suffers from a chronic lung disease. In some modalities, the chronic lung disease is cystic fibrosis or chronic obstructive pulmonary disease (COPD). In some modalities that can be combined with any of the above modalities, the subject is a human being. In some embodiments which may zcoonn / i znz / R / v be combined with any of the above embodiments, the subject's genome comprises a loss-of-function mutation in a CFTR gene. In some modalities that may be combined with any of the above modalities, the recombinant herpes virus genome, the herpes virus, and / or the pharmaceutical composition are administered orally, intranasally, intratracheally, sublingually, buccally, topically, rectally, by inhalation, transdermal, subcutaneous, intravenous intradermal, intraarterial, intramuscular, intracardial, intraosseous, intraperitoneal, transmucosal, vaginal, intravitreal, intraorbital, subretinal, intraarticular, periarticular, local and / or epicutaneous to the subject. In some embodiments, the recombinant herpes virus genome, herpes virus, and / or pharmaceutical composition are administered orally, intranasally, intratracheally, or by inhalation to the subject. In some embodiments, the recombinant herpes virus genome, herpes virus, and / or pharmaceutical composition are administered by inhalation to the subject. In some embodiments, the recombinant herpes virus genome, herpes virus, and / or pharmaceutical composition are administered by non-invasive inhalation to the subject. In some embodiments, the recombinant herpes virus genome, herpes virus, and / or pharmaceutical composition are administered using a dry powder inhaler, pressurized metered-dose inhaler, fine mist inhaler, nebulizer, or electrohydrodynamic aerosol device. . In some embodiments, the recombinant herpes virus genome, herpes virus, and / or the pharmaceutical composition are administered via a nebulizer (eg, a vibrating mesh nebulizer). Other aspects of the present disclosure relate to a method of providing prophylactic, palliative, or therapeutic relief of one or more cystic fibrosis signs or symptoms in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the genomes of the recombinant herpes virus described herein, any of the herpes viruses described herein, and / or any of the compositions described herein. In some forms, the one or more signs or symptoms of cystic fibrosis are selected from a persistent cough that produces thick mucus, thick sticky mucus that accumulates in the airways, wheezing, dyspnea, sinusitis, repeated lung infections, inflammation of nasal passages, bronchiectasis, nasal polyps, hemoptysis, pneumothorax, pancreatitis, recurrent pneumonia, respiratory failure, and any combination of these. In some modalities that can be combined with any of the above modalities, the subject is a human being. In some embodiments that may be combined with any of the above embodiments, the subject's genome comprises a loss-of-function mutation in a CFTR gene. In some modalities that may be combined with any of the above modalities, the recombinant herpes virus genome, the herpes virus, and / or the pharmaceutical composition are administered orally, intranasally, intratracheally, sublingually, buccally, topically, rectally, by inhalation, transdermal, subcutaneous, intravenous intradermal, intraarterial, intramuscular, intracardial, intraosseous, intraperitoneal, transmucosal, vaginal, intravitreal, intraorbital, subretinal, intraarticular, periarticular, local and / or epicutaneous to the subject. In some embodiments, the recombinant herpes virus genome, herpes virus, and / or pharmaceutical composition are administered orally, intranasally, intratracheally, or by inhalation to the subject. In some embodiments, the recombinant herpes virus genome, herpes virus, and / or pharmaceutical composition are administered by inhalation to the subject. In some embodiments, the recombinant herpes virus genome, herpes virus, and / or pharmaceutical composition are administered by non-invasive inhalation to the subject. In some embodiments, the recombinant herpes virus genome, zcoonn / i znz / R / v herpes virus and / or the pharmaceutical composition are administered using a dry powder inhaler, pressurized metered dose inhaler, fine mist inhaler, a nebulizer or an electrohydrodynamic aerosol device. In some embodiments, the recombinant herpes virus genome, herpes virus, and / or the pharmaceutical composition are administered via a nebulizer (eg, a vibrating mesh nebulizer). Other aspects of the present disclosure relate to a method of providing prophylactic, palliative, or therapeutic relief of one or more signs or symptoms of COPD in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the genomes of the recombinant herpes virus described herein, any of the herpes viruses described herein, and / or any of the compositions described herein. In some forms, the one or more signs or symptoms of COPD are selected from shortness of breath, wheezing, chest tightness, excess mucus in the lungs, chronic cough, cyanosis, frequent respiratory infections, and any combination of these. In some modalities that can be combined with any of the above modalities, the subject is a human being. In some embodiments that may be combined with any of the above embodiments, the subject's genome comprises a loss-of-function mutation in a CFTR gene. In some modalities that may be combined with any of the above modalities, the recombinant herpes virus genome, the herpes virus, and / or the pharmaceutical composition are administered orally, intranasally, intratracheally, sublingually, buccally, topically, rectally, by inhalation, transdermal, subcutaneous, intravenous intradermal, intraarterial, intramuscular, intracardial, intraosseous, intraperitoneal, transmucosal, vaginal, intravitreal, intraorbital, subretinal, intraarticular, periarticular, local and / or epicutaneous to the subject. In some embodiments, the recombinant herpes virus genome, herpes virus, and / or pharmaceutical composition are administered orally, intranasally, intratracheally, or by inhalation to the subject. In some embodiments, the recombinant herpes virus genome, herpes virus, and / or pharmaceutical composition are administered by inhalation to the subject. In some embodiments, the recombinant herpes virus genome, herpes virus, and / or pharmaceutical composition are administered by non-invasive inhalation to the subject. In some embodiments, the recombinant herpes virus genome, herpes virus, and / or pharmaceutical composition are administered using a dry powder inhaler, pressurized metered-dose inhaler, fine mist inhaler, nebulizer, or electrohydrodynamic aerosol device. . In some embodiments, the recombinant herpes virus genome, herpes virus, and / or the pharmaceutical composition are administered via a nebulizer (eg, a vibrating mesh nebulizer). Other aspects of the present disclosure relate to an article of manufacture or kit comprising any of the recombinant herpes virus genomes, herpes viruses, medicaments and / or pharmaceutical compositions described herein and instructions for administering the virus genome. of recombinant herpes, herpes virus, medicament or pharmaceutical composition. In some embodiments, the article of manufacture or kit further comprises a device for aerosolizing the recombinant herpes virus genome, herpes virus, drug, and / or pharmaceutical composition. In some embodiments, the device is a dry powder inhaler, a pressurized metered dose inhaler, a fine mist inhaler, a nebulizer, or an electrohydrodynamic aerosol device. In some embodiments, the device is a nebulizer (for example, a mesh nebulizer 7CQQnn / l 7Π7 / Β / Υ vibratory). BRIEF DESCRIPTION OF THE FIGURES FIGURES 1A-1I show schematics of wild-type and modified herpes simplex virus genomes. FIGURE 1A shows a wild-type herpes simplex virus genome. FIGURE 1B shows a modified herpes simplex virus genome comprising ICP4 coding sequence deletions (both copies), with an expression cassette containing a nucleic acid encoding a human CFTR polypeptide integrated into each of the loci. ICP4. FIGURE 1C shows a modified herpes simplex virus genome comprising deletions of the coding sequences for ICP4 (both copies) and UL41, with an expression cassette containing a nucleic acid encoding a human CFTR polypeptide integrated into each of the . ICP4 loci. FIGURE 1D shows a modified herpes simplex virus genome comprising deletions of the ICP4 (both copies) and UL41 coding sequences, with an expression cassette containing a nucleic acid encoding a CFTR polypeptide integrated into the UL41 locus. FIGURE 1E shows a modified herpes simplex virus genome comprising deletions of the coding sequences for ICP4 (both copies) and ICP22, with an expression cassette containing a nucleic acid encoding a human CFTR polypeptide integrated into each of the . ICP4 loci. FIGURE 1F shows a modified herpes simplex virus genome comprising deletions of the ICP4 (both copies) and ICP22 coding sequences, with an expression cassette containing a nucleic acid encoding a CFTR polypeptide integrated into the ICP22 locus. FIGURE 1G shows a modified herpes simplex virus genome comprising deletions of the coding sequences for ICP4 (both copies), UL41 and ICP22, with an expression cassette containing a nucleic acid encoding a human CFTR polypeptide integrated into each. of the ICP4 loci. FIGURE 1H shows a modified herpes simplex virus genome comprising deletions of the coding sequences for ICP4 (both copies), UL41 and ICP22, with an expression cassette containing a nucleic acid encoding a CFTR polypeptide integrated into the UL41 locus. . FIGURE 11 shows a modified herpes simplex virus genome comprising deletions of the coding sequences for ICP4 (both copies), UL41 and ICP22, with an expression cassette containing a nucleic acid encoding a CFTR polypeptide integrated into the ICP22 locus. . FIGURE 2 shows human CFTR expression in primary airway epithelial cells (SAECs) derived from cystic fibrosis (CF) patients infected at multiplicities of infection (MCI) indicated with an HSV-CFTR vector, as assessed by qRTPCR analysis. SAEC FQs with mock infection were used as a negative control. Data are presented as the average of two replicates ± SEM. FIGURE 3 shows human CFTR protein expression in primary SAECs derived from CF patients infected at the indicated MOIs with an HSV-CFTR vector, as assessed by Western blot analysis. SAEC FQs with mock infection were used as a negative control. GAPDH was used as a loading control. FIGURES 4A-4B show representative immunofluorescence images of human CFTR protein expression in SAEC from HSV-CFTR-infected or mock-infected primary CF patients. la zcoonn / i znz / r / v FIGURE 4A shows the dose-dependent increase in human CFTR protein expression following infection of primary SAEC CF with increasing HSV-CFTR MOI. FIGURE 4B shows the relative cellular localization of human CFTR protein in primary FQ SAECs mock-infected (MOI 0) or HSVCFTR-infected (MOI 3). DAPI staining was used to visualize the nuclei. FIGURE 5 shows the functionality of human CFTR protein in primary SAECs derived from CF patients infected at the indicated MOIs with an HSV-CFTR vector, as assessed by a fluorescent dye uptake assay. SAEC FQs with mock infection were used as a negative control. Data are presented as the mean ± SEM. FIGURES 6A-6C show analyzes of intestinal organoids derived from G542X / G542X cystic fibrosis patients (PDOs) infected with HSV-CFTR at the indicated MOIs. Vehicle alone or an HSV vector encoding mCherry (mCherry) were used as negative controls; G418 was used as a positive control. FIGURE 6A shows representative brightfield images of G542X / G542X PDOs 24 hours after vehicle treatment, or after transduction with HSV-CFTR or HSV-mCherry at an MOI of 10. Vehicle-treated PDOs from a healthy individual (wild type) were included and images were taken as a comparator. FIGURE 6B shows representative images of calcein-stained organoids and quantification of average organoid size prior to the addition of forskolin (Frsk) (t=0). FIGURE 6C shows representative images of calcein-stained organoids and quantification of average organoid size 60 minutes after the addition of Frsk 2μΜ (t=60). ***p<0.001; ****p<0.0001. FIGURES 7A-7B show analyzes of intestinal organoids derived from F508del / F508del cystic fibrosis patients (PDOs) infected with HSV-CFTR at the indicated MOIs. Vehicle alone or an HSV vector encoding mCherry (mCherry) were used as negative controls; Orkambi® was used as a positive control. FIGURE 7A shows representative images of calcein-stained organoids and quantification of average organoid size prior to the addition of forskolin (Frsk) (t=0). FIGURE 7B shows representative images of calcein-stained organoids and quantification of average organoid size 60 minutes after the addition of Frsk 2μΜ (t=60). *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001. FIGURES 8A-8B show analyzes of intestinal organoids derived from W1282X / W1282X cystic fibrosis patients (PDOs) infected with HSV-CFTR at the indicated MOIs. Vehicle alone or an HSV vector encoding mCherry (mCherry) were used as negative controls. FIGURE 8A shows representative images of calcein-stained organoids and quantification of average organoid size prior to the addition of forskolin (Frsk) (t=0). FIGURE 8B shows representative images of calcein-stained organoids and quantification of average organoid size 60 minutes after the addition of Frsk 2μΜ (t=60). *p<0.05; ***p<0.001. FIGURES 9A-9B show analyzes of intestinal organoids derived from F508del / F508del cystic fibrosis patients (PDOs) infected with HSV-CFTR at the indicated MOIs. Vehicle alone or an HSV vector encoding mCherry (mCherry) were used as negative controls; Orkambi® was used as a positive control. FIGURE 9A shows representative images of calcein-stained organoids and quantification of the 7CQQnn / l 7Π7 / Β / Υ average size of organoids before the addition of forskolin (Frsk) (t=0). FIGURE 9B shows representative images of calcein-stained organoids and quantification of average organoid size 60 minutes after the addition of Frsk 2μΜ (t=60). ****p<0.0001. FIGURES 10A-10C show analysis of mCherry protein and nucleic acid in cultured lung and trachea biopsies 48 hours after intranasal or intratracheal administration of an HSV vector encoding mCherry (HSV-mCherry) or vehicle control (mock). FIGURE 10A shows the levels of mCherry transcripts present in trachea and lung biopsies, as assessed by qRT-PCR analysis. Data are presented as the average of six replicates ± SEM for HSV-mCherry; data are presented as the average of four replicates ± SEM for the vehicle control. FIGURE 10B shows representative immunofluorescence images of mCherry protein expression in lung biopsies after intranasal administration of HSV-mCherry or vehicle control. DAPI staining was used to visualize nuclei; cytokeratin staining was used to visualize epithelial cells. FIGURE 10C shows representative immunofluorescence images of mCherry protein expression in lung biopsies after intratracheal administration of HSV-mCherry or vehicle control. DAPI staining was used to visualize nuclei; cytokeratin staining was used to visualize epithelial cells. DETAILED DESCRIPTION The description below sets forth examples of methods, parameters, and the like. However, it should be recognized that such a description is not intended as a limitation on the scope of the present disclosure, but rather is provided as a description of exemplary embodiments. I. General techniques The techniques and procedures described or stated herein are generally commonly understood and used by those skilled in the art using conventional methodology, such as, for example, the widely used methodologies described in Sambrook et al., Molecular Cloning: A Laboratory Manual 3rd Edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; Current Protocol in Molecular Biology (F.M. Ausubel, et al. eds., (2003)); Methods in Enzymology series (Academic Press, Inc.): PCR 2: A Practical Approach (M.J. MacPherson, B.D. Hames, and G.R. Taylor eds. (1995)), Harlowy Lane, eds. (1988); Oligonucleotide Synthesis (M.J. Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Blology: A Laboratory Notebook (J.E. Cellis, ed., 1998) Academic Press; Animal Cell Culture (R.l. Freshney), ed., 1987); Introductory to Cell and Tissue Culture (J.P. Mather and P.E. Roberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (A. Doyle, J.B. Griffiths and D.G. Newell, eds., 1993-8) J. Wiley and Sons; Gene Transfer Vectors for Mammalian Cells (J.M. Miller and M.P. Calos, eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994); Short Protocols in Molecular Biology (Wiley and Sons, 1999). II. Definitions Before describing the present disclosure in detail, it should be understood that the present disclosure is not limited to particular compositions or biological systems, which, of course, can vary. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be zcoonn / i znz / R / v exhaustive. As used herein, the singular forms "a", "one" and "the" include plural referents, unless the content clearly indicates otherwise. Thus, for example, reference to "a molecule" optionally includes a combination of two or more such molecules and the like. As used herein, the term "and / or" may include any and all of one or more of the associated listed items. For example, the term "a and / or b" may refer to "a alone," "b alone," "a or b," or "a and b"; the term a, b and / or c” can refer to “a alone”, “b alone”, “c alone”, “a or b”, “a or c”, “b or o”, a, b, or c”, “a and b”, “ a and c”, “b and c”, or “a, b and o”; etc As used herein, the term "about" refers to the usual error range for the respective value that is readily known to one skilled in the art. Reference to about a value or parameter herein includes (and describes) modalities that refer to that value or parameter itself. Aspects and embodiments of the present disclosure are understood to include aspects and embodiments of comprising, consisting of, and consisting essentially of. As used herein, the terms polynucleotide, nucleic acid sequence, nucleic acid, and variations thereof will be generic to polydeoxyribonucleotides (containing 2-deoxy-D-ribose), to polyribonucleotides (containing D-ribose), to any other type of polynucleotide that is an N-glycoside of a purine or pyrimidine base, and for other polymers containing non-nucleotide backbones, provided that the polymers contain nucleobases in a configuration that allows for base pairing and base stacking, as found in DNA and RNA. Thus, these terms include known types of nucleic acid sequence modifications, eg, substitution of one or more naturally occurring nucleotides with an analogue, and internucleotide modifications. As used herein, a nucleic acid is "operably linked" or "operably linked" when it is placed into a functional relationship with another nucleic acid sequence. For example, a promoter or enhancer is operably linked to a coding sequence if it affects transcription of the sequence, or a ribosome binding site is operably linked to a coding sequence if it is positioned to facilitate translation. Generally, "operably linked" or "operably linked" means that the DNA or RNA sequences being linked are contiguous. As used herein, the term "vector" refers to discrete elements that are used to introduce heterologous nucleic acids into cells for expression or replication. An expression vector includes vectors capable of expressing nucleic acids that are operably linked to regulatory sequences, such as promoter regions, that are capable of effecting expression of said nucleic acids. Thus, an expression vector can refer to a DNA or RNA construct, such as a plasmid, phage, recombinant virus, or other vector that, upon introduction into an appropriate host cell, results in the expression of the nucleic acids . Appropriate expression vectors are well known to those skilled in the art and include those that are replicable in eukaryotic cells and those that remain episomal or those that integrate into the host cell genome. zcoonn / i znz / R / viAi As used herein, an "open reading frame" or "ORF" refers to a continuous stretch of nucleic acids, either DNA or RNA, that encode a protein or polypeptide. Typically, nucleic acids comprise a translation start signal or start codon, such as ATG or AUG, and a stop codon. As used herein, an "untranslated region" or UTR" refers to untranslated nucleic acids at the 5' and / or 3' ends of an open reading frame. Inclusion of one or more UTRs in a polynucleotide can affect post-transcriptional regulation, mRNA stability, and / or translation of the polynucleotide. As used herein, the term "transgene" refers to a polynucleotide that is capable of being transcribed into RNA and translated and / or expressed under appropriate conditions, after being introduced into a cell. In some embodiments, it confers a desired property on a cell into which it is introduced, or otherwise leads to a desired therapeutic or diagnostic result. As used herein, the terms "polypeptide", "protein" and "peptide" are used interchangeably and can refer to a polymer of two or more amino acids. As used herein, a subject, "host" or an "individual" refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sporting or companion animals, such as dogs, horses, cats, cows, as well as animals used in research, such as mice, rats, hamsters, rabbits and non-human primates, etc. In some embodiments, the mammal is a human. As used herein, the terms "pharmaceutical formulation" or "pharmaceutical composition" refer to a preparation in such a way as to allow the efficacy of the biological activity of the active ingredient(s) and that it does not contain additional components with a toxicity unacceptable to a subject to whom the composition or formulation would be administered. "Pharmaceutically acceptable" excipients (eg, carriers, additives) are those that can reasonably be administered to a subject mammal to provide an effective dose of the active ingredient(s) employed. As used herein, an "effective amount" is