Compositions and methods for the treatment of congenital ichthyosis

Abstract

This provides a new treatment option for all forms of congenital ichthyosis. [Solution] The present invention provides recombinant nucleic acids comprising one or more polynucleotides encoding ichthyosis-related polypeptides, viruses comprising the recombinant nucleic acids, compositions comprising the recombinant nucleic acids and / or the viruses, methods of using the same, and products or kits thereof. TIFF2026082974000002.tif35138

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of priority of U.S. Provisional Application No. 62 / 895,045, filed on September 3, 2019, which is hereby incorporated by reference in its entirety.

[0002] Submission of Sequence Listing in ASCII Text File The following submission in ASCII text file is hereby incorporated by reference in its entirety: Sequence Listing in Computer - Readable Format (CRF) (filename: 761342001240SEQLIST.txt, recording date: September 2, 2020, size: 500,384 KB).

[0003] Field of the Invention The present disclosure relates, in part, to recombinant nucleic acids, viruses, pharmaceuticals, pharmaceutical compositions, and methods of use for treating a subject having a loss - of - function mutation in one or more ichthyosis - related genes and / or for providing prophylactic, palliative, or therapeutic relief of the signs or symptoms of one or more ichthyosis (such as X - linked ichthyosis (XLI), epidermolytic ichthyosis (EI), ichthyosis vulgaris (IV), lamellar ichthyosis (LI), congenital ichthyosiform erythroderma (CIE), harlequin ichthyosis (HI), etc.).

Background Art

[0004] Congenital ichthyosis is a group of heterogeneous disorders that appear at birth or in infancy, characterized by visible scaling and / or thickening of the skin, and may be accompanied by varying degrees of redness (erythema), skin fragility, and / or blistering, as well as abnormalities of the hair, nails, and / or mucous membranes. The scaling and / or thickening of the outermost layer of skin (hyperkeratosis) may be systemic or localized, may be associated with other organ systems (syndrome-like ichthyosis), or may be limited to the skin and skin appendages (non-syndromic ichthyosis). Treatment of congenital ichthyosis is a lifelong endeavor and is primarily symptomatic. Currently, disease treatment or management is largely supportive, generally focusing on skin lubrication and / or scaling reduction. Therefore, there is a clear need for new treatment options for all forms of congenital ichthyosis. This disclosure addresses this need and others.

[0005] All references cited herein, including patent applications, patent publications, non-patent literature, and UniProtKB / Swiss-Prot accession numbers, are incorporated herein by reference in whole, as if each individual reference were specifically and individually indicated to be incorporated by reference. [Overview of the project]

[0006] In some embodiments, the recombinant nucleic acids provided herein (e.g., recombinant herpesvirus genomes) include coding sequences of one or more ichthyosis-related genes (e.g., polynucleotides encoding wild-type and / or functional ichthyosis-related polypeptides) for use in viruses (e.g., herpesviruses), compositions, pharmaceutical formulations, pharmaceuticals, and / or methods, which are useful for supplementing or treating deficiencies in ichthyosis-related genes in subjects requiring such deficiencies (e.g., subjects born with pathogenic variants of such genes), and / or for providing preventive, mitigating, or therapeutic relief for skin wounds, disorders, or diseases in subjects having, or at risk of developing, one or more signs or symptoms of congenital ichthyosis (such as X-linked ichthyosis, phyllodes ichthyosis, or harlequin ichthyosis).

[0007] Certain aspects of this disclosure relate to recombinant herpesvirus genomes comprising one or more polynucleotides encoding ichthyosis-associated polypeptides. In some embodiments, the recombinant herpesvirus genome is replication-capable. In some embodiments, the recombinant herpesvirus genome is replication-deficient. In some embodiments, which can be combined with any of the prior embodiments, the recombinant herpesvirus genome is selected from recombinant herpes simplex virus genome, recombinant varicella-zoster virus genome, recombinant human cytomegalovirus genome, recombinant herpesvirus 6A genome, recombinant herpesvirus 6B genome, recombinant herpesvirus 7 genome, recombinant Kaposi's sarcoma-associated herpesvirus genome and any derivative thereof. In some embodiments, which can be combined with any of the prior embodiments, the recombinant herpesvirus 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 (HSV-1) 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 herpes simplex virus type 1 (HSV-1) genome.

[0008] In some embodiments, which can be combined with any of the prior embodiments, recombinant herpes simplex virus genomes have been engineered to reduce or eliminate the expression of one or more virulent herpes simplex virus genes. In some embodiments, which can be combined with any of the prior embodiments, recombinant herpes simplex virus includes an inactivating mutation. In some embodiments, the inactivating mutation is present in the herpes simplex virus gene. In some embodiments, the inactivating mutation is a deletion in the coding sequence of the herpes simplex virus gene. In some embodiments, the herpes simplex virus gene is selected from infecting cell protein (ICP) 0, ICP4, ICP22, ICP27, ICP47, thymidine kinase (tk), long unique region (UL) 41 and / or UL55. In some embodiments, which can be combined with any of the prior embodiments, recombinant herpes simplex virus genomes include an inactivating mutation in one or both copies of the ICP4 gene. In some embodiments, which can be combined with any of the prior embodiments, recombinant herpes simplex virus genomes include an inactivating mutation in the ICP22 gene. In some embodiments, which can be combined with any of the prior embodiments, the recombinant herpes simplex virus genome includes an inactivating mutation in the UL41 gene. In some embodiments, which can be combined with any of the prior embodiments, the recombinant herpes simplex virus genome includes an inactivating mutation in one or both copies of the ICP0 gene. In some embodiments, which can be combined with any of the prior embodiments, the recombinant herpes simplex virus genome includes an inactivating mutation in the ICP27 gene. In some embodiments, which can be combined with any of the prior embodiments, the recombinant herpes simplex virus genome includes an inactivating mutation in the UL55 gene. In some embodiments, which can be combined with any of the prior embodiments, the recombinant herpes simplex virus genome includes an inactivating mutation in the joint region. In some embodiments, the recombinant herpes simplex virus genome includes a deletion in the joint region.In some embodiments, which can be combined with any of the prior embodiments, the recombinant herpes simplex virus genome contains one or more polynucleotides encoding an ichthyosis-related polypeptide within one or both copies of the ICP4 viral locus. In some embodiments, which can be combined with any of the prior embodiments, the recombinant herpes simplex virus genome contains one or more polynucleotides encoding an ichthyosis-related polypeptide within the ICP22 viral locus. In some embodiments, which can be combined with any of the prior embodiments, the recombinant herpes simplex virus genome contains one or more polynucleotides within the UL41 viral locus.

[0009] In some embodiments, which can be combined with any of the prior embodiments, the ichthyosis-related polypeptide is not a transglutaminase (TGM) polypeptide. In some embodiments, the ichthyosis-related polypeptide is neither a transglutaminase 1 (TGM1) polypeptide nor a transglutaminase 5 (TGM5) polypeptide. In some embodiments that can be combined with any of the prior embodiments, the ichthyosis-related polypeptides include ATP-binding cassette subfamily A member 12 polypeptide (ABCA12), 1-acylglycerol-3-phosphate O-acyltransferase ABHD5 polypeptide (ABHD5), aldehyde dehydrogenase family 3 member A2 polypeptide (ALDH3A2), arachidonate 12-lipoxygenase 12R polypeptide (ALOX12B), hydroperoxide isomerase ALOXE3 polypeptide (ALOXE3), AP-1 complex subunit sigma-1A polypeptide (AP1S1), arylsulfatase E polypeptide (ARSE), caspase-14 polypeptide (CASP14), corneodesmosine polypeptide (CDSN), ceramide synthase 3 polypeptide (CERS3), carbohydrate sulfotransferase 8 polypeptide (CHST8), claudin-1 polypeptide (CLDN1), cystatin A polypeptide (CSTA), and cytochrome P450. 4F22 polypeptide (CYP4F22), 3-β-hydroxysteroid delta(8), delta(7)-isomerase polypeptide (EBP), elongation of very long chain fatty acids protein 4 polypeptide (ELOVL4), filaggrin polypeptide (FLG), filaggrin 2 polypeptide (FLG2), gap junction β-2 polypeptide (GJB2), gap junction β-3 polypeptide (GJB3), gap junction β-4 polypeptide (GJB4), gap junction β-6 polypeptide (GJB6), 3-ketodihydrosphingosine reductase polypeptide (KDSR), keratin, type II cytoskeletal 1 polypeptide (KRT1),Keratin, type II cytoskeletal 2 epidermal polypeptide (KRT2), Keratin, type I cytoskeletal 9 polypeptide (KRT9), Keratin, type I cytoskeletal 10 polypeptide (KRT10), lipase member N polypeptide (LIPN), loricrin polypeptide (LOR), membrane-bound transcription factor (MEBN-2) site-2) Protease polypeptide (MBTPS2), magnesium transporter NIPA4 polypeptide (NIPAL4), sterol-4-α-carboxylate 3-dehydrogenase, decarboxylated polypeptide (NSDHL), peroxisome-targeted signal 2 receptor polypeptide (PEX7), D-3-phosphoglycerate dehydrogenase polypeptide (PHGDH), phytanoyl-CoA dioxygenase, peroxysomal polypeptide (PHYH), patatin-like phospholipase domain-containing protein 1 polypeptide (PNPLA1), proteasome mature protein polypeptide (POMP), phosphoserine aminotransferase polypeptide (PSAT1), short-chain dehydrogenase / reductase family 9C member 7 polypeptide (SDR9C7), serpin B8 polypeptide (SERPINB8), long-chain fatty acid transport protein 4 polypeptide (SLC27A4), synaptosome-related protein 29 polypeptide (SNAP29), tumorigenicity inhibitor 14 14) Selected from protein polypeptide (ST14), steryl sulfatase polypeptide (STS), sulfotransferase 2B1 polypeptide (SULT2B1), vacuolar protein sorting-related protein 33B polypeptide (VPS33B), and CAAX prenylprotease 1 homolog polypeptide (ZMPSTE24). In some embodiments which can be combined with any of the prior embodiments, the ichthyosis-related polypeptide is a human ichthyosis-related polypeptide. In some embodiments which can be combined with any of the prior embodiments,Ichthyosis-related polypeptides contain sequences that have 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 an amino acid sequence selected from SEQ ID NOs. 102-152 or 155. In some embodiments that can be combined with any of the prior embodiments, the ichthyosis-related polypeptide is selected from ABCA12, ABHD5, ALDH3A2, ALOX12B, ALOXE3, AP1S1, ARSE, CASP14, CDSN, CERS3, CHST8, CLDN1, CSTA, CYP4F22, ELOVL4, KDSR, LIPN, MBTPS2, NIPAL4, PEX7, PHGDH, PHYH, PNPLA1, POMP, PSAT1, SDR9C7, SERPINB8, SLC27A4, SNAP29, ST14, STS, VPS33B, and ZMPSTE24. In some embodiments, the ichthyosis-related polypeptide is selected from ABCA12, ABHD5, ALDH3A2, ALOX12B, ALOXE3, AP1S1, CASP14, CDSN, CERS3, CHST8, CLDN1, CSTA, CYP4F22, ELOVL4, KDSR, LIPN, NIPAL4, PEX7, PHGDH, PHYH, PNPLA1, POMP, PSAT1, SDR9C7, SERPINB8, SLC27A4, SNAP29, ST14, VPS33B, and ZMPSTE24. In some embodiments, the ichthyosis-related polypeptide is selected from ARSE, MBTPS2, and STS. In some embodiments, the ichthyosis-related polypeptide is STS.