at least the minimal amount necessary to effect medial amelioration or prevention of one or more symptoms of a particular disorder. An effective amount may vary according to factors such as the disease state, age, sex and weight of the patient. An effective amount is also an amount in which any toxic or detrimental effects of the treatment are outweighed by therapeutically favorable effects. For prophylactic use, favorable or desired outcomes include outcomes such as elimination or reduction of risk, decreased severity or delayed onset of the disease, its complications, and intermediate pathologic phenotypes present during the course of the disease. For therapeutic use, favorable or desired results include clinical results such as a decrease in one or more symptoms arising from the disease, an increase in the quality of life of those suffering from the disease, a decrease in the dose of other drugs used to treat the disease, disease, delay in disease progression and / or prolongation of survival. An effective amount can be administered in one or more administrations. For purposes of the present disclosure, an effective amount of a recombinant nucleic acid, virus, and / or pharmaceutical composition is an amount sufficient to directly or indirectly achieve prophylactic or therapeutic treatment. As understood in the clinical context, an effective amount of a recombinant nucleic acid, virus, and / or zcoonn / i znz / R / v pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an "effective amount" may be considered in the context of the administration of one or more therapeutic agents and a single agent may be considered delivered in an effective amount if, in conjunction with one or more additional agents, a specific result can be or is achieved. desirable. As used herein, "treatment" refers to a clinical intervention designed to alter the natural course of the individual or cell under treatment during the course of clinical pathology. Desirable effects of treatment include reduction in the rate of progression of the disease / disorder / defect, improvement or mitigation of the disease / disorder / defect status, and remission or improved prognosis. For example, an individual is "successfully treated" if one or more symptoms associated with a chronic lung disease (eg, cystic fibrosis or COPD) are mitigated or eliminated. As used herein, the term "delaying the progression of a disease / disorder / defect" refers to delaying, hindering, slowing down, retarding, stabilizing, and / or postponing the development of the disease / disorder / defect (eg, fibrosis cystic or COPD). This delay may be of different length or time, depending on the history of the disease / disorder / defect and / or the individual being treated. As is apparent to one skilled in the art, a sufficient or considerable delay may effectively imply prevention, in the sense that the individual does not develop the disease. III. recombinant nucleic acids Certain aspects of this disclosure relate to recombinant nucleic acids (eg, isolated recombinant nucleic acids) that comprise one or more polynucleotides (eg, one or more, two or more, three or more, four or more, five or more , ten or more, etc.) that encode a CFTR polypeptide (eg, a human CFTR polypeptide). In some embodiments, the recombinant nucleic acid comprises a polynucleotide encoding a CFTR polypeptide. In some embodiments, the recombinant nucleic acid comprises two polynucleotides that encode a CFTR polypeptide. In some embodiments, the recombinant nucleic acid comprises three polynucleotides that encode a CFTR polypeptide. In some embodiments, the recombinant nucleic acid is a vector. In some embodiments, the recombinant nucleic acid is a viral vector. In some embodiments, the recombinant nucleic acid is a herpes viral vector. In some embodiments, the recombinant nucleic acid is a herpes simplex virus amplicon. In some embodiments, the recombinant nucleic acid is a recombinant herpesvirus genome. In some embodiments, the recombinant nucleic acid is a recombinant herpes simplex virus genome. In some embodiments, the recombinant nucleic acid is a recombinant herpes simplex virus type 1 (HSV-1) genome. Polynucleotides Encoding Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Polypeptides In some embodiments, the present disclosure relates to a recombinant nucleic acid comprising one or more polynucleotides comprising the coding sequence for a CFTR gene (eg, a human CFTR gene), or any part thereof. The sequence of any CFTR gene (including any isoform thereof) known in the art may be encoded by a polynucleotide of the present disclosure, including, for example, 7CQQnn / l 7Π7 / Β / Υ a human CFTR gene (see, for example, NCBI gene ID: 1080; SEQ ID NO: 1 or SEQ ID NO: 3), a chimpanzee CFTR gene (see, for example, , NCBI gene ID: 463674), a mouse CFTR gene (see, for example, NCBI gene ID: 12638), a rat CFTR gene (see, for example, NCBI gene ID: 24255), a dog CFTR gene (see, for example, NCBI gene ID: 492302), a rabbit CFTR gene (see, for example, NCBI gene ID: 100009471), a cow CFTR gene (see, for example, , NCBI gene ID: 281067), a rhesus monkey CFTR gene (see, for example, NCBI gene ID: 574346), etc. In some embodiments, a polynucleotide of the present disclosure comprises a sequence that is at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of any of the CFTR genes described herein or known in the art (and / or the coding sequences thereof). Methods for identifying homologs / orthologs of the CFTR gene from additional species are known to one of skill in the art, including, for example, using a nucleic acid sequence alignment program such as the BLAST® Blastn package. In some embodiments, a polynucleotide of the present disclosure comprises a codon-optimized variant of any of the CFTR genes described herein or known in the art. In some embodiments, a polynucleotide of the present disclosure comprises a codon-optimized variant of the coding sequence of any of the CFTR genes described herein or known in the art. In some embodiments, the use of a codon-optimized variant of a CFTR gene increases the stability and / or yield of heterologous expression (RNA and / or protein) of the encoded CFTR polypeptide in a target cell (eg, a target human cell). such as a human airway epithelial cell), compared to the stability and / or yield of heterologous expression of a corresponding non-codon-optimized wild-type sequence. Any suitable method known in the art can be used to perform codon optimization of a sequence for expression in one or more target cells (eg, one or more lung cells), including, for example, the methods described by Fath et al. (PLoS One. 2011 Mar 3; 6(3): e17596). In some embodiments, one or more polynucleotides of the present disclosure comprise the coding sequence for a human CFTR gene. In some embodiments, a polynucleotide of the present disclosure comprises a sequence that is at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of SEQ ID NO: 1. In some embodiments, a polynucleotide of the present disclosure comprises the sequence of SEQ ID NO: 1. In some embodiments, a polynucleotide of the present disclosure comprises a 5' truncation, 3' truncation, or fragment of the sequence of SEQ ID NO: 1. In some embodiments, the 5' truncation, 3' truncation, or fragment of the sequence of SEQ ID NO: 1 is a polynucleotide having at least 25, at least 50, at least 75, at least 100, at least 125, at least 150, at least 175, at least 200, at least 250, at least 300, or at least 350, at least 400, at least 450, at least 500, at least 750, at least 1000, at least 1250, zcoonn / i znz / R / v at least 1500, at least 1750 , at least 2000, at least 2250, at least 2500, at least 2750, at least 3000, at least 3250, at least 3500, at least 3750, at least 4000, at least 4250, but less than 4443 consecutive nucleotides of SEQ ID NO: 1. In some embodiments, a polynucleotide of the present disclosure comprises a sequence that is at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the nucleic acid sequence 1-4440 of SEQ ID NO: 1. In some embodiments, a polynucleotide of the present disclosure comprises the nucleic acid sequence 1-4440 of SEQ ID NO: 1. SEQ ID NO: 1. In some embodiments, a polynucleotide of the present disclosure comprises a sequence that is at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of SEQ ID NO: 3. In some embodiments, a polynucleotide of the present disclosure comprises the sequence of SEQ ID NO: 3. In some embodiments, a polynucleotide of the present disclosure comprises a 5' truncation, 3' truncation, or fragment of the sequence of SEQ ID NO: 3. In some embodiments, the 5' truncation, 3' truncation, or fragment of the sequence of SEQ ID NO: 3 is a polynucleotide having at least 25, at least 50, at least 75, at least 100, at least 125, at least 150, at least 175, at least 200, at least 250, at least 300, or at least 350, at least 400, at least 450, at least 500, at least 750, at least 1000, at least 1250, at least 1500, at least 1750, at least 2000, at least 2250 , at least 2500, at least 2750, at least 3000, at least 3250, at least 3500, at least 3750, at least 4000, at least 4250, but less than 4260 consecutive nucleotides of SEQ ID NO: 3. In some embodiments , a polynucleotide of the present disclosure comprises a sequence having at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90 %, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% of sequence identity with the nucleic acid sequence 1-4257 of SEQ ID NO: 3. In some embodiments, a polynucleotide of the present disclosure comprises the nucleic acid sequence 1-4257 of SEQ ID NO: 3. In some embodiments, a polynucleotide of the present disclosure comprises the coding sequence for a codon-optimized variant of a human CFTR gene. In some embodiments, a polynucleotide of the present disclosure comprises a sequence that is at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of SEQ ID NO: 2. In some embodiments, a polynucleotide of the present disclosure comprises the sequence of SEQ ID NO: 2. In some embodiments, a polynucleotide of the present disclosure comprises a 5' truncation, 3' truncation, or fragment of the sequence of SEQ ID NO: 2. In some embodiments, the 5' truncation, 3' truncation, or fragment of the sequence of SEQ ID NO: 2 is a polynucleotide that has at least 25, at 7CQQnn / l 7Π7 / Ε / Υ minus 50, at least 75, at least 100, at least 125, at least 150, at least 175, at least 200, at least 250, at least 300, or at least 350, at least 400, at least 450, at least 500, at least 750, at least 1000, at least 1250, at least 1500, at least 1750, at least 2000, at least 2250, at least 2500, at least 2750, at least 3000, at least 3250, at least 3500, at least 3750, at least 4000, at least 4250, but less than 4443 consecutive nucleotides of SEQ ID NO: 2. In some embodiments, a polynucleotide of the present disclosure comprises a sequence having at least least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to nucleic acid sequence 1-4440 of SEQ ID NO: 2. In some embodiments, a polynucleotide of the present disclosure comprises the nucleic acid sequence 1-4440 of SEQ ID NO: 2. In some embodiments, a polynucleotide of the present disclosure comprises a sequence that is at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of SEQ ID NO: 4. In some embodiments, a polynucleotide of the present disclosure comprises the sequence of SEQ ID NO: 4. In some embodiments, a polynucleotide of the present disclosure comprises a 5' truncation, 3' truncation, or fragment of the sequence of SEQ ID NO: 4. In some embodiments, the 5' truncation, 3' truncation, or fragment of the sequence of SEQ ID NO: 4 is a polynucleotide having at least 25, at least 50, at least 75, at least 100, at least 125, at least 150, at least 175, at least 200, at least 250, at least 300, or at least 350, at least 400, at least 450, at least 500, at least 750, at least 1000, at least 1250, at least 1500, at least 1750, at least 2000, at least 2250 , at least 2500, at least 2750, at least 3000, at least 3250, at least 3500, at least 3750, at least 4000, at least 4250, but less than 4260 consecutive nucleotides of SEQ ID NO: 4. In some embodiments , a polynucleotide of the present disclosure comprises a sequence having at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90 %, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% of sequence identity with the nucleic acid sequence 1-4257 of SEQ ID NO: 4. In some embodiments, a polynucleotide of the present disclosure comprises the nucleic acid sequence 1-4257 of SEQ ID NO: 4. In some embodiments, a polynucleotide of the present disclosure comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to a nucleic acid sequence that is selected from SEQ ID NO: 1-4 In some embodiments, a polynucleotide of the present disclosure comprises a sequence that is selected from SEQ ID NO: 1-4 In some embodiments, a polynucleotide of the present disclosure comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to a selected nucleic acid sequence zcoonn / i ζηζ / Ε / γ of SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, a polynucleotide of the present disclosure comprises a sequence which is selected from SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, a polynucleotide of the present disclosure comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with a nucleic acid sequence selected from SEQ ID NO: 3 or SEQ ID NO: 4. In some embodiments, a polynucleotide of the present disclosure comprises a sequence that is selected from SEQ ID NO: 3 or SEQ ID NO : 4. A polynucleotide of the present disclosure (eg, encoding a human CFTR polypeptide) may further encode additional coding and non-coding sequences. Examples of additional coding and non-coding sequences may include, but are not limited to, sequences encoding additional polypeptide tags (eg, encoded in frame with the CFTR protein to produce a fusion protein), introns (eg, native, modified, or heterologous introns), 5' and / or 3' UTR (eg, native, modified, or heterologous 5' and / or 3' UTR), and the like. Examples of suitable polypeptide tags may include, but are not limited to, any combination of purification tags, such as his tags, flag tags, maltose-binding proteins, and glutathione-S-transferase tags), detection tags (such as tags that can be detected photometrically (eg, green fluorescent protein, red fluorescent protein, etc.) and tags that have detectable enzymatic activity (eg, alkaline phosphatase, etc.), tags containing secretory sequences, signal sequences, leader sequences , and / or stabilizing sequences, protease cleavage sites (eg, furin cleavage sites, TEV cleavage sites, thrombin cleavage sites, etc.) and the like.In some embodiments, the 5' UTRs and / or or 3' increase the stability, localization, and / or translational efficiency of polynucleotides In some embodiments, 5' and / or 3' UTRs enhance the level and / or duration of protein expression. In some embodiments, the 5' and / or 3' UTRs include elements (eg, one or more miRNA binding sites, etc.) that can block or reduce off-target expression (eg, inhibit expression in types specific cells (for example, neuronal cells), at specific moments in the cell cycle, at specific stages of development, etc.). In some embodiments, the 5' and / or 3' UTRs include elements (eg, one or more miRNA binding sites, etc.) that can enhance CFTR expression in specific cell types. In some embodiments, a polynucleotide of the present disclosure (eg, encoding a human CFTR polypeptide) is operatively linked to one or more (eg, one or more, two or more, three or more, four or more, five or more, ten or more, etc.) regulatory sequences. The term "regulatory sequence" can include enhancers, insulators, promoters, and other expression control elements (eg, polyadenylation signals). Any suitable enhancer known in the art may be used, including, for example, enhancer sequences from mammalian genes (such as globin, elastase, albumin, α-fetoprotein, insulin, and the like), enhancer sequences from a eukaryotic cell virus ( such as the SV40 enhancer on the late side of the replication origin (bp 100-270), the cytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the replication origin, adenovirus enhancers, and the like), and any combination of these. Any suitable isolate known in the art may be used, including, for example, zcoonn / i znz / R / v herpes simplex virus (HSV) chromatin boundary elements (CTRL / CTCF isolate / binding) CTRL1 and / o CTRL2, isolate of chicken hypersensitive site 4 (cHS4), human HNRPA2B1—ubiquitous CBX3 chromatin opening element (UCOE), the scaffold / matrix junction region (S / MAR), English) of the human interferon beta gene (IFNB1) and any combination of these. Any suitable promoter (eg, suitable for transcription in mammalian host cells) known in the art can be used, including, for example, promoters derived from the genomes of viruses (such as polyoma virus, avian pox virus, adenovirus ( such as Adenovirus 2), bovine papilloma virus, avian sarcoma virus, cytomegalovirus, a retrovirus, hepatitis B virus, simian virus 40 (SV40) and the like), mammalian heterologous gene promoters (such as the actin promoter (for example, the βactin promoter), a ubiquitin promoter (for example, a ubiquitin C (UbC) promoter), a phosphoglycerate kinase (PGK) promoter, an immunoglobulin promoter, heat shock promoters, and the like) , native and / or homologous mammalian gene promoters (eg, a human CFTR gene promoter), synthetic promoters (such as the CAGG promoter), and any combination of these, provided that such promoters are compatible with the host cells. Regulatory sequences may include those that directly express a nucleic acid constitutively, as well as repressible or inducible and / or tissue-specific regulatory sequences. In some embodiments, a polynucleotide of the present disclosure is operably linked to one or more heterologous promoters. In some embodiments, the one or more heterologous promoters are one or more of constitutive promoters, tissue-specific promoters, temporal promoters, spatial promoters, inducible promoters, and repressible promoters. In some embodiments, the one or more heterologous promoters are one or more of the human cytomegalovirus (HCMV) immediate early promoter, the human elongation factor 1 (EF1) promoter, the human β-actin promoter, human UbC promoter, human PGK promoter, synthetic CAGG promoter, and any combination of these. In some embodiments, a polynucleotide of the present disclosure (eg, encoding a human CFTR polypeptide) is operatively linked to an HCMV promoter. In some embodiments, a polynucleotide of the present disclosure does not comprise the coding sequence for (eg, a transgene encoding) a collagen alpha-1 (Vil) chain (COL7) polypeptide. In some embodiments, a polynucleotide of the present disclosure does not comprise the coding sequence for (eg, a transgene encoding) a lysylhydroxylase 3 (LH3) polypeptide. In some embodiments, a polynucleotide of the present disclosure does not comprise the coding sequence for (eg, a transgene encoding) a keratin type I cytoskeletal 17 (KRT17) polypeptide. In some embodiments, a polynucleotide of the present disclosure does not comprise the coding sequence for (eg, a transgene encoding) a transglutaminase (TGM) polypeptide (eg, a human transglutaminase polypeptide such as a human TGM1 polypeptide and / or or a human TGM5 polypeptide). In some embodiments, a polynucleotide of the present disclosure does not comprise the coding sequence for (eg, a transgene encoding) a cosmetic protein (eg, collagen proteins, fibronectins, elastins, lumicans, vitronectins / vitronectin receptors, laminins , neuromodulators, fibrillins, additional proteins of the dermal extracellular matrix, etc.). In some embodiments, a polynucleotide of the present disclosure does not comprise the coding sequence for (eg, a transgene encoding zcoonn / i znz / R / v) an antibody (eg, a full-length antibody, an antibody fragment , etc.). In some embodiments, a polynucleotide of the present disclosure does not comprise the coding sequence for (eg, a transgene encoding) a serine protease inhibitor Kazal-like (SPINK) polypeptide (eg, a human SPINK polypeptide, such as a SPINK5 polypeptide). In some embodiments, a polynucleotide of the present disclosure does not comprise the coding sequence for (eg, a transgene encoding) a filaggrin or filaggrin 2 polypeptide (eg, a human filaggrin or filaggrin 2 polypeptide). In some embodiments, a polynucleotide of the present disclosure does not comprise the coding sequence for (eg, a transgene encoding) an alpha-1 (Vil) collagen chain polypeptide, a lysylhydroxylase 3 polypeptide, a cytoskeletal polypeptide 17 type I keratin and / or any chimeric polypeptide thereof. In some embodiments, a polynucleotide of the present disclosure does not comprise the coding sequence for (eg, a transgene encoding) a collagen alpha-1 (Vil) chain polypeptide, a lysylhydroxylase 3 polypeptide, a cytoskeletal polypeptide 17 type I keratin polypeptide, a transglutaminase (TGM) polypeptide, a filaggrin polypeptide, a cosmetic protein, an antibody, a SPINK polypeptide, and / or any chimeric polypeptide thereof. Cystic fibrosis transmembrane conductance regulator (CFTR) polypeptides In some embodiments, the present disclosure relates to one or more polynucleotides that encode a CFTR polypeptide (eg, a human CFTR polypeptide) or any part thereof. Any suitable CFTR polypeptide known in the art can be encoded by a polynucleotide of the present disclosure, including, for example, a human CFTR polypeptide (see, for example, Uniprot Accession Number P13569; SEQ ID NO: 5 or SEQ ID NO: 6), a chimpanzee CFTR polypeptide (see, for example, Uniprot accession number Q2QLE5), a mouse CFTR polypeptide (see, for example, Uniprot accession number P26361), a rat CFTR polypeptide (see, for example, Uniprot accession number P34158), a rabbit CFTR polypeptide (see, for example, Uniprot accession number Q00554), a Rhesus monkey CFTR polypeptide (see, for example, Uniprot accession number Q00553), etc. In some embodiments, a CFTR polypeptide of the present disclosure comprises a sequence that is at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89% , at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to the amino acid sequence of any of the CFTR polypeptides described herein or known in the art. Methods for identifying homologs / orthologs of the CFTR polypeptide from additional species are known to one of ordinary skill in the art, including, for example, using an amino acid sequence alignment program such as the BLAST® Blastp package or OrthoDB. In some embodiments, a CFTR polypeptide of the present disclosure is a human CFTR polypeptide. In some embodiments, a polynucleotide encoding a human CFTR polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid sequence that is at least 75%, at least 80%, at least 85%, at least 86%, at least 87% %, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97 %, at least 98%, at least 99%, or 100% sequence identity to the sequence of SEQ ID NO: 5. In some embodiments, a polynucleotide that zcoonn / i znz / R / v encodes a human CFTR polypeptide is a polynucleotide that encodes a polypeptide comprising the amino acid sequence of SEQ ID NO: 5. In some embodiments, a polynucleotide encoding a human CFTR polypeptide is a polynucleotide encoding an N-terminal truncation, a C-terminal truncation, or a fragment of the amino acid sequence of SEQ ID NO: 5. N-terminal truncations, the O-terminal truncations or fragments may comprise at least 10, at least 12, at least 14, at least 16, at least 18, at least 20, at least 30, at least 40, at least 50, at least 75, at least 100, at least 150, at least 200, at least 250, at least 300, at least 350, at least 400, at least 450, at least 500, at least 550, at least 600, at least 650, at least 700, at least 750, at least 800, at least 850, at least 900, at least 950, at least 1000, at least 1100, at least 1200, at least 1300, at least 1400, but less than 1480, consecutive amino acids of SEQ ID NO: 5. In some embodiments, a polynucleotide encoding a human CFTR polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid sequence that is at least 75%, at least 80%, at least 85%, at least 86%, at least 87% %, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97 %, at least 98%, at least 99%, or 100% sequence identity to the sequence of SEQ ID NO: 6. In some embodiments, a polynucleotide encoding a human CFTR polypeptide is a polynucleotide encoding a polypeptide that comprises the amino acid sequence of SEQ ID NO: 6. In some embodiments, a polynucleotide encoding a human CFTR polypeptide is a polynucleotide encoding an N-terminal truncation, a C-terminal truncation, or a fragment of the amino acid sequence of SEQ ID NO: 6. N-terminal truncations, the O-terminal truncations or fragments may comprise at least 10, at least 12, at least 14, at least 16, at least 18, at least 20, at least 30, at least 40, at least 50, at least 75, at least 100, at least 150, at least 200, at least 250, at least 300, at least 350, at least 400, at least 450, at least 500, at least 550, at least 600, at least 650, at least 700, at least 750, at least 800, at least 850, at least 900, at least 950, at least 1000, at least 1100, at least 1200, at least 1300, at least 1400, but less than 1419, consecutive amino acids of SEQ ID NO: 6. In some embodiments, a polynucleotide of the present disclosure that encodes a CFTR polypeptide is a polynucleotide that encodes a polypeptide that comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to amino acid sequence of SEQ ID NO: 5 or SEQ ID NO: 6. In some embodiments, a polynucleotide of the present disclosure that encodes a human CFTR polypeptide is a polynucleotide that encodes a polypeptide comprising the amino acid sequence of SEQ ID NO: 5 or SEQ ID NO: 6. In some embodiments, a polynucleotide of the present disclosure that encodes a CFTR polypeptide (eg, a human CFTR polypeptide) expresses the CFTR polypeptide when the polynucleotide is delivered into one or more target cells of a subject (eg, one or more cells of the respiratory tract and / or lungs of the subject). In some embodiments, expression of the CFTR polypeptide (eg, a human CFTR polypeptide) is increased, zcoonn / i znz / B / v increases, enhances, and / or complements the levels, function, and / or activity of a CFTR polypeptide in one or more target cells from a subject (eg, compared to before CFTR polypeptide expression). In some embodiments, expression of the CFTR polypeptide (eg, a human CFTR polypeptide) reduces mucus secretion in one or more cells and / or in one or more organs (eg, the lungs) of the subject (eg, in comparison with before CFTR polypeptide expression). In some embodiments, expression of the CFTR polypeptide (eg, a human CFTR polypeptide) reduces and / or inhibits the accumulation of mucus in one or more organs (eg, the lungs) of the subject (eg, compared to before CFTR polypeptide expression). In some embodiments, expression of the CFTR polypeptide (eg, a human CFTR polypeptide) reduces, prevents, or treats airway obstruction in a subject (eg, compared to prior to CFTR polypeptide expression). In some embodiments, expression of the CFTR polypeptide (eg, a human CFTR polypeptide) reduces, prevents, or treats chronic bacterial infections and / or associated chronic inflammation in the lungs of a subject (eg, compared to before CFTR polypeptide expression). In some embodiments, expression of the CFTR polypeptide (eg, a human CFTR polypeptide) reduces, inhibits, prevents, or treats bronchiectasis in a subject (eg, compared to prior CFTR polypeptide expression). In some embodiments, expression of the CFTR polypeptide (eg, a human CFTR polypeptide) reduces, prevents, or treats progressive destruction of the lungs in a subject (eg, compared to prior to CFTR polypeptide expression). In some embodiments, expression of the CFTR polypeptide (eg, a human CFTR polypeptide) provides prophylactic, palliative, or therapeutic relief of chronic lung disease (eg, cystic fibrosis, chronic obstructive pulmonary disorder) in a subject (eg, in comparison with before CFTR polypeptide expression). In some embodiments, expression of the CFTR polypeptide (eg, a human CFTR polypeptide) provides prophylactic, palliative, or therapeutic relief of one or more signs or symptoms of cystic fibrosis in a subject (eg, compared to prior to expression). CFTR polypeptide). recombinant nucleic acids In some embodiments, the present disclosure relates to recombinant nucleic acids comprising one or more of the polynucleotides described herein. In some embodiments, the recombinant nucleic acid is a vector (eg, an expression vector, a display vector, etc.). In some embodiments, the vector is a DNA vector or an RNA vector. In general, vectors suitable for maintaining, propagating and / or expressing polynucleotides can be used to produce one or more polypeptides in a subject. Examples of suitable vectors may include, for example, plasmids, cosmids, episomes, transposons, and viral vectors (for example, adenoviral vectors, adeno-associated viral vectors, vaccinia viral vectors, Sindbis viral vectors, measles vectors, viral vectors herpes, lentiviral vectors, retroviral vectors, etc.). In some embodiments, the vector is a herpes viral vector. In some embodiments, the vector is capable of autonomous replication in a host cell. In some embodiments, the vector is incapable of autonomous replication in a host cell. In some embodiments, the vector can integrate into host DNA. In some embodiments, the vector cannot integrate into a host's DNA (eg, it is episomal). Methods for making vectors containing one or more polynucleotides of interest are well known to those skilled in the art, including, for example, by chemical synthesis or by artificial manipulation of isolated nucleic acid segments. (for example, through genetic engineering techniques). In some embodiments, a recombinant nucleic acid of the present disclosure is a herpes simplex virus (HSV) amplicon. Herpes virus amplicons, including structural features and methods for making them, are generally known to those skilled in the art (see, for example, de Silva S. and Bowers W. Herpes Virus Amplicon Vectors.” Viruses 2009, 1 , 594-629). In some embodiments, the herpes simplex virus amplicon is an HSV-1 amplicon. In some embodiments, the herpes simplex virus amplicon is a hybrid HSV-1 amplicon. Examples of HSV-1 hybrid amplicons may include, but are not limited to, HSV / AAV hybrid amplicons, HSV / EBV hybrid amplicons, HSV / EBV / RV hybrid amplicons, and / or HSV / Sleeping Beauty hybrid amplicons. In some embodiments, the amplicon is a hybrid HSV / AAV amplicon. In some embodiments, the amplicon is a hybrid HSV / Sleeping Beauty amplicon. In some embodiments, a recombinant nucleic acid of the present disclosure is a recombinant herpes virus genome. The recombinant herpes virus genome may be a recombinant genome of any member of the Herpesviridae family of DNA viruses known in the art, including, for example, a herpes simplex virus recombinant genome, a varicella zoster virus recombinant genome , a recombinant human cytomegalovirus genome, a recombinant herpesvirus 6A genome, a recombinant herpesvirus 6B genome, a recombinant herpesvirus 7 genome, a recombinant Kaposi sarcoma-associated herpesvirus genome, and any combination or any derivative thereof. As used herein, a "knockout mutation" can refer to any mutation that generates a gene product or region (RNA or protein) with reduced, undetectable, or eliminated quantity and / or function (for example, in comparison with a corresponding sequence without the knockout mutation). Examples of inactivating mutations may include, but are not limited to, deletions, insertions, point mutations, and rearrangements in the transcriptional control sequences (promoters, enhancers, insulators, etc.) and / or coding sequences of a given gene or region. Any suitable method for measuring the amount of a gene product or region known in the art can be used, including, for example, qPCR, Northern blots, RNAseq, Western blots, ELISA, etc. In some embodiments, the recombinant herpes virus genome comprises one or more (for example, one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more , nine or more, ten or more, etc.) inactivating mutations. In some embodiments, the one or more knockout mutations are in one or more (for example, one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more). more, nine or more, ten or more, etc.) herpes virus genes. In some embodiments, the recombinant herpesvirus genome is attenuated (eg, compared to a corresponding wild-type herpesvirus genome). In some embodiments, the recombinant herpesvirus genome is capable of replication. In some embodiments, the recombinant herpes virus genome is replication defective. In some embodiments, the recombinant nucleic acid is a recombinant herpes simplex virus (HSV) genome. In some embodiments, the recombinant herpes simplex virus genome is a recombinant herpes simplex virus type 1 (HSV-1) genome, a recombinant herpes simplex virus type 2 (HSV-2) genome, or zcoonn / i znz / R / v any derivative thereof. In some embodiments, the recombinant herpes simplex virus genome comprises one or more (for example, one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, etc.) inactivating mutations. In some embodiments, the one or more knockout mutations are in one or more (for example, one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more). more, nine or more, ten or more, etc.) herpes simplex virus genes. In some embodiments, the recombinant herpes simplex virus genome is attenuated (eg, compared to a corresponding wild-type herpes simplex virus genome). In some embodiments, the recombinant herpes simplex virus genome is capable of replication. In some embodiments, the recombinant herpes simplex virus genome is replication defective. In some embodiments, the recombinant herpes simplex virus genome is a recombinant HSV-1 genome. In some embodiments, the recombinant HSV-1 genome can be from any HSV-1 strain known in the art including, for example, strains 17, Ty25, R62, S25, Ku86, S23, R11, Ty148, Ku47, H166syn, 13192005 F-13 M-12 90237 F-17 KOS 3083-2008 F12g L2 CD38 H193 M-15 India 2011 0116209 F-111 66-207 2762 369 -2007, 3355, Maclntyre, McKrae, 7862, 7-hse, HF10, 1394,2005, 270-2007, OD4, SC16, M-19, 4J1037, 5J1060, J1060, KOS79, 132-1988, 160-1982, H166 2158-2007 RE 78326 F18g F11 172-2010 H129 F E4 CJ994 F14g E03 E22 E10 E06 E11 E25 E23 E35 E15 E07 E12 E14 , E08, E19, E13, ATCC 2011, etc. (see for example, Bowen et al. J Virol. 2019 Apr 3; 93(8)). In some embodiments, the recombinant HSV-1 genome is from the KOS strain. In some embodiments, the recombinant HSV-1 genome is not from the McKrae strain. In some embodiments, the recombinant HSV-1 genome is attenuated. In some embodiments, the recombinant HSV-1 genome is capable of replication. In some embodiments, the recombinant HSV-1 genome is replication defective. In some embodiments, the recombinant HSV-1 genome comprises one or more (eg, one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, etc.) inactivating mutations. In some embodiments, the one or more knockout mutations are in one or more (for example, one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more). more, nine or more, ten or more, etc.) HSV-1 genes. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or all eight genes of the infected cell protein (ICP) 0 (one or both copies), ICP4 (one or both copies), ICP22, ICP27, ICP47, thymidine kinase (tk), unique long region (UL) 41 and / or UL55 of the virus from herpes simplex. In some embodiments, the recombinant herpes simplex virus genome does not comprise an inactivating mutation in (eg, is capable of expressing) the ICP0 herpes simplex virus gene (one or both copies). In some embodiments, the recombinant herpes simplex virus genome does not comprise an inactivating mutation in (eg, is capable of expressing) the ICP27 herpes simplex virus gene. In some embodiments, the recombinant herpes simplex virus genome does not comprise an inactivating mutation in (eg, is capable of expressing) the ICP47 herpes simplex virus gene. In some embodiments, the recombinant herpes simplex virus genome does not comprise an inactivating mutation in (eg, is capable of expressing) the zcoonn / i znz / R / v herpes simplex virus genes ICPO (one or both copies), ICP27 and / or ICP47. In some embodiments, the recombinant herpes simplex virus genome does not comprise an inactivating mutation in the joint region. In some embodiments, the recombinant herpes simplex virus genome does not comprise an inactivating mutation in the herpes simplex virus genes ICP34.5 (one or both copies) and / or ICP47 (eg, to prevent production of a virus immunostimulant). In some embodiments, the recombinant herpes simplex virus genome does not comprise an inactivating mutation in the ICP34.5 herpes simplex virus gene (one or both copies). In some embodiments, the recombinant herpes simplex virus genome does not comprise an inactivating mutation in the ICP47 herpes simplex virus gene. In some embodiments, the recombinant herpes simplex virus genome does not comprise an inactivating mutation in the herpes simplex virus genes ICP34.5 (one or both copies) and ICP47. In some embodiments, the recombinant herpes simplex virus genome is not oncolytic. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICPO gene (one or both copies). In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICPO gene (one or both copies), and further comprises an inactivating mutation in the ICP4 genes (one or both copies) ICP22, ICP27, ICP47 , UL41 and / or GUL55. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICPO gene (one or both copies) and an inactivating mutation in the ICP4 gene (one or both copies). In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICPO gene (one or both copies) and an inactivating mutation in the ICP22 gene. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICPO gene (one or both copies) and an inactivating mutation in the UL41 gene. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICPO gene (one or both copies), an inactivating mutation in the ICP4 gene (one or both copies), and an inactivating mutation in the ICP4 gene. ICP22. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICPO gene (one or both copies), an inactivating mutation in the ICP4 gene (one or both copies), and an inactivating mutation in the UL41 gene. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICPO gene (one or both copies), an inactivating mutation in the ICP22 gene, and an inactivating mutation in the UL41 gene. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICPO gene (one or both copies), an inactivating mutation in the ICP4 gene (one or both copies), an inactivating mutation in the ICP22 and an inactivating mutation in the UL41 gene. In some embodiments, the inactivating mutation is a deletion of the coding sequence of the ICPO (one or both copies), ICP4 (one or both copies), ICP22 and / or UL41 genes. In some embodiments, the recombinant herpes simplex virus genome further comprises an inactivating mutation in the ICP27, ICP47 and / or UL55 genes. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP4 gene (one or both copies). In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP4 gene (one or both copies), and further comprises a zcoonn / i znz / R / v inactivating mutation in the ICPO genes (one or both copies). both copies) ICP22, ICP27, ICP47, UL41 and / or GUL55. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP4 gene (one or both copies) and an inactivating mutation in the ICP22 gene. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP4 gene (one or both copies) and an inactivating mutation in the UL41 gene. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP4 gene (one or both copies), an inactivating mutation in the ICP22 gene, and an inactivating mutation in the UL41 gene. In some embodiments, the inactivating mutation is a deletion of the coding sequence of the ICP4 (one or both copies), ICP22 and / or UL41 genes. In some embodiments, the recombinant herpes simplex virus genome further comprises an inactivating mutation in the ICPO (one or both copies), ICP27, ICP47 and / or UL55 genes. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP22 gene. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP22 gene and further comprises an inactivating mutation in the ICPO (one or both copies), ICP4 (one or both copies), ICP27, ICP47 genes. , UL41 and / or UL55. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP22 gene and an inactivating mutation in the UL41 gene. In some embodiments, the knockout mutation is a deletion of the coding sequence of the ICP22 and / or UL41 genes. In some embodiments, the recombinant herpes simplex virus genome further comprises an inactivating mutation in the ICPO (one or both copies), ICP4 (one or both copies), ICP27, ICP47, and / or UL55 genes. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP27 gene. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP27 gene and further comprises an inactivating mutation in the ICPO (one or both copies), ICP4 (one or both copies), ICP22, ICP47 genes. , UL41 and / or UL55. In some embodiments, the inactivating mutation is a deletion of the coding sequence of the ICP27 gene. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP47 gene. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP47 gene and further comprises an inactivating mutation in the ICPO (one or both copies), ICP4 (one or both copies), ICP22, ICP27 genes. , UL41 and / or UL55. In some embodiments, the inactivating mutation is a deletion of the coding sequence of the ICP47 gene. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the UL41 gene. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the UL41 gene and further comprises an inactivating mutation in the ICPO (one or both copies), ICP4 (one or both copies), ICP22, ICP27 genes. , ICP47 and / or UL55. In some embodiments, the inactivating mutation is a deletion of the coding sequence of the UL41 gene. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the UL55 gene. In some embodiments, the recombinant herpes simplex virus genome zcoonn / i znz / R / v comprises an inactivating mutation in the UL55 gene and further comprises an inactivating mutation in the genes ICPO (one or both copies), ICP4 (one or both copies), ICP22, ICP27, ICP47 and / or UL41. In some embodiments, the inactivating mutation is a deletion of the coding sequence of the UL55 gene. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in (eg, a deletion of) the inner repeat (joint) region comprising the inner long repeat (IRL) and inner short repeat (IRL) regions. IRS). In some embodiments, inactivation (eg, deletion) of the splice region removes one copy each of the ICP4 and ICPO genes. In some embodiments, inactivation (eg, deletion) of the co-region additionally inactivates (eg, deletes) the promoter of the ICP22 and ICP47 genes. If desired, expression of one or both genes can be restored by insertion of an immediate early promoter into the recombinant herpes simplex virus genome (see for example, HUI et al. (1995). Nature 375(6530): 411-415, Goldsmith et al (1998) J Exp Med 187(3):341-348). Without wishing to be bound by theory, it is believed that inactivation (eg, deletion) of the junction region may contribute to the stability of the recombinant herpes simplex virus genome and / or allow the recombinant herpes simplex virus genome to receive more transgenes and / or larger transgenes. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP4 (one or both copies), ICP22 and ICP27 genes. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP4 (one or both copies), ICP27 and UL55 genes. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP4 (one or both copies), ICP22, ICP27, ICP47 and UL55 genes. In some embodiments, the inactivating mutation in the ICP4 (one or both copies), ICP27 and / or UL55 genes is a deletion of the ICP4 (one or both copies), ICP27 and / or UL55 coding sequence. In some embodiments, the inactivating mutation in the ICP22 and ICP47 genes is a deletion in the promoter region of the ICP22 and ICP47 genes (eg, the ICP22 and ICP47 coding sequences are intact but not transcriptionally active). In some embodiments, the recombinant herpes simplex virus genome comprises a deletion in the coding sequence of the ICP4 (one or both copies), ICP27 and UL55 genes, and a deletion in the promoter region of the ICP22 and ICP47 genes. In some embodiments, the recombinant herpes simplex virus genome further comprises an inactivating mutation in the ICPO (one or both copies) and / or UL41 genes. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICPO (one or both copies) and ICP4 (one or both copies) genes. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICPO (one or both copies), ICP4 (one or both copies) and ICP22 genes. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICPO (one or both copies), ICP4 (one or both copies), ICP22 and ICP27 genes. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICPO (one or both copies), ICP4 (one or both copies), ICP22, ICP27, and UL55 genes. In some embodiments, the inactivating mutation in the ICPO (one or both copies), ICP4 (one or both copies), ICP22, ICP27, and / or UL55 genes comprises a deletion of the ICPO (one or both zcoonn / i znz / R / v copies), ICP4 (one or both copies), ICP22, ICP27 and / or UL55. In some embodiments, the recombinant herpes simplex virus genome further comprises an inactivating mutation in the ICP47 and / or UL41 genes. In some embodiments, a recombinant herpes simplex virus genome comprises one or more polynucleotides of the present disclosure within one, two, three, four, five, six, seven, or more viral gene loci. Examples of suitable viral loci may include, but are not limited to, the ICPO (one or both copies), ICP4 (one or both copies), ICP22, ICP27, ICP47, tk, UL41 and / or herpes simplex viral gene loci. or UL55. In some embodiments, a recombinant herpes simplex virus genome comprises one or more polynucleotides of the present disclosure at one or both loci of the viral ICP4 gene (for example, a recombinant virus carrying a polynucleotide encoding a human CFTR polypeptide at one or both ICP4 loci In some embodiments, a recombinant herpes simplex virus genome comprises one or more polynucleotides of the present disclosure in the viral ICP22 gene locus (for example, a recombinant virus carrying a polynucleotide encoding a CFTR polypeptide at the ICP22 locus.) In some embodiments, a recombinant herpes simplex virus genome comprises one or more polynucleotides of the present disclosure at the viral UL41 gene locus (eg, a recombinant virus carrying a first polynucleotide encoding a human CFTR polypeptide at the UL41 locus.) In some embodiments, a recombinant herpes simplex virus genome comprises one or more polynucleotides of the present disclosure at one or both loci of the viral ICPO gene (eg, a recombinant virus carrying a polynucleotide encoding a human CFTR polypeptide at one or both of the ICPO loci. In some embodiments, a recombinant herpes simplex virus genome comprises one or more polynucleotides of the present disclosure at the viral ICP27 gene locus (eg, a recombinant virus carrying a polynucleotide encoding a human CFTR polypeptide at the ICP27 locus ). In some embodiments, a recombinant herpes simplex virus genome comprises one or more polynucleotides of the present disclosure at the viral ICP47 gene locus (for example, a recombinant virus carrying a first polynucleotide encoding a human CFTR polypeptide at the ICP47 gene locus). ICP47). In some embodiments, a recombinant herpes simplex virus genome comprises one or more polynucleotides of the present disclosure at one or both of the viral ICP4 gene loci, and one or more polynucleotides of the present disclosure within the viral ICP22 gene locus (for example , a recombinant virus carrying a polynucleotide encoding a human CFTR polypeptide at one or both of the ICP4 loci, and a polynucleotide encoding a human CFTR polypeptide at the ICP22 locus). In some embodiments, a recombinant herpes simplex virus genome comprises one or more polynucleotides of the present disclosure at one or both of the viral ICP4 gene loci, and one or more polynucleotides of the present disclosure within the viral UL41 gene locus (eg, , a recombinant virus carrying a polynucleotide encoding a human CFTR polypeptide at one or both of the ICP4 loci, and a polynucleotide encoding a human CFTR polypeptide at the UL41 locus). In some embodiments, a recombinant herpes simplex virus genome comprises one or more polynucleotides of the present disclosure within the ICP22 viral gene locus, and one or more polynucleotides of the present disclosure within the UL41 viral gene locus (eg, a recombinant virus carrying a polynucleotide encoding a human CFTR polypeptide at the ICP22 locus, and a polynucleotide encoding a human CFTR polypeptide at the UL41 locus). In some embodiments, a recombinant herpes simplex virus genome comprises one or more polynucleotides of the present disclosure within one or both of the loci of the zcoonn / i znz / R / v viral ICP4 gene, one or more polynucleotides of the present disclosure within the viral ICP22 gene locus, and one or more polynucleotides of the present disclosure within the viral UL41 gene locus (for example, a recombinant virus carrying a polynucleotide encoding a human CFTR polypeptide at one or both ICP4 loci, a polynucleotide encoding a human CFTR polypeptide at the ICP22 locus, and a polynucleotide encoding a human CFTR polypeptide at the UL41 locus).In some embodiments, a recombinant herpes simplex virus genome comprises one or more polynucleotides of the present disclosure within one or both of the viral ICP4 gene loci, one or more polynucleotides of the present disclosure within the viral ICP22 gene locus, one or more polynucleotides of the present disclosure within the viral UL41 gene locus, one or more polynucleotides of the present disclosure within one or both of the viral ICPO gene loci, one or more polynucleotides of the present disclosure within the viral ICP27 gene locus , and / or one or more polynucleotides of the present disclosure within the viral ICP47 gene locus. In some embodiments, the recombinant herpes virus genome (eg, a recombinant herpes simplex virus genome) has been genetically altered to decrease or eliminate the expression of one or more herpes virus genes (eg, one or more toxic herpes virus genes), such as one or both copies of the HSV ICPO gene, one or both copies of the HSV ICP4 gene, the HSV ICP22 gene, the HSV UL41 gene, the HSV ICP27 gene, the HSV ICP47, etc. In some embodiments, the recombinant herpesvirus genome (eg, a recombinant herpes simplex virus genome) has been genetically altered to reduce the cytotoxicity of the recombinant genome (eg, when introduced into a target cell) compared to a corresponding wild type herpes virus genome. In some embodiments, the target cell is a human cell (primary cells or a cell line derived therefrom). In some embodiments, the target cell is a mucosal cell. In some embodiments, the target cell is a respiratory tract cell (primary cells or a cell line derived therefrom). In some embodiments, the target cell is an airway epithelial cell (primary cells or a cell line derived therefrom). In some embodiments, the target cell is a lung cell (primary cells or a cell line derived therefrom). In some embodiments, the cytotoxicity of the recombinant herpes virus genome is reduced by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, to least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about less than about 99% compared to a corresponding wild-type herpesvirus genome (for example, by measuring the relative cytotoxicity of a recombinant ΔΙΟΡ4 herpes simplex virus genome (one or both copies) compared to a virus genome of wild-type herpes simplex virus in a target cell; to measure the relative cytotoxicity of a recombinant ΔΙΟΡ4 herpes simplex virus (one or both copies) / AICP22 genome compared to a wild-type herpes simplex virus genome in a target cell , etc.). In some embodiments, the cytotoxicity of the recombinant herpesvirus genome is reduced by at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold , at least about 6 times, at least about 7 times, at least zcoonn / i znz / R / v about 8 times, at least about 9 times, at least about 10 times, at least about 15 times , at least around 20 times, at least around 25 times, at least around 50 times, at least around 75 times, at least around 100 times, at least around 250 times, at least around 500 times, at least about 750-fold, at least about 1000-fold, or more, compared to a corresponding wild-type herpes virus genome (for example, by measuring the relative cytotoxicity of a recombinant AICP4 herpes simplex virus genome ( one or both copies) compared to a wild-type herpes simplex virus genome in a target cell; by measuring the relative cytotoxicity of an AICP4 (one or both copies) / AICP22 recombinant herpes simplex virus genome compared to a wild-type herpes simplex virus genome in a target cell, etc.). Methods for measuring cytotoxicity are known in the art, including, for example, through the use of vital dyes (formazan dyes), protease biomarkers, an MTT assay (or an assay using related tetrazolium salts such as water soluble tetrazolium, MTS, XTT, etc.), measurement of ATP content, etc. In some embodiments, the recombinant herpesvirus genome (eg, a recombinant herpes simplex virus genome) has been genetically altered to reduce its impact on host cell proliferation after exposure of a target cell to the recombinant genome. , compared to a corresponding wild-type herpes virus genome. In some embodiments, the target cell is a human cell (primary cells or a cell line derived therefrom). In some embodiments, the target cell is a mucosal cell. In some embodiments, the target cell is a respiratory tract cell (primary cells or a cell line derived therefrom). In some embodiments, the target cell is an airway epithelial cell (primary cells or a cell line derived therefrom). In some embodiments, the target cell is a lung cell (primary cells or a cell line derived therefrom). In some embodiments, target cell proliferation after exposure to the recombinant genome is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25% , at least around 30%, at least around 35%, at least around 40%, at least around 45%, at least around 50%, at least around 55%, at least around 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99% faster compared to target cell proliferation after exposure to a corresponding wild-type herpes virus genome (for example, by measuring relative cell proliferation after exposure to a wild-type herpes virus genome). Recombinant herpes simplex AICP4 (one or both copies) compared with cell proliferation after exposure to a wild-type herpes simplex virus genome in a target cell; measuring relative cell proliferation after exposure to a recombinant AICP4 (one or both copies) / AICP22 herpes simplex virus genome compared to a wild-type herpes simplex virus genome in a target cell, etc.). In some embodiments, target cell proliferation after exposure to the recombinant genome is at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold , at least about 6 times, at least about 7 times, at least about 8 times, at least about 9 times, al zcoonn / i znz / R / v at least about 10 times, at least about 15 times , at least around 20 times, at least around 25 times, at least around 50 times, at least around 75 times, at least around 100 times, at least around 250 times, at least around 500 times, at least about 750-fold or at least about 1000-fold faster compared to target cell proliferation after exposure to a corresponding wild-type herpesvirus genome (for example measuring relative cell proliferation after exposure to a recombinant AICP4 herpes simplex virus genome (one or both copies) compared to cell proliferation upon exposure to a wild-type herpes simplex virus genome in a target cell; measuring relative cell proliferation upon exposure to a recombinant AICP4 (one or both copies) / AICP22 herpes simplex virus genome compared to a wild-type herpes simplex virus genome in a target cell, etc.). Methods for measuring cell proliferation are known to those skilled in the art, including, for example, through the use of a K¡67 cell proliferation assay, a BrdU cell proliferation assay, etc. A vector (eg, a herpes viral vector) can include one or more polynucleotides of the present disclosure in a form suitable for expression of the polynucleotide in a host cell. Vectors can include one or more regulatory sequences operatively linked to the polynucleotide to be expressed (eg, as described above). In some embodiments, a recombinant nucleic acid (eg, a recombinant herpes simplex virus genome) of the present disclosure comprises one or more of the polynucleotides described herein, inserted in any orientation into the recombinant nucleic acid. If the recombinant nucleic acid comprises two or more polynucleotides described herein (eg, two or more, three or more, etc.), the polynucleotides can be inserted in the same or opposite orientations from one another. Without wishing to be bound by theory, the incorporation of two polynucleotides (eg, two transgenes) into a recombinant nucleic acid (eg, a vector) in an antisense orientation can help to avoid read-through and ensure correct expression of each. polynucleotide. IV. Virus Certain aspects of the present disclosure relate to viruses comprising any of the recombinant polynucleotides and / or nucleic acids described herein. In some embodiments, the virus is capable of infecting one or more target cells of a subject (eg, a human). In some embodiments, the virus is suitable for delivery of the recombinant polynucleotides and / or nucleic acids into one or more target cells of a subject (eg, a human). In some embodiments, the one or more target cells are human cells. In some embodiments, the one or more target cells are one or more cells with a CFTR deficiency (eg, one or more cells that comprise a genomic mutation in the wild-type CFTR gene). In some embodiments, the one or more target cells are one or more mucosal cells. In some embodiments, the one or more target cells are one or more airway epithelial cells. In some embodiments, the one or more cells targeted are one or more cells of the respiratory tract (for example, airway epithelial cells (such as goblet cells, hair cells, Clara cells, neuroendocrine cells, basal cells, intermediate or parabasal cells, serous cells, brush cells, oncocytes, nonciliated columnar cells, and / or metaplastic cells); zcoonn / i znz / R / v alveolar cells (such as type 1 pneumocytes, type 2 pneumocytes, and / or nonciliated cuboidal cells); cells of the salivary glands in the bronchi (such as serous cells, mucous cells and / or ductal cells); etc.). In some embodiments, the one or more target cells are one or more lung cells. Any suitable virus known in the art may be used, including, for example, adenovirus, adeno-associated virus, retrovirus, lentivirus, sendai virus, herpes virus, vaccinia virus, and / or any hybrid virus or derivative thereof. In some modalities, the virus is attenuated. In some forms, the virus is capable of replication. In some embodiments, the virus is replication defective. In some embodiments, the virus has been modified to alter its tissue tropism relative to the tissue tropism of a corresponding unmodified wild-type virus. In some embodiments, the virus has reduced cytotoxicity (eg, in a target cell) compared to a corresponding wild-type virus. Methods for producing a virus comprising recombinant nucleic acids are well known to those skilled in the art. In some embodiments, the virus is a member of the Herpesviridae family of DNA viruses, which includes, for example, a herpes simplex virus, a varicella zoster virus, a human cytomegalovirus, a herpes virus 6A, a herpes virus 6B , a herpes virus 7 and a Kaposi's sarcoma-associated herpes virus, etc. In some modalities, the herpes virus is attenuated. In some embodiments, the herpes virus is replication defective. In some forms, the herpes virus is capable of replication. In some embodiments, the herpes virus has been genetically altered to reduce or eliminate the expression of one or more herpes virus genes (eg, one or more toxic herpes virus genes). In some embodiments, the herpes virus has reduced cytotoxicity compared to a corresponding wild-type herpes virus. In some modalities, the herpes virus is not oncolytic. In some embodiments, the virus is a herpes simplex virus. Herpes simplex viruses comprising recombinant nucleic acids can be produced by a process described, for example, in WO2015 / 009952, WO2017 / 176336, WO2019 / 200163, WO2019 / 210219, and / or WO2020 / 006486. In some modalities, the herpes simplex virus is attenuated. In some forms, the herpes simplex virus is replication defective. In some forms, the herpes simplex virus is capable of replication. In some embodiments, the herpes simplex virus has been genetically altered to reduce or eliminate the expression of one or more herpes simplex virus genes (eg, one or more toxic herpes simplex virus genes). In some embodiments, the herpes simplex virus has reduced cytotoxicity compared to a corresponding wild-type herpes simplex virus. In some modalities, the herpes simplex virus is not oncolytic. In some embodiments, the herpes simplex virus is an HSV-1 virus, an HSV-2 virus, or any of their derivatives. In some embodiments, the herpes simplex virus is an HSV-1 virus. In some embodiments, the herpes simplex virus is an HSV-1. In some modalities, HSV-1 is grayed out. In some embodiments, HSV-1 is replication defective. In some embodiments, HSV-1 is capable of replication. In some embodiments, HSV-1 has been genetically altered to reduce or eliminate the expression of one or more HSV-1 genes (eg, one or more toxic HSV-1 genes). In some embodiments, HSV-1 has reduced cytotoxicity compared to a corresponding wild-type HSV-1. In some modalities, HSV-1 is not oncolytic. zcoonn / i znz / R / v In some embodiments, the herpes simplex virus has been modified to alter its tissue tropism relative to the tissue tropism of an unmodified wild-type herpes simplex virus. In some embodiments, the herpes simplex virus comprises a modified envelope. In some embodiments, the modified envelope comprises one or more (eg, one or more, two or more, three or more, four or more, etc.) mutant herpes simplex virus glycoproteins. Examples of herpes simplex virus glycoproteins may include, but are not limited to, the gB, gC, gD, gH, and gL glycoproteins. In some embodiments, the modified envelope alters the tissue tropism of the herpes simplex virus relative to a wild-type herpes simplex virus. In some embodiments, the transduction efficiency (in vitro and / or in vivo) of a virus of the present disclosure (eg, a herpes virus) to one or more target cells (eg, one or more cells of the respiratory tract ) is at least about 25%. For example, the transduction efficiency of the virus for one or more target cells may be at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80 %, at least about 85%, at least about 90%, at least about 95%, at least about 99%, at least about 99.5%, or more. In some embodiments, the virus is a herpes simplex virus and the transduction efficiency of the virus for one or more target cells (eg, one or more respiratory tract cells) is about 85% to about 100%. In some embodiments, the virus is a herpes simplex virus and the transduction efficiency of the virus for one or more target cells (eg, one or more respiratory tract cells) is at least about 85%, at least about 86%. %, at least around 87%, at least around 88%, at least around 89%, at least around 90%, at least around 91%, at least around 92%, at least around 93% , at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% or 100%. Methods for measuring the efficiency of viral transduction in vitro or in vivo are well known to those skilled in the art, including, for example, qPCR analysis, deep sequencing, Western blotting, fluorometric analysis (such as fluorescent in situ hybridization ( FISH), fluorescent reporter gene expression, immunofluorescence, FACS), etc. V. Formulations and pharmaceutical compositions Certain aspects of the present disclosure refer to pharmaceutical compositions or formulations comprising either recombinant nucleic acid (for example, a recombinant herpes virus genome) and / or virus (for example, a herpes virus comprising a recombinant genome). ) described herein (such as a herpes simplex virus comprising a recombinant herpes simplex virus genome) and a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition or formulation comprises one or more of the viruses (eg, herpes virus) described herein. In some embodiments, the pharmaceutical composition or formulation comprises from about 104 to about 1012 plaque forming units (PFU) / mL of virus. For example, the pharmaceutical composition or formulation may comprise of about 104a about 1012, about 105a zcoonn / i znz / R / v about 1012, about 108a about 1012, about 107a about 1012, about 108a around 1012, around 109a around 1012, around 1010a around 1012, around 1011a around 1012, around 104a around 1011, around 105a around 1011, around 106a around 1011, around 107a around around 1011, around 108a around 1011, around 109a around 1011, around 1010a around 1011, around 104a around 1010, around 105a around 1010, around 106a around 1010, around 107a around 1010, around 108a around 1010, around 109a around 1010, around 104a around 109, around 105a around 109, around 106a around 109, around 107a around 109, around 108a around 109 , around 104a around 108, around 105a around 108, around 106a around 108, around 107a around 108, around 104a around 107, around 105a around 107, around 106a around 107, about 104a about 106, about 105a about 106o about 104a about 105PFU / mL of the virus. In some embodiments, the pharmaceutical composition or formulation comprises about 104, about 105, about 106, about 107, about 108, about 109, about 1010, about 1011, or about 1012 PFU / mL of virus. . Pharmaceutical compositions and formulations can be prepared by mixing the active ingredient(s) (such as recombinant nucleic acid and / or virus) having the desired degree of purity with one or more pharmaceutically acceptable carriers or excipients. Pharmaceutically acceptable carriers or excipients are generally nontoxic to recipients at the doses and concentrations employed and may include, but are not limited to: buffers (such as phosphate, citrate, acetate, and other organic acids); antioxidants (such as ascorbic acid and methionine); preservatives (such as octadecyldimethylbenzylammonium chloride, benzalkonium chloride, benzethonium chloride, phenolic, butyl, or benzyl alcohol, alkylparabens, catechol, resorcinol, cyclohexanol, 3-pentanol, and mcresol); amino acids (such as glycine, glutamine, asparagine, histidine, arginine or Usine); low molecular weight polypeptides (less than about 10 residues); proteins (such as serum albumin, gelatin, or immunoglobulins); polyols (such as glycerol, eg, formulations including 10% glycerol); hydrophilic polymers (such as polyvinylpyrrolidone); monosaccharides, disaccharides, and other carbohydrates (including glucose, mannose, or dextrins); chelating agents (such as EDTA); sugars (such as sucrose, mannitol, trehalose, or sorbitol); salt-forming counterions (such as sodium); metal complexes (such as Zn protein complexes); and / or non-ionic surfactants (such as polyethylene glycol (PEG)). An in-depth review of pharmaceutically acceptable carriers is available from REMINGTON'S PHARMACEUTICAL SCIENCES (Mack Pub. Co„ N.J. 1991). In some embodiments, the pharmaceutical composition or formulation comprises one or more lipid carriers (eg, cationic lipids). In some embodiments, the pharmaceutical composition or formulation comprises one or more nanoparticle carriers. Nanoparticles are submicron-sized (less than about 1000 nm) drug delivery vehicles that can carry encapsulated drugs (such as synthetic small molecules, proteins, peptides, cells, viruses, and nucleic acid-based biotherapeutics) for rapid release or controlled. A variety of molecules (eg, proteins, peptides, recombinant nucleic acids, etc.) can be efficiently encapsulated in nanoparticles by processes well known in the zcoonn / i znz / R / v art. In some embodiments, a nanoparticle-encapsulated molecule can refer to a molecule (such as a virus) that is contained within the nanoparticle or attached to and / or associated with the surface of the nanoparticle, or any combination of these. The nanoparticles for use in the compositions or formulations described herein can be any type of biocompatible nanoparticle known in the art, including, for example, nanoparticles comprising poly(lactic acid), poly(glycolic acid), PLGA, PLA, PGA and any combination of these (see, for example, Vauthier et al. Adv Drug Del Rev. (2003) 55: 519-48; US2007 / 0148074; US2007 / 0092575; US2006 / 0246139; US5753234; US7081483; and WO2006 / 052285 ). In some embodiments, the pharmaceutically acceptable carrier or excipient may be adapted or suitable for any route of administration known in the art, including, for example, intravenous, intramuscular, subcutaneous, dermal, oral, intranasal, intratracheal, sublingual, buccal administration. , topical, transdermal, intradermal, intraperitoneal, intraorbital, intravitreal, subretinal, transmucosal, intraarticular, by implantation, by inhalation, intrathecal, intraventricular, and / or intranasal. In some embodiments, the pharmaceutically acceptable carrier or excipient is adapted or suitable for oral, intranasal, intrathecal, and / or inhaled administration. In some embodiments, the pharmaceutically acceptable carrier or excipient is adapted or suitable for inhaled administration. In some embodiments, the pharmaceutically acceptable carrier or excipient is adapted or suitable for non-invasive inhaled administration. In some embodiments, the pharmaceutically acceptable carrier or excipient is adapted or suitable for nebulization (eg, using a vibrating mesh nebulizer). In some embodiments, the pharmaceutical composition or formulation is adapted or suitable for any route of administration known in the art, including, for example, intravenous, intramuscular, subcutaneous, cutaneous, oral, intranasal, intratracheal, sublingual, buccal, topical, transdermal, intradermal, intraperitoneal, intraorbital, intravitreal, subretinal, transmucosal, intraarticular, implantable, inhalative, intrathecal, intraventricular, or intranasal. In some embodiments, the pharmaceutical composition or formulation is adapted or suitable for oral, intranasal, intrathecal, or inhaled administration. In some embodiments, the pharmaceutical composition or formulation is adapted or suitable for inhaled administration. In some embodiments, the pharmaceutical composition or formulation is adapted or suitable for non-invasive inhaled administration. In some embodiments, the pharmaceutical composition or formulation is adapted or suitable for nebulization (eg, using a vibrating mesh nebulizer). In some embodiments, the pharmaceutical composition or formulation further comprises one or more additional components. Examples of additional components may include, but are not limited to, binding agents (eg, pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose, etc.); fillers (for example, lactose and other sugars, microcrystalline cellulose, pectin, gelatin, calcium sulfate, ethylcellulose, polyacrylates or calcium hydrogen phosphate, etc.); lubricants (for example, magnesium stearate, talc, silica, colloidal silicon dioxide, stearic acid, metal stearates, hydrogenated vegetable oils, corn starch, polyethylene glycols, sodium benzoate, sodium acetate, etc.); disintegrants (eg starch, sodium starch glycolate, etc.); wetting agents (eg sodium lauryl sulfate, etc.); saline solutions; alcohols; zcoonn / i znz / R / v polyethylene glycols; jelly; lactose; amylase; magnesium stearate; talcum powder; silicic acid; viscous paraffin; hydroxymethylcellulose; polyvinylpyrrolidone; sweeteners; flavorings; perfuming agents; dyes; moisturizers; Sunscreens; antibacterial agents; agents capable of stabilizing polynucleotides or preventing their degradation, and the like. In some embodiments, the pharmaceutical composition or formulation comprises a phosphate buffer. In some embodiments, the pharmaceutical composition or formulation comprises glycerol (for example, at about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7% , about 8%, about 9%, about 10%, about 15%, etc.). In some embodiments, the pharmaceutical composition or formulation comprises a glycerol phosphate buffer. In some embodiments, the pharmaceutical composition or formulation comprises less than about 15%, less than about 14%, less than about 13%, less than about 12%, less than about 11%, less than about 10 %, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3% , less than about 2%, less than about 1%, less than about 0.5%, or less than about 0.1% glycerol. In some embodiments, the pharmaceutical composition or formulation does not comprise glycerol. Pharmaceutical compositions and formulations that can be used for administration in vivo are generally sterile. Sterility can be easily achieved, for example, by filtration through sterile filtration membranes. In some embodiments, any of the recombinant nucleic acids, viruses, and / or pharmaceutical compositions or formulations described herein can be used to deliver one or more polynucleotides encoding a CFTR polypeptide into one or more cells of a subject (eg, one or more CFTR-deficient cells, one or more cells harboring a CFTR gene mutation, one or more respiratory tract cells, etc.). In some embodiments, any of the recombinant nucleic acids, viruses, and / or pharmaceutical compositions or formulations described herein may be used in the treatment of a disease or condition that benefits from expression of a CFTR polypeptide (eg, a disease associated with a CFTR deficiency and / or a disease associated with a CFTR gene mutation). In some embodiments, any of the recombinant nucleic acids, viruses, and / or pharmaceutical compositions or formulations described herein may be used in the prevention or treatment of chronic lung disease (such as cystic fibrosis, COPD, etc.). In some embodiments, any of the recombinant nucleic acids, viruses, and / or pharmaceutical compositions or formulations described herein can be used in the prevention or treatment of cystic fibrosis. In some embodiments, any of the recombinant nucleic acids, viruses, and / or pharmaceutical compositions or formulations described herein can be used in the preparation of a medicament useful for delivering one or more polynucleotides encoding a CFTR polypeptide to one or more cells. from a subject (eg, one or more CFTR-deficient cells, one or more cells harboring a CFTR gene mutation, one or more respiratory tract cells, etc.). In some embodiments, any of the recombinant nucleic acids, viruses, and / or pharmaceutical compositions or formulations described herein may be used in the preparation of a medicament useful for the prevention or treatment of a disease or condition that benefits from the expression of 7CQQnn / l 7Π7 / Β / Υ a CFTR polypeptide (eg, a disease associated with a CFTR deficiency and / or a disease associated with a CFTR gene mutation). In some embodiments, any of the recombinant nucleic acids, viruses, and / or pharmaceutical compositions or formulations described herein may be used in the preparation of a medicament useful for the prevention or treatment of chronic lung disease (such as cystic fibrosis). , COPD, etc.). In some embodiments, any of the recombinant nucleic acids, viruses, and / or pharmaceutical compositions or formulations described herein may be used in the preparation of a medicament useful for the prevention or treatment of cystic fibrosis. SAW. methods Certain aspects of the present disclosure refer to potentiating, increasing, increasing and / or complementing the levels of a CFTR polypeptide in one or more cells of a subject comprising administering to the subject any of the recombinant nucleic acids, viruses, drugs and / or pharmaceutical compositions or formulations described herein. In some embodiments, the subject is a human. In some embodiments, the subject's genome comprises a mutation (eg, a loss-of-function mutation) in an endogenous CFTR gene (one or both copies). In some embodiments, the subject suffers from a chronic lung disease, eg, cystic fibrosis, COPD, etc. In some embodiments, the subject suffers from cystic fibrosis. In some embodiments, administration of the recombinant nucleic acid, virus, drug, and / or pharmaceutical composition or formulation to the subject increases CFTR levels (protein or transcript levels) by at least about 2-fold in one or more treated cells or in contact of the subject, compared to endogenous CFTR levels in one or more corresponding untreated cells in the subject. For example, administration of the recombinant nucleic acid, virus, drug, and / or pharmaceutical composition or formulation can increase CFTR levels (transcript or protein levels) by at least about 2-fold, at least about 3-fold, at least about 4 times, at least about 5 times, at least about 6 times, at least about 7 times, at least about 8 times, at least about 9 times, at least about 10 times, at least about 15 times, at least about 20 times, at least around 25 times, at least around 50 times, at least around 75 times, at least around 100 times, at least around 250 times, at least around 500 times, at least around 750 times, at least around 1000 times or more in one or more treated or contacted cells of the subject, compared to endogenous CFTR levels in one or more corresponding untreated cells in the subject. In some embodiments, the one or more cells contacted or treated are one or more cells of the respiratory tract (eg, one or more cells of the respiratory tract epithelia and / or one or more cells of the submucosal glands). Methods for measuring transcript or protein levels of a sample are known to those skilled in the art, including, for example, qPCR, Western blotting, mass spectrometry, etc. Other aspects of the present disclosure refer to a method for reducing cellular sodium levels in a subject in need thereof, which comprises administering to the subject any of the recombinant nucleic acids, viruses, drugs and / or pharmaceutical compositions or formulations described at the moment. In some embodiments, the subject is a human. In some embodiments, the subject's genome comprises a mutation (eg, a loss-of-function mutation) in an endogenous CFTR gene (one or both copies). In zcoonn / i znz / R / v some modalities, the subject has a chronic lung disease, eg, cystic fibrosis, COPD, etc. In some embodiments, the subject suffers from cystic fibrosis. In some embodiments, administration of the recombinant nucleic acid, virus, drug, and / or pharmaceutical composition or formulation to the subject decreases intracellular sodium levels by at least about 10%, at least about 15%, at least about 20% , at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 90% less than about 95%, at least about 99% or more in one or more contacted or treated cells, compared to intracellular sodium levels in one or more corresponding untreated cells in the subject. Methods for measuring intracellular sodium levels are generally known to the person skilled in the art. Other aspects of the present disclosure refer to a method for improving a measure of at least one respiratory volume in a subject in need thereof, which comprises administering to the subject any of the recombinant nucleic acids, viruses, drugs and / or pharmaceutical compositions or formulations that are described herein. In some embodiments, the subject is a human. In some embodiments, the subject's genome comprises a mutation (eg, a loss-of-function mutation) in an endogenous CFTR gene (one or both copies). In some embodiments, the subject suffers from a chronic lung disease, eg, cystic fibrosis, COPD, etc. In some embodiments, administration of the recombinant nucleic acid, virus, drug, and / or pharmaceutical composition or formulation to the subject improves a measure of at least one respiratory volume by at least about 5%, at least about 10%, at least about of 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85 %, at least about 90%, at least about 95%, at least about 99% or more compared to at least one reference respiratory volume measured in the subject before treatment. Examples of suitable tidal volumes that can be measured include, for example: Total Lung Capacity (TLC), the volume of the lungs at peak inflation; Tidal volume (TV), the volume of air that moves in or out of the lungs during calm breathing; Residual volume (RV), the volume of air remaining in the lungs after a maximal expiration; Expiratory Reserve Volume (ERV), the maximum volume of air that can be exhaled (above tidal volume) during a forced expiration; Inspiratory Reserve Volume (ERV), the maximum volume of air that can be inhaled from the end-inspiratory position; Inspiratory capacity (IC), the sum of IRV and TV; Inspiratory Vital Capacity (IVC), the maximum volume of air inhaled from the point of maximum expiration; Vital capacity (VC), the volume of air breathed after the deepest inhalation; Functional residual capacity (FRC), the volume in the lungs at the end of expiration; Forced Vital Capacity zcoonn / i znz / R / v (FVC), the determination of vital capacity from a forced maximal expiratory effort; Forced expiratory volume (time) (FEVt), the volume of air exhaled under forced conditions in the first t seconds; Forced Inspiratory Flow (FIF), a specific measure of the forced inspiratory curve; Peak expiratory flow (PEF), the highest forced expiratory flow measured with a peak flow meter; Maximal voluntary ventilation (MW), the volume of air expired in a specified period during a repetitive maximal effort; etc Methods of measuring respiratory volumes are generally known to a person skilled in the art. Other aspects of the present disclosure refer to a method of reducing or preventing chronic bacterial infections in the lungs of a subject in need thereof, which comprises administering to the subject any of the recombinant nucleic acids, viruses, drugs and / or pharmaceutical compositions or formulations that are described herein. In some embodiments, the subject is a human. In some embodiments, the subject's genome comprises a mutation (eg, a loss-of-function mutation) in an endogenous CFTR gene (one or both copies). In some embodiments, the subject suffers from a chronic lung disease, eg, cystic fibrosis, COPD, etc. In some embodiments, the subject suffers from cystic fibrosis. Direct and indirect methods of monitoring bacterial infections in the lungs, including improvements thereto, are known to one skilled in the art, including, for example, by performing: blood tests or cultures, oximetry, arterial blood gas measurements , bronchoscopy, transtracheal mucus cultures, lung biopsies, thoracentesis, computed tomography, etc. Other aspects of the present disclosure refer to a method of reducing, preventing or treating chronic inflammation in the lungs of a subject in need thereof, which comprises administering to the subject any of the recombinant nucleic acids, viruses, drugs and / or compositions or formulations pharmaceuticals described herein. In some embodiments, the subject is a human. In some embodiments, the subject's genome comprises a mutation (eg, a loss-of-function mutation) in an endogenous CFTR gene (one or both copies). In some embodiments, the subject suffers from a chronic lung disease, eg, cystic fibrosis, COPD, etc. In some embodiments, the subject suffers from cystic fibrosis. Methods for measuring inflammation in the lungs, including improvements therein, are known to those skilled in the art, including, for example, measuring exhaled nitric oxide, determining the percentage of eosinophils in sputum and / or blood, etc Other aspects of the present disclosure refer to a method for reducing, inhibiting, or treating progressive lung destruction in a subject in need thereof, which comprises administering to the subject any of the recombinant nucleic acids, viruses, drugs, and / or compositions or formulations pharmaceuticals described herein. In some embodiments, the subject is a human. In some embodiments, the subject's genome comprises a mutation (eg, a loss-of-function mutation) in an endogenous CFTR gene (one or both copies). In some embodiments, the subject suffers from a chronic lung disease, eg, cystic fibrosis, COPD, etc. In some embodiments, the subject suffers from cystic fibrosis. Methods for measuring lung destruction are known to those skilled in the art, including, for example, by the methods described by Saetta et al. (Am Rev Respir Dis. 1985 May;131(5):764-9). zcoonn / i znz / R / v Other aspects of the present disclosure relate to a method of providing prophylactic, palliative, or therapeutic relief of one or more signs or symptoms of cystic fibrosis in a subject in need thereof, comprising administering to the subject an effective amount of any of the nucleic acids recombinants, viruses, drugs and / or pharmaceutical compositions or formulations described herein. In some embodiments, the subject is a human. In some embodiments, the subject's genome comprises a mutation (eg, a loss-of-function mutation) in an endogenous CFTR gene (one or both copies). Signs and symptoms of cystic fibrosis may include, but are not limited to: persistent cough that brings up thick mucus; thick, sticky mucus that collects in the airways; wheezing; dyspnoea; sinusitis; repeated lung infections; inflammation of the nasal passages; bronchiectasis; nasal polyps; hemoptysis; pneumothorax; pancreatitis; recurrent pneumonia: respiratory failure and any combination of these. Other aspects of the present disclosure relate to a method of providing prophylactic, palliative, or therapeutic relief of one or more signs or symptoms of COPD in a subject in need thereof, comprising administering to the subject an effective amount of any of the recombinant nucleic acids , viruses, drugs and / or pharmaceutical compositions or formulations described herein. In some embodiments, the subject is a human. In some embodiments, the subject is a smoker or a former smoker. Signs and symptoms of COPD may include, but are not limited to: shortness of breath; wheezing; chest tightness; excess mucus in the lungs; a chronic cough; cyanosis; frequent respiratory infections and any combination of these. The recombinant nucleic acids, viruses, drugs, and / or pharmaceutical compositions or formulations described herein may be administered by any suitable method or route known in the art, including, but not limited to, oral, intranasal, intratracheal, sublingual, buccal, topical, rectal, inhalative, transdermal, subcutaneous, intradermal, intravenous, intraarterial, intramuscular, intracardiac, intraosseous, intraperitoneal, transmucosal, vaginal, intravitreal, intraorbital, subretinal, intraarticular, periarticular, local, epicutaneous, or any combination of these. The present disclosure therefore encompasses methods of administering any of the recombinant nucleic acids, viruses, drugs, or pharmaceutical compositions or formulations described herein to an individual (for example, an individual who has, or is at risk of developing, a lung disease chronic such as cystic fibrosis). In some embodiments, the recombinant nucleic acids, viruses, drugs, and / or pharmaceutical compositions or formulations described herein are administered orally, intranasally, intratracheally, and / or by inhalation. Methods of delivering drugs to the lungs by oral, intranasal, intratracheal, and / or inhaled routes of administration or generally known to one skilled in the art (see, for example, Gardenhire et al. A Guide to Aerosol Delivery Devices for Respiratory Therapists 4th Edition, American Association for Respiratory care, 2017, Patil et al., Pulmonary Drug Delivery Strategies: AConcise, Systematic Review, Lung India, 2012. 