[0010] In some embodiments, which can be combined with any of the prior embodiments, the recombinant herpesvirus genome exhibits reduced cytotoxicity when introduced into target cells compared to the corresponding wild-type herpesvirus genome. In some embodiments, the target cells are epidermal and / or dermal cells. In some embodiments, the target cells are human cells.

[0011] Other aspects of this disclosure relate to herpesviruses comprising any of the recombinant herpesvirus genomes described herein. In some embodiments, the herpesvirus is capable of replication. In some embodiments, the herpesvirus is replication-deficient. In some embodiments, which can be combined with any of the prior embodiments, the herpesvirus is less cytotoxic compared to the corresponding wild-type herpesvirus. In some embodiments, which can be combined with any of the prior embodiments, the herpesvirus is selected from herpes simplex virus, varicella-zoster virus, human cytomegalovirus, herpesvirus 6A, herpesvirus 6B, herpesvirus 7, and Kaposi's sarcoma-associated herpesvirus. In some embodiments, which can be combined with any of the prior embodiments, the herpesvirus is herpes simplex virus. In some embodiments, the herpes simplex virus is herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), or any derivative thereof. In some embodiments, the herpes simplex virus is herpes simplex virus type 1 (HSV-1).

[0012] Other aspects of this disclosure relate to pharmaceutical compositions comprising any of the recombinant herpesvirus genomes and / or any of the herpesviruses described herein, and pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition is suitable for topical, transdermal, subcutaneous, intradermal, oral, intranasal, intratracheal, sublingual, buccal, rectal, vaginal, inhalation, intravenous, intra-arterial, intramuscular, intracardiac, intraosseous, intraperitoneal, transmucosal, intravitreous, subretinal, intra-articular, peri-articular, local, or transcutaneous administration. In some embodiments, the pharmaceutical composition is suitable for topical, transdermal, subcutaneous, intradermal, or transmucosal administration. In some embodiments, the pharmaceutical composition is suitable for topical, transdermal, or intradermal administration. In some embodiments, the pharmaceutical composition is suitable for topical administration.

[0013] Other aspects of this disclosure relate to the use of recombinant herpesvirus genomes and / or herpesviruses as drugs as