29(1):44-9, Marx et al., Intranasal Drug Administration - An Attractive Delivery Route for Some Drugs, 2015). In some embodiments, the recombinant nucleic acids, viruses, drugs, and / or pharmaceutical compositions or formulations are delivered to the lungs by inhalation of an aerosolized formulation. Inhalation zcoonn / i znz / R / v may occur through the subject's nose and / or mouth. Exemplary devices for delivering the recombinant nucleic acids, viruses, drugs, and / or pharmaceutical compositions or formulations to the lung may include, but are not limited to, dry powder inhalers, pressurized metered-dose inhalers, fine mist inhalers, nebulizers (eg, jet nebulizers, ultrasonic nebulizers, vibrating mesh nebulizers), colliding jets, extruded jets, surface wave microfluidic atomization, capillary aerosol generation, electrohydrodynamic aerosol devices, etc, (see, for example, Carvalho and McConville. The function and performance of aqueous devices for inhalation therapy.(2016) Journal of Pharmacy and Pharmacology. Liquid formulations can be administered to a subject's lungs, for example, using a pressurized metered dose inhaler (pMDI). pMDIs generally include at least two components: a can in which the liquid formulation is held under pressure in combination with one or more propellants, and a receptacle used to hold and drive the can. The canister may contain a single dose or multiple doses of the formulation. The can may include a valve, typically a metering valve from which the contents of the can can be discharged. Aerosolized drug is dispensed from the pMDI by applying a force to the canister to push it toward the receptacle, thereby opening the valve and causing drug particles to be transported from the valve through the receptacle outlet. Upon discharge of the can, the liquid formulation is atomized, which forms an aerosol. pMDIs typically employ one or more propellants to pressurize the contents of the can and propel the liquid formulation out of the receptacle outlet, which forms an aerosol. Any suitable propellant can be used, and can take a variety of forms, including, for example, a compressed gas or a liquefied gas. Liquid formulations can be administered to a subject's lungs, for example, through the use of a nebulizer. Nebulizers are liquid aerosol generators that convert the liquid formulation into mists or clouds of small droplets, often with diameters less than about 5 microns mass median aerodynamic diameter, which can be inhaled into the lower respiratory tract. The droplets carry the active agent(s) into the nose, upper respiratory tract, and / or deep lungs when the aerosol cloud is inhaled. Any type of nebulizer known in the art can be used to administer the formulation to a patient, including, but not limited to, pneumatic (jet) nebulizers, electromechanical nebulizers (eg, ultrasonic nebulizers, vibrating mesh nebulizers, etc. ) etc. Pneumatic (jet) nebulizers use a pressurized gas supply as a pushing force for atomization of the liquid formulation. Compressed gas is delivered through a nozzle or jet to create a low pressure field that entrains a surrounding liquid formulation and shears it into a thin film or filaments. The film or filaments are unstable and break into small droplets that are carried by the compressed gas flow towards the inspiratory breath. Baffles inserted into the small droplet boom filter out larger droplets and return them to the bulk liquid reservoir. Electromechanical nebulizers use electrically generated mechanical force to atomize liquid formulations. The electromechanical driving force can be applied, for example, by vibrating the liquid formulation at ultrasonic frequencies, or by forcing the bulk liquid through small holes in a thin film. The forces generate thin liquid films or filamentary streams that break up into small zcoonn / i znz / R / v droplets to form a slow-moving aerosol stream that can be entrained in an inspiratory flow. In some embodiments, the nebulizer is a vibrating mesh nebulizer. Examples of vibrating mesh nebulizers include, for example, the Phillips InnoSpire, the Aerogen Solo, the PARI eFlow, etc. Liquid formulations can be delivered to the lungs of a subject, for example, through the use of an electrohydrodynamic (EHD) aerosol device. EHD aerosol devices use electrical energy to aerosolize liquid drug solutions or suspensions. Dry powder formulations can be delivered to the lungs of a subject, for example, through the use of a dry powder inhaler (DPI). DPIs typically use a mechanism such as a gas explosion to create a cloud of dry powder inside a container, which can then be inhaled by the subject. In a DPI, the dose to be administered is stored in the form of a non-pressurized dry powder, after actuation of the inhaler, the powder particles are inhaled by the subject. In some cases, a compressed gas can be used to dispense the powder, similar to pMDIs. In some cases, the DPI can be breath actuated (an aerosol is created in precise response to inspiration). Dry powder inhalers typically deliver a dose of less than a few hundred milligrams per inhalation to avoid inducing coughing. Examples of DPI include, for example, the Turbohaler® inhaler (AstraZeneca), the Clickhaler® inhaler (Innovata), the Diskus® inhaler (Glaxo), the EasyHaler® (Orion), the Exúbera® inhaler (Pfizer), etc. In some embodiments, the recombinant nucleic acids, viruses, drugs, and / or pharmaceutical compositions or formulations are administered once to the subject. In some embodiments, the recombinant nucleic acids, viruses, drugs, and / or pharmaceutical compositions are administered to the subject at least twice (eg, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 10 times, etc.). In some embodiments, at least about 1 hour elapses (for example, at least about 1 hour, at least about 6 hours, at least about 12 hours, at least about 18 hours, at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 7 days, at least about 15 days, at least about least about 20 days, at least about 30 days, at least about 40 days, at least about 50 days, at least about 60 days, at least about 70 days, at least about 80 days, at least about 90 days, at least about 100 days, at least about 120 days, etc.) between administrations (eg, between the first and second administration, between the second and third administration, etc.). In some embodiments, the recombinant nucleic acids, viruses, drugs, and / or pharmaceutical compositions or formulations are administered one, two, three, four, five, or more times per day to the subject. In some embodiments, the recombinant nucleic acids, viruses, drugs, and / or pharmaceutical compositions or formulations are administered one, two, three, four, five, or more times per month to the subject. In some embodiments, the recombinant nucleic acids, viruses, drugs, and / or pharmaceutical compositions or formulations are administered one, two, three, four, five, or more times per year to the subject. VIL Host cells Certain aspects of the present disclosure relate to one or more host cells comprising any of the recombinant nucleic acids described herein. Any suitable host cell (prokaryotic or eukaryotic) known in the art can be used, including, for example: prokaryotic cells, including eubacteria, such as Gram-negative or Gram-positive organisms, for example , Enterobacteriaceae such as Escherichia (for example, E. coti}, Enterobacter, Erminia, Klebsiella, Proteus, Salmonella (for example, S. typhimurium), Serratia (for example, S. marcescans) and Shigella, as well as Bacilli such as B subtilis and B. licheniformis', fungal cells (eg, S. cerevisiae)', insect cells (eg, S2 cells, etc.), and mammalian cells, including the CV1 monkey kidney line transformed by SV40 (COS-7, ATCC CRL 1651), the human embryonic kidney line (293 or 293 cells subcloned for growth in suspension culture), baby hamster kidney cells (BHK, ATCC CCL 10), mouse Sertoli cells ( TM4), monkey kidney cells (CV1 ATCC CCL 70), African green monkey kidney cells (VERO-76, ATCC CRL-1587), human cervical carcinoma cells (HELA, ATCC CCL 2), canine kidney (MDCK, ATCC CCL 34), rat and buffalo liver cells (BRL 3A, ATCC CRL 1442), human lung cells (W138, ATCC CCL 75), human liver cells (Hep G2, HB 8065), mouse mammary tumor (MMT 060562, ATCC CCL51), TRI cells, MRC 5 cells, FS4 cells, human hepatoma line (Hep G2), Chinese hamster ovary (CHO) cells in English), which includes CHO DHFR cells and myeloma cell lines such as NS0 and Sp2 / 0. In some embodiments, the host cell is a human or non-human primate cell. In some embodiments, the host cells are cells of a cell line. Examples of suitable host cells or cell lines may include, but are not limited to, 293, HeLa, SH-Sy5y, Hep G2, CACO-2, A549, L929, 3T3, K562, CHO-K1, MDCK, HUVEC, Vero, N20, COS-7, PSN1, VCaP, CHO cells and the like. In some embodiments, the recombinant nucleic acid is a herpes simplex viral vector. In some embodiments, the recombinant nucleic acid is a herpes simplex virus amplicon. In some embodiments, the recombinant nucleic acid is an HSV-1 amplicon or a hybrid HSV-1 amplicon. In some embodiments, a host cell comprising a helper virus is contacted with an HSV-1 amplicon or HSV-1 hybrid amplicon described herein, resulting in the production of a virus comprising one or more recombinant nucleic acids. described herein. In some embodiments, the virus is harvested from the supernatant of the contacted host cell. Methods for generating virus by contacting host cells comprising a helper virus with an HSV-1 amplicon or HSV-1 hybrid amplicon are known in the art. In some embodiments, the host cell is a complementary host cell. In some embodiments, the complementary host cell expresses one or more genes that are inactivated in any of the viral vectors described herein. In some embodiments, the complementary host cell is contacted with a recombinant herpes virus genome (eg, a recombinant herpes simplex virus genome) described herein. In some embodiments, contacting a complementary host cell with a recombinant herpes virus genome results in the production of a herpes virus comprising one or more recombinant nucleic acids described herein. In some embodiments, the virus is harvested from the supernatant of the contacted host cell. Methods for generating virus by contacting complementary host cells with a recombinant herpes simplex virus are described generally in WO2015 / 009952, WO2017 / 176336, WO2019 / 200163, WO2019 / 210219 and / or WO2020 / 006486. zcoonn / i znz / R / v VIII. Crafting Items or Kits Certain aspects of this disclosure refer to an article of manufacture or kit comprising any of the recombinant nucleic acids, viruses, drugs, and / or pharmaceutical compositions or formulations described herein. In some embodiments, the article of manufacture or kit comprises a package insert comprising instructions for administering the recombinant nucleic acid, virus, drug, and / or pharmaceutical composition or formulation to treat a CFTR deficiency (for example, in a subject harboring homozygous CFTR mutations). CFTR loss-of-function gene) and / or to provide prophylactic, palliative or therapeutic relief of one or more signs or symptoms of a chronic lung disease (such as cystic fibrosis or COPD). In some embodiments, the article of manufacture or kit further comprises a device for delivering (eg, aerosolizing) the recombinant nucleic acid, virus, drug, and / or pharmaceutical composition or formulation. In some embodiments, the device is a nebulizer (eg, a vibrating mesh nebulizer). Suitable containers for the recombinant nucleic acids, viruses, drugs, and / or pharmaceutical compositions or formulations can include, for example, bottles, vials, bags, tubes, and syringes. The container can be of a variety of materials such as glass, plastic (such as polyvinyl chloride or polyolefin), or metal alloys (such as stainless steel or hastelloy). In some embodiments, the container comprises a label on or associated with the container, where the label indicates instructions for use. The article of manufacture or kit may further include other materials desirable from a user and commercial point of view, including other buffers, diluents, filters, inhalers, nebulizers, intranasal delivery devices, a package insert, and the like. The specification is believed to be sufficient to enable one skilled in the art to practice the present disclosure. Various modifications of the present disclosure in addition to those shown and described herein will be apparent to those skilled in the art from the foregoing description and fall within the scope of the appended claims. EXAMPLES The present disclosure will be more fully understood with reference to the following examples. However, it should not be construed as limiting the scope of the present disclosure. It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes will occur to those skilled in the art in light of these and are to be included within the spirit and scope of the present application and scope of the attached claims. Example 1: Modified Herpes Simplex Virus Vectors Encoding a Human CFTR Prompt To make vectors of modified herpes simplex virus genomes capable of expressing CFTR polypeptides in a target mammalian cell (such as lung cells), a herpes simplex virus genome is first modified (FIGURE 1 A) to inactivate one or more herpes simplex virus genes. Such modifications can decrease genome toxicity in mammalian cells. Variants of these modified / attenuated recombinant viral constructs are then generated such that they contain one or more polynucleotides encoding the desired CFTR polypeptide. These variants include: 1) a zcoonn / i znz / R / v modified HSV-1 genome with recombinant AICP4 comprising the expression cassettes containing the coding sequence (eg, SEQ ID NO: 2) of a CFTR polypeptide human (eg, SEQ ID NO: 5) under the control of a heterologous promoter integrated into each ICP4 locus (FIGURE 1B); 2) a recombinant AICP4 / AUL41-modified HSV-1 genome comprising expression cassettes containing the coding sequence for a human CFTR polypeptide under the control of a heterologous promoter integrated into each ICP4 locus (FIGURE 1C); 3) a recombinant AlCP4 / AUL41 modified HSV-1 genome comprising an expression cassette containing the coding sequence for a human CFTR polypeptide under the control of a heterologous promoter integrated into the UL41 locus (FIGURE 1D); 4) a recombinant AICP4 / AICP22-modified HSV-1 genome comprising expression cassettes containing the coding sequence for a human CFTR polypeptide under the control of a heterologous promoter integrated into each ICP4 locus (FIGURE 1E); 5) a recombinant AICP4 / AICP22 modified HSV-1 genome comprising an expression cassette containing the coding sequence for a human CFTR polypeptide under the control of a heterologous promoter integrated into the ICP22 locus (FIGURE 1F); 6) a recombinant AICP4 / AUL41 / AICP22 modified HSV-1 genome comprising expression cassettes containing the coding sequence for a human CFTR polypeptide under the control of a heterologous promoter integrated into each ICP4 locus (FIGURE 1G); 7) a recombinant AICP4 / AUL41 / AICP22 modified HSV-1 genome comprising an expression cassette containing the coding sequence for a human CFTR polypeptide under the control of a heterologous promoter integrated into the UL41 locus (FIGURE 1H); and 8) a recombinant AICP4 / AUL41 / AICP22 modified HSV-1 genome comprising an expression cassette containing the coding sequence for a human CFTR polypeptide under the control of a heterologous promoter integrated into the ICP22 locus (FIGURE 11). These modified herpes simplex virus genome vectors are transfected into genetically altered cells that are modified to express one or more herpes virus genes. These genetically altered cells secrete into the cell culture supernatant a replication-defective herpes simplex virus with the modified genomes wrapped therein. The supernatant is then collected, concentrated and sterile filtered through a 5 pm filter. Example 2: Construction and in vitro characterization of an HSV-1 vector encoding the human CFTR in 2D cultures Initial lung gene therapy clinical trials occurred in the early 1990s after the discovery of the genetic defect responsible for cystic fibrosis. Recombinant adenovirus was one of the early vectors evaluated for CFTR delivery, however, adeno-based vectors failed these trials due to the paucity of viral receptors on the apical lung surface and the severity of the host's immune response to the virus. repeated viral administration. The other viral gene therapy vectors administered to CF patients were adeno-associated virus-based (numerous AAV serotypes have been evaluated in the CF clinical setting). Large-scale, repeat-dose studies of AAV-based gene therapy vectors have provided disappointing results in terms of improvement in CF lung function in dosed patients. Like adenoviruses, recombinant AAV vectors do not efficiently infect the apical lung surface and, due to physical limitations on the size of the encoded payload, AAV vectors do not efficiently deliver zcoonn / i znz / R / v the full length of the CFTR human. Despite more than two decades of intensive efforts, virus-based gene therapies have still not helped patients with CF (or any other obstructive lung disease). Currently, according to the US Cystic Fibrosis Foundation, there are no ongoing clinical trials of viral gene therapies in CF, and there are only two virus-based gene therapy vectors in preclinical development (both AAV-based, a vector that, as noted above, has already failed in multiple clinical trials in CF patients). Instead, attention has shifted from virus-based vectors to non-viral methods of CFTR delivery (eg, plasmid DNA or mRNA complexed with liposomes). Unfortunately, these non-viral vectors have had only limited success, due, at least in part, to significant obstacles faced by product instability and / or inefficient delivery / transfection of liposomal formulations. In total, more than 25 clinical trials involving more than 470 patients testing viral and non-viral gene vectors have failed to show clinical benefit, largely due to ineffective gene transfer to target cells. and to immune-mediated clearance from the host upon repeated exposure. Therefore, a recombinant herpes simplex virus type 1 (HSV-1) vector encoding the full-length human CFTR (HSV-CFTR) has been developed as a novel gene therapy for the treatment of CF patients. Without wishing to be bound by theory, an HSV-based approach is believed to overcome many of the obstacles experienced by other CF gene therapy vectors, including the ability to encode full-length human CFTR, high efficiency of target cell transduction (HSV preferentially infects the apical membrane of polarized epithelial cells), virus stability, and the established clinical safety of repeated administration of a product employing the same viral backbone as HSV-CFTR in the setting of the highly inflammatory environment of wounded skin (ClinicalThals.gov Identifier: NCT03536143). The following example describes experiments showing that this novel HSV-based gene therapy vector was able to express functional full-length human CFTR in patient-derived small airway epithelial cells (SAEC) in a dose-dependent manner. HSV-CFTR was constructed as described in Example 1 above. Primary SAEC from CF patients cultured in 2D were left uninfected (mock) or infected with HSV-CFTR at multiplicities of infection (MCI) of 0.3, 1, or 3. Human CFTR expression was assessed 48 hours later. of infection in harvested cells by quantitative reverse transcription PCR (qRT-PCR). Codon-optimized CFTR transcripts were detected in infected primary CF SAECs at an MOI as low as 0.3, and appeared to show a dose-dependent increase in transgene expression up to an MOI of 3.0 (FIGURE 2). . Little or no exogenous CFTR RNA was observed in mock-infected control samples, demonstrating the specificity of the assay for the human HSV-encoded transgene. CFTR protein expression in HSV-CFTR-infected primary CF SAECs was assessed by Western blot analysis. GAPDH was used as a control to ensure consistent loading of the samples. SAEC from CF patients overexpressed human CFTR when infected with HSV-CFTR, in zcoonn / i znz / B / v compared to mock-infected control cells (FIGURE 3). Interestingly, while the endogenous CFTR protein in mock-infected cells resolved as a single band slightly larger than 150 kDa (the predicted size of full-length human CFTR is 168 kDa), the exogenous CFTR protein expressed in cells transduced by HSV-CFTR appeared as a doublet of significantly larger size. Human CFTR is known to exist in three different forms depending on the glycosylation state: (1) unglycosylated; (2) glycosylated in the nucleus; and (3) complex glycosylated, fully mature (Scanlin, 2001, Respir Res, 2(5), pp. 276-9). The appearance of the single lower molecular weight band in cells from mock-infected CF patients suggested that the endogenous (mutant) protein only exists in the unglycosylated form, indicating an immature protein variant that does not adequately transit the endoplasmic reticulum (ER) to the cell surface. In contrast, the appearance of the two largest forms of CFTR in HSV-CFTR-infected cells revealed extensive post-translational modification of the human transgene, likely representing the core-glycosylated and complex-glycosylated variants of CFTR, suggesting proper maturation and trafficking of the exogenous protein through the ER. CFTR protein expression and relative localization was then examined by immunofluorescence. Primary SAECs from CF patients were transduced with HSV-CFTR at the indicated MCIs for 48 hours, and immunofluorescence staining for human CFTR was performed. A mock-infected control sample was added to show baseline levels and cellular localization of endogenous mutant CFTR protein in these diseased cells. When analyzed in the context of control cells, immunofluorescence data demonstrated that transduced SAECs displayed a HSV-CFTR dose-dependent increase in CFTR protein expression (FIGURE 4A). When comparing the relative cellular localization of CFTR expressed in SAEC from mock-infected vs. HSV-CFTR-infected CF patients (FIGURE 4B), CFTR expressed in uninfected cells appeared to be relegated to the perinuclear region (suggesting entrapment and turnover in the ER), while CFTR was found throughout the cytoplasm and on the cell surface of cells transduced by HSV-CFTR (indicating proper maturation in the ER and trafficking through ER). this). These data are consistent with Western blot data suggesting that the wild-type CFTR expressed by the HSVCFTR was fully glycosylated whereas the mutant endogenous CFTR was unglycosylated (FIGURE 3). Finally, the functionality of human CFTR expressed by HSV-CFTR in SAECs from infected CF patients was confirmed using a dihydrorhodamine 6G (dR6G) fluorescent dye uptake assay that was previously validated as a functional endpoint for restoration. virus-mediated CFTR in 2D cultured epithelial cells from CF patients (Wersto, 1996, Proc Nati Acad Sci USA, 93(3), pp. 1167-72). Briefly, SAECs from HSV-CFTR-infected or mock-infected primary CF patients were incubated with dR6G-containing cell culture medium for 15 min, washed four times with PBS, used in RIPA buffer, and the concentration read. 526 nm excitation / 555 nm emission fluorescence for each sample in a plate reader. dR6G does not fluoresce itself, but is converted to the fluorescent compound rhodamine 6G upon cellular uptake and exposure to intracellular dehydrogenases, a process that depends on the presence of functional CFTR (Wersto, 1996, Proc Nati Acad Sci USA, 93(3), pp. 1167-72). A BCA assay was performed on zcoonn / i znz / R / v each cell lysate to quantify total protein content, and relative fluorescence per total protein in pg was calculated for each sample (FIGURE 5). HSV-CFTR infection of SAEC from primary CF patients caused a modest dose-dependent increase in dR6G uptake compared with mock-infected controls, indicating that HSV-CFTR was able to restore CFTR function in these diseased primary epithelial cells. Example 3: In Vitro Pharmacology and Dosage of HSV-CFTR in 3D Organotypic Cultures Using Organoids Derived from CF Patients Mutations in the CFTR gene are classified into one of six classes based on the primary mechanism that leads to CFTR malfunction. Mutations that affect synthesis and processing result in more severe disease, as little or no protein reaches the cell surface; mutations that do not interfere with luminal trafficking but reduce CFTR-mediated anion efflux typically result in less severe symptoms due to retention of some residual CFTR function at the apical membrane (Foundation, 2019, 2018 Annual Data Repcrt, Bethesda : Cystic Fibrosis Foundation). Because CFTR mutations affect distinctive steps in protein synthesis and function, recent drug development efforts have focused on small molecule modulatory therapies that target a specific source of the protein defect. For example, ivacaftor, subclassified as a CFTR protein enhancer, increases membrane CFTR chloride secretion (providing clinical benefit for people with specific CFTR conductance and gating class III and IV mutations), while that elexacaftor, subclassified as a CFTR protein proofreader, acts by facilitating the correct folding and cellular processing of CFTR that would otherwise be degraded by the endoplasmic reticulum quality control pathway (providing clinical benefit to people with specific mutations of class II CFTR traffic) (Clancy, 2019, Am J Respir Crit Care Med, 186(7), pp. 593-7). Although the recent FDA approval of four of these modulating therapies has been a boon for CF patients who harbor the specific mutations that respond to these drugs, these modulators only treat a subset of the CF population. Patients harboring class I mutations (responsible for approximately 10% of CF cases worldwide), which encompass frameshift, splicing, and nonsense mutations that result in severely severe CFTR expression. reduced or absent, they need effective pharmacological intervention, as these patients suffer from the harshest and deadliest forms of CF (Wilschanski, 2012, Front Pharmacol, 20(3), pp. 1-3). Due to the lack of suitable animal models for CF, efficacy studies on differentiated air-fluid interface bronchial epithelial cells derived from lung explant materials from CF patients have been used for some drug development efforts following testing of proof of concept in 2D heterologous cell systems (Neuberger, 2011, Methods Mol Biol, 741(1), pp. 39-54) (Randell, 2011, Methods Mol Biol, 742(1), pp. 285-310). However, the limited availability of lung explant tissues from tissues and the invasive procedures required to obtain bronchial cells from CF patients without end-stage disease have led to the development of 3D organotypic systems derived from readily accessible tissues collected from CF mutant patients. CFTR, to test new therapies to treat CF. One such technology, using a zcoonn / i znz / R / v forskolin-induced inflammation (FIS) assay, uses CF patient-derived intestinal organoids (PDOs) to studying the function of the CFTR protein alone or in response to pharmaceutical intervention (Dekkers, 2013, NatMed, 19(7), pp. 939-45), and has proven to be a breakthrough in CF drug development. When exposed to forskolin, organoids rapidly increase their cyclic AMP content, which in turn causes the CFTR channel to open. Organoids derived from biopsies taken from healthy individuals swell as a consequence of CFTR-mediated transport of ions and water into the lumen of the organoid, whereas organoids derived from biopsies from CFTR motant patients (or from wild-type organoids exposed to inhibition pharmacological function-specific CFTR protein) have a reduced or completely inhibited swelling capacity (Boj, 2017, J Vis Exp, 120(1), p. e55159). The use of CF PDO allows quantitative measurement of CFTR protein function (through detection of organoid swelling) following treatment with new therapies, and positive results from this 3D organotypic system have been shown to be directly correlate with clinical benefit, which includes both changes in lung responses and sweat chloride concentration in treated CF patients (Berkers, 2019, CelIRep, 26(7), pp. 1701-1708). . The following example describes experiments showing that the recombinant HSV-1 vector HSVCFTR, characterized in Example 2 above, was capable of rescuing the cystic phenotype of CF PDOs, independent of the underlying CFTR mutation. The ability of HSV-CFTR to restore functional CFTR expression was tested in clinically relevant 3D organotypic cultures using intestinal organoids derived from four different CF patients; (1) a female patient homozygous for a CFTR mutation F508del (class II mutation), (2) a male patient also homozygous for the F508del mutation, (3) a female patient homozygous for a CFTR nonsense mutation G542X (mutation class I), and (4) a female patient homozygous for a CFTR missense mutation W1282X (class I mutation). To assess CFTR activity in transduced organoids, organoid morphology and size were assessed 24 or 48 hours post-infection, and FIS assay performed as previously described (Boj, 2017, J Vis Exp, 120(1), p.e55159). For efficient infection of CF organoids, organoids were cut into small fragments, incubated in solution with HSV-CFTR at the indicated MOIs for 1 hour, and plated in 96-well clear bottom plates for analysis. The FIS assay was carried out 24 or 48 hours after seeding, as described in more detail below. First, PDO G542X / G542X was infected at MOIs of 10, 20 and 40 to assess both the impact of the vector on organoid swelling and cell viability. Intestinal organoids derived from a healthy patient were plated in parallel for comparison. Surprisingly, HSV-CFTR transduced organoids showed lumen formation and clear cystic morphology mimicking wild-type PDOs 24 hours after infection, suggesting complete functional correction of the diseased phenotype by the genetically altered vector. before the addition of forskolin (FIGURE 6A). An HSV vector expressing mCherry was used as a negative control to demonstrate that alterations in PDO morphology observed in HSV-CFTR-treated samples were not due to a non-specific response to viral infection. Next, a zcoonn / i znz / R / v FIS assay was performed 48 hours after infection. At t=0, prior to forskolin addition and subsequent CFTR activation, HSV-CFTR-treated organoids already possessed significantly greater lumen area, compared with vehicle-treated or mCherry-infected organoids, consistent with with observations made 24 hours after infection (FIGURE 6B). Interestingly, only a moderate increase in organoid swelling was observed 60 minutes after forskolin addition (t=60) in HSV-CFTR transduced organoids, probably because these organoids were already near their maximum. swelling potential prior to forskolin exposure (FIGURE 6C). The G542X / G542X mutation can be (at least partially) corrected by exposure to the aminoglycoside geneticin (G418) which allows translational readout of the nonsense mutation, and G418 was included in this assay as a positive control. Although G542X / G542X PDOs swelled in the presence of G418 at t=60, the average size of organoids in these positive control samples was significantly smaller than that of HSV-CFTR challenged PDOs (FIGS. 6B and 6C). Mild to moderate vector toxicity was observed in G542X / G542X PDOs 48 hours post-infection when HSV-CFTR was used at MOI 20 or 40, and toxicity at MOI^20 is likely the cause of the toxicity. lower swelling capacity observed in these organoids, compared to samples infected at an MOI of 10. However, although a cytotoxic effect was observed at high MOIs, the treated organoids still outperformed the small molecule positive control. Because HSV-CFTR corrected diseased organoids to wild-type morphology (large cystic lumen) in all MOIs tested within 24 hours, and higher doses of HSV-CFTR appeared to have a negative impact on organoids. in swelling assays, the three remaining cystic fibrosis PDOs were evaluated with lower doses of HSV-CFTR (MOIs of 1, 5, and 10) and analyzed by FIS assay 24 hours post infection. First, HSV-CFTR was evaluated in PDOs derived from a patient who is homozygous for the CFTR F508del mutation. F508del is the most common mutation in patients with cystic fibrosis; at least one copy of this allele is found in approximately 85% of CF patients worldwide, and F508del accounts for approximately 70% of CFTR loss-of-function mutations (Maiuri, 2015, Ann Transí Med, 3 (Supple 1), p. S24). Most of the F508del organoid cultures tested showed a cystic (wild-type) morbidity 24 hours after infection with HSV-CFTR, even at the lowest dose tested (MOI of 1). The mean size of HSV-CFTR-treated F508del organoids was significantly increased compared to vehicle control or mCHerry-infected organoids before the addition of forskolin (FIGURE 7A). No significant change in mean organoid size was detected upon addition of forskolin in HSV-CFTR-transduced samples, as these organoids are believed to be already at or near their maximum swelling capacity, i.e., pre-inflated” (FIGURE 7B). Importantly, the functional correction of the CFTR defect in F508del organoids was found to be similar between organoids treated with HSV-CFTR before forskolin treatment and organoids exposed to Orkambi® positive control 60 minutes after forskolin treatment ( FIGURE 7A versus FIGURE 7B). Orkambi® is a lumacaftor / ivacaftor combination therapy that is FDA-approved for the treatment of CF patients 2 years of age and older who are homozygous for the F508del mutation. No apparent cytotoxicity attributable to the vector was observed in any of the MOIs evaluated. zcoonn / i znz / R / v Next, organoids derived from a patient homozygous for a second nonsense CFTR mutation (W1282X) were infected with HSV-CFTR, and organoid size quantified before and after forskolin addition. Consistent with the data presented in FIGURE 6 above, HSV-CFTR effectively restored the wild-type cystic phenotype and increased mean organoid size 24 hours post-infection in W1282X / W1282X nonsense-CFTR PDOs before the addition of forskolin (FIGURE 8A). Again, the HSVCFTR at an MCI as low as 1 appeared to correct disease morphology both before and after the addition of forskolin (FIGS. 8A and 8B). G418 was also included in these experiments; however, W1282X / W1282X PDOs were found to be unresponsive to this aminoglycoside readout, so no positive control could be included in this experiment (as no effective therapy currently exists for all CFTR nonsense mutations). These data suggest that HSV-CFTR could restore CFTR function in both G418-responsive and non-responsive CFTR-null patient samples. Finally, the organoids of a second F508del homozygous patient were evaluated. HSV-CFTR-infected PDOs had a slightly larger mean size compared to vehicle-treated organoids, but this difference was not statistically significant (FIGS. 9A and 9B). Data from these studies revealed that transduction of CF intestinal organoids with HSV-CFTR resulted in a striking alteration of organoid morphology, from a compact budding CF phenotype to a cystic organoid phenotype containing a lumen. well-defined showing wild-type characteristics within 24 hours of infection with MOIs ranging from 1 to 40. This wild-type pre-swollen phenotype was quantitatively demonstrated by measuring the total organoid size, prior to the addition of forskolin and the resulting activation of CFTR, compared to multiple negative controls. Due to the pre-swollen nature of the HSV-CFTR transduced organoids, the ability of forskolin to stimulate further swelling was limited. The observation of corrected cystic morphology in CF organoids exposed to low doses of HSV-CFTR suggested that high levels of exogenous wild-type CFTR expressed in a minority of cells was sufficient to establish correction of the disease, indicating a dominant effect of this therapeutic modality. One F508del organoid showed slightly less efficient restoration of the wild-type phenotype compared to the other CF organoid cultures examined; however, cystic morphology was observed in all HSV-CFTR-infected CF organoids at an MOI of 5 or higher. The differences observed between the different cultures of CF intestinal organoids were probably due to slight alterations in their proliferative or differentiation status at the time of infection, and therefore it is unlikely that the CFTR genotype itself contributed significantly. significantly to the efficiency of HSV-CFTR transduction or to the functional expression of CFTR. In other words, HSV-CFTR corrected the diseased CF phenotype regardless of the underlying CFTR mutation in this clinically translatable 3D organotypic system. Taken together, the data provided in these Examples indicate that HSV-CFTR ably infected relevant airway epithelia, efficiently produced functional human CFTR, and molecularly corrected multiple CFTR defects without significant toxicity. Without wishing to be bound by theory, these studies are considered to represent the first case of experimental validation of an attenuated HSV-based gene therapy vector for zcoonn / i znz / R / v delivery of full-length functional human CFTR, supporting the application of HSV-CFTR as a novel and widely applicable gene therapy for the treatment of CF. Example 4: proof of concept of in vivo delivery of an HSV-based inhaled vector The following example describes a proof-of-concept in vivo study examining the feasibility of delivering an HSV-based vector to the trachea and / or lungs of immunocompetent animals following intranasal or intratracheal administration of the virus. All procedures performed in this example complied with applicable animal welfare laws and were approved by the local Institutional Animal Care and Use Committee (IACUC). 10 C57BL / 6 mice, five to six weeks old, were used in the study, five of which received either HSV-mCherry (described above) or vehicle control by intratracheal administration, and five of which received HSV-mCherry or vehicle control. vehicle by intranasal administration. Before the experimental procedures, the animals were sedated with an intraperitoneal injection of a telazol / dexdomitor mixture, and an ophthalmic ointment was applied to the eyes to prevent drying of the corneas. For intratracheal administration, the neck of each mouse was shaved with an electric shaver and depilatory cream was applied to remove all remaining hair. Next, the surgical area was swabbed twice with 70% ethanol-soaked swabs, and the anesthetized mice were placed in an inclined holding bracket. A small incision was made in the neck with surgical scissors, and the thymus, platysma, and anterior tracheal muscles were removed to allow visualization and access to the tracheal rings. A 25pL intratracheal injection of 4.9375x108 plaque-forming units (PFU) HSV-mCherry was given to three animals, while a 25pL intratracheal injection of vehicle control was given to two animals, and each mouse was held in a hanging position until their breathing gradually returned to normal. The incision site was closed with single, individually knotted sutures. For intranasal administration, mice were anesthetized as described above, and placed in an inclined clamp. Three mice were each inoculated intranasally with 4.9375x108 PFU of virus formulated in 25pL (12.5pL per nostril). The release rate of the formulation was adjusted to allow the mouse to inhale the inoculum, without forming bubbles, during the inspiration phase of respiration. Two mice were given 25pL of vehicle control following the same procedure. After administration, the animals were kept in a hanging position until their respiration returned to normal. All animals were allowed to recover from anesthesia and provided ad libitum food and water until sacrifice. 48 hours after administration, the mice were sacrificed and bronchoalveolar lavage (BAL) was performed on the left and right lungs using sterile saline. The BAL fluid was collected, centrifuged, and cell pellets collected. The upper parts of the trachea were then collected and subjected to flash freezing in liquid nitrogen for nucleic acid quantification. Lungs (left lobe, right upper lobe, right middle lobe, and right lower and postcaval lobes) were harvested individually and flash frozen in liquid nitrogen for nucleic acid analysis or perfused in 4% neutral buffered formalin and paraffin embedded for zcoonn / i znz / R / v immunofluorescence analysis. For immunofluorescence staining of paraffin-embedded lung tissue, an Alexa Fluor® 488-conjugated pancytokeratin antibody was used to detect epithelial cells (Invitrogen cat. no. 53-9003-82), and an anti- mCherry rabbit (Abcam cat# ab213511) and an Alexa Fluor® 594-conjugated secondary antibody (Abcam cat# ab150080) to detect infected cells. Tissue samples were mounted in mounting media containing DAPI to visualize nuclei. Intranasal versus intratracheal administration of HSV-mCherry resulted in similar levels of mCherry transcripts that are detected in lung tissue of transduced animals (FIGURE 10A). Interestingly, while little or no transgene transcription was identified in the tracheas of intranasally challenged mice, a strong mCherry transcript was detected in the tracheas of intratracheally challenged mice, with no statistical difference observed. in the expression of transgenes between the lungs and the tracheas of these animals treated by invasive route. In addition, a higher total cell count per mL of BAL fluid was observed in intratracheally administered animals (646,667 cells / mL and 393,333 cells / mL for intratracheal and intranasal administration, respectively), suggesting a higher cell influx. inflammation in the lungs after intratracheal administration of the HSV-based vector. Expression of transgenic proteins in lung epithelial tissue was observed in both intranasal (FIGURE 10B) and intratracheally challenged (FIGURE 10C) animals with HSV-mCherry, but not in the corresponding vehicle controls. Taken together, these data indicate that a genetically altered HSV vector can be delivered to the lungs of immunocompetent animals via multiple routes of administration and, furthermore, that a non-invasive inhaled route of administration allows for similar levels of transgene expression in the lungs than a more direct and invasive route of administration, while inducing less cell invasion (inflammatory). Example 5: nebulization of HSV-CFTR The following example describes a study examining a non-invasive nebulizer-based route for delivery of HSV-CFTR into the airways of immunocompetent wild-type and CFTR-deficient mice. 16 mice are used in the study: 12 immunocompetent C57BL / 6 animals and 4 immunocompetent gut-corrected CFTR-deficient animals. Table 1 provides a summary of the study. 4 wild-type animals are administered HSV-CFTR by intranasal instillation, while the remaining animals are administered HSV-CFTR (or vehicle control) by nebulization (eg, using a vibrating mesh nebulizer). 48 hours after dosing, animals are sacrificed, BAL fluid is collected, and tissue samples are collected throughout the respiratory tract and lungs, i.e., upper and lower trachea, left and right bronchi, lung left and right lung (upper, middle, lower, and post-cavus lobes, individually). Tissues from two animals / group are snap frozen in liquid nitrogen and processed for nucleic acid analysis. Vector genomes / 50ng total DNA in each tissue are quantitated by qPCR analysis; human CFTR transcripts / 50ng total RNA in each tissue are quantitated by zcoonn / i znz / R / v qRT-PCR assay. Tissues from the remaining two animals / group are perfused and paraffin embedded for immunofluorescence / immunohistochemistry. BAL fluid is processed to examine the infiltration of immune cells into the lungs. zcoonn / i znz / R / v Table 1 - Study design Group Treatment Route n Animals Necropsy 1 Vehicle Inhalation 4 C57BL / 6 48 hours 2 HSV-CFTR Intranasal instillation 4 C57BL / 6 3 HSV-CFTR Inhalation 4 C57BL / 6 4 HSV-CFTR Inhalation 4 CFTRfmíU™Tg(FABPCFTR)

Claims

1. A recombinant herpesvirus genome comprising one or more polynucleotides encoding a cystic fibrosis transmembrane conductance regulator (CFTR) polypeptide.

2. The recombinant herpesvirus genome of claim 1, wherein the recombinant herpesvirus genome is capable of replication.

3. The recombinant herpesvirus genome of claim 1, wherein the recombinant herpesvirus genome has defective replication.

4. The recombinant herpesvirus genome of any of claims 1-3, wherein the recombinant herpesvirus genome comprises one or more polynucleotides encoding the CFTR polypeptide within one or more viral gene loci.

5. The recombinant herpesvirus genome of any of claims 1-4, wherein the recombinant herpesvirus genome is selected from the group consisting of a recombinant herpes simplex virus genome, a recombinant varicella zoster virus genome, a recombinant human cytomegalovirus genome, a recombinant herpesvirus 6A genome, a recombinant herpesvirus 6B genome, a recombinant herpesvirus 7 genome, a recombinant herpesvirus Kaposi's sarcoma-associated herpesvirus genome, and any derivatives thereof.

6. The recombinant herpesvirus genome of any of claims 1-5, wherein the CFTR polypeptide is a human CFTR polypeptide.

7. The recombinant herpesvirus genome of any of claims 1-6, wherein the CFTR polypeptide comprises a sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 5 or SEQ ID NO:

6.

8. The recombinant herpesvirus genome of any of claims 1-7, wherein the CFTR polypeptide comprises a sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO:

5.

9. The recombinant herpesvirus genome of any of claims 1-8, wherein the recombinant herpesvirus genome is a recombinant herpes simplex virus genome.

10. The recombinant herpesvirus genome of claim 9, wherein the recombinant herpes simplex virus genome is a recombinant herpes simplex virus type 1 (HSV-1) genome, a recombinant herpes simplex virus type 2 (HSV-2) genome, or any of its derivatives.

11. The recombinant herpesvirus genome of claim 9 or claim 10, wherein the recombinant herpes simplex virus genome is a recombinant HSV-1 genome.

12. The recombinant herpesvirus genome of any of claims 9-11, wherein the recombinant herpes simplex virus genome has been genetically altered to reduce or eliminate the expression of one or more toxic herpes simplex virus genes.

13. The recombinant herpesvirus genome of any of claims 9-12, wherein the recombinant herpes simplex virus genome comprises an inactivation mutation.

14. The recombinant herpesvirus genome of claim 13, wherein the inactivation mutation is located in a herpes simplex virus gene.

15. The recombinant herpesvirus genome of claim 14, wherein the inactivation mutation is a deletion from the coding sequence of the herpes simplex virus gene.

16. The recombinant herpesvirus genome of claim 14 or claim 15, wherein the herpes simplex virus gene is selected from the group consisting of infected cell protein (ICP) 0, ICP4, ICP22, ICP27, ICP47, thymidine kinase (tk), single extensive region (UL) 41 and UL55.

17. The recombinant herpesvirus genome of claim 16, wherein the recombinant herpes simplex virus genome comprises an inactivation mutation in one or both copies of the ICP4 gene.

18. The recombinant herpesvirus genome of claim 16 or claim 17, wherein the recombinant herpes simplex virus genome comprises an inactivation mutation in the ICP22 gene.

19. The recombinant herpesvirus genome of any of claims 16-18, wherein the recombinant herpes simplex virus genome comprises an inactivation mutation in the UL41 gene.

20. The recombinant herpesvirus genome of any of claims 16-19, wherein the recombinant herpes simplex virus genome comprises an inactivation mutation in one or both copies of the ICP0 gene.

21. The recombinant herpesvirus genome of any of claims 16-20, wherein the recombinant herpes simplex virus genome comprises an inactivation mutation in the ICP27 gene.

22. The recombinant herpesvirus genome of any of claims 16-21, wherein the recombinant herpes simplex virus genome comprises an inactivation mutation in the ICP47 gene.

23. The recombinant herpesvirus genome of any of claims 16-22, wherein the recombinant herpes simplex virus genome comprises an inactivation mutation in the UL55 gene.

24. The recombinant herpesvirus genome of any of claims 9-23, wherein the recombinant herpes simplex virus genome comprises one or more polynucleotides encoding the CFTR polypeptide within one or both loci of the viral gene ICP4.

25. The recombinant herpesvirus genome of any of claims 9-24, wherein the recombinant herpesvirus genome comprises one or more polynucleotides encoding the CFTR polypeptide within the ICP22 viral gene locus.

26. The recombinant herpesvirus genome of any of claims 9-25, wherein the recombinant herpes simplex virus genome comprises one or more polynucleotides encoding the CFTR polypeptide within the viral gene locus UL41.

27. The recombinant herpesvirus genome of any of claims 9-26, wherein the recombinant herpes simplex virus genome comprises one or more polynucleotides encoding the zcoonn / i znz / B / v CFTR polypeptide within one or both loci of the viral ICPO gene.

28. The recombinant herpesvirus genome of any of claims 9-27, wherein the recombinant herpesvirus genome comprises one or more polynucleotides encoding the CFTR polypeptide within the viral gene locus ICP27.

29. The recombinant herpesvirus genome of any of claims 9-28, wherein the recombinant herpes simplex virus genome comprises one or more polynucleotides encoding the CFTR polypeptide within the ICP47 viral gene locus.

30. The recombinant herpesvirus genome of any of claims 9-29, wherein the recombinant herpes simplex virus genome comprises one or more polynucleotides encoding the CFTR polypeptide within the viral gene locus UL55.

31. The recombinant herpesvirus genome of any of claims 1-30, wherein the recombinant herpesvirus genome has reduced cytotoxicity when introduced into a target cell, compared to a corresponding wild-type herpesvirus genome.

32. The recombinant herpesvirus genome of claim 31, wherein the target cell is a human cell.

33. The recombinant herpesvirus genome of claim 31 or claim 32, wherein the target cell is an epithelial cell of the respiratory tract.

34. The recombinant herpesvirus genome of claim 31 or claim 32, wherein the target cell is a respiratory tract cell.

35. A herpes virus comprising the recombinant herpes virus genome of any of claims 1-34.

36. The herpes virus of claim 35, wherein the herpes virus is capable of replicating.

37. The herpes virus of claim 35, wherein the herpes virus exhibits defective replication.

38. The herpes virus of any of claims 35-37, wherein the herpes virus exhibits lower cytotoxicity compared to a corresponding wild-type herpes virus.

39. The herpes virus of any of claims 35-38, wherein the herpes virus is selected from the group consisting of a herpes simplex virus, a varicella zoster virus, a human cytomegalovirus, a herpesvirus 6A, a herpesvirus 6B, a herpesvirus 7, and a herpesvirus associated with Kaposi's sarcoma.

40. The herpes virus of any of claims 35-39, wherein the herpes virus is a herpes simplex virus.

41. The herpes virus of claim 39 or claim 40, wherein the herpes simplex virus is a herpes simplex virus type 1 (HSV-1), a herpes simplex virus type 2 (HSV-2) or any derivative thereof.

42. The herpes virus of any of claims 39-41, wherein the herpes simplex virus is a zcoonn / i znz / R / v HSV-1 43. A pharmaceutical composition comprising the recombinant herpesvirus genome of any of claims 1-34 or the herpesvirus of any of claims 35-42 and a pharmaceutically acceptable excipient.

44. The pharmaceutical composition of claim 43, wherein the pharmaceutical composition is suitable 5 for topical, transdermal, subcutaneous, intradermal, oral, intranasal, intratracheal, sublingual, buccal, rectal, vaginal, inhaled, intravenous, intra-arterial, intramuscular, intracardiac; intraosseous, intraperitoneal, transmucosal, intravitreal, subretinal, intra-articular, periarticular, local or epicutaneous administration.

45. The pharmaceutical composition of claim 43 or claim 44, wherein the pharmaceutical composition is suitable for oral, intranasal, intrathecal, or inhaled administration. 10 46. ​​The pharmaceutical composition of any of claims 43-45, wherein the pharmaceutical composition is suitable for inhalation administration.

47. The pharmaceutical composition of any of claims 43-46, wherein the pharmaceutical composition is suitable for non-invasive inhalation administration. zcoonn / i znz / R / v 48. The pharmaceutical composition of any of claims 43-47, wherein the pharmaceutical composition is suitable for use in a dry powder inhaler, a pressurised metered-dose inhaler, a fine mist inhaler, a nebulizer, an electrohydrodynamic aerosol device, or any combination thereof.

49. The pharmaceutical composition of any of claims 43-48, wherein the pharmaceutical composition is suitable for use in a nebulizer. The pharmaceutical composition of claim 49, wherein the nebulizer is a vibrating mesh nebulizer.

51. The pharmaceutical composition of any of claims 43-50, wherein the pharmaceutical composition comprises a phosphate buffer.

52. The pharmaceutical composition of any of claims 43-51, wherein the composition comprises glycerol.

53. The pharmaceutical composition of any of claims 43-52, wherein the pharmaceutical composition comprises a lipid carrier.

54. The pharmaceutical composition of any of claims 43-53, wherein the pharmaceutical composition comprises a nanoparticle carrier.

55. A method for enhancing, boosting, increasing and / or supplementing the levels of a CFTR 30 polypeptide in one or more cells of a subject, the method comprising administering to the subject an effective amount of the herpes virus of any of claims 35-42 or the pharmaceutical composition of any of claims 43-54.

56. The method of claim 55, wherein the one or more cells are one or more cells of the respiratory tract. 35 57. The method of claim 55 or claim 56, wherein the one or more cells are one or more respiratory tract epithelial cells or one or more submucosal gland cells.

58. A method for reducing or inhibiting progressive lung destruction in a subject in need, the method comprising administering to the subject an effective amount of the herpes virus of any of claims 35-42 or the pharmaceutical composition of any of claims 43-54.

59. The method of any of claims 55-58, wherein the subject suffers from a chronic lung disease.

60. The method of claim 59, wherein the chronic lung disease is cystic fibrosis or chronic obstructive pulmonary disease (COPD).

61. A method for providing prophylactic, palliative or therapeutic relief from one or more signs or symptoms of cystic fibrosis in a subject in need, the method comprising administering to the subject an effective amount of the herpes virus of any of claims 35-42 or the pharmaceutical composition of any of claims 43-54.

62. The method of claim 61, wherein one or more signs or symptoms of cystic fibrosis are selected from the group consisting of a persistent cough producing thick mucus, thick and sticky mucus accumulating in the airways, wheezing, dyspnea, sinusitis, repeated lung infections, inflammation of the nasal passages, bronchiectasis, nasal polyps, hemoptysis, pneumothorax, pancreatitis, recurrent pneumonia, respiratory failure, and any combination thereof.

63. A method for providing prophylactic, palliative or therapeutic relief from one or more signs or symptoms of COPD in a subject in need, the method comprising administering to the subject an effective amount of the herpes virus of any of claims 35-42 or the pharmaceutical composition of any of claims 43-54.

64. The method of claim 63, wherein one or more signs or symptoms of COPD are selected from the group consisting of shortness of breath, wheezing, chest tightness, excess mucus in the lungs, chronic cough, cyanosis, frequent respiratory infections, and any combination thereof.

65. The method of any of claims 55-64, wherein the subject is a human being.

66. The method of any of claims 55-65, wherein the subject's genome comprises a loss-of-function mutation in a CFTR gene.

67. The method of any of claims 55-66, wherein the herpes virus or the pharmaceutical composition is administered orally, intranasally, intratracheally or by inhalation to the subject.

68. The method of any of claims 55-67, wherein the herpes virus or the pharmaceutical composition is administered to the subject by inhalation.

69. The method of any of claims 55-68, wherein the herpes virus or the pharmaceutical composition is administered by non-invasive inhalation administration.

70. The method of any of claims 55-69, wherein the herpes virus or the pharmaceutical composition is administered using a dry powder inhaler, a pressurised metered-dose inhaler, a fine mist inhaler, a nebulizer or an electrohydrodynamic aerosol device.

71. The method of any of claims 55-70, wherein the herpes virus or the pharmaceutical composition zcoonn / i znz / R / v is administered by using a nebulizer.

72. The method of claim 71, wherein the nebulizer is a vibrating mesh nebulizer. zcoonn / i znz / R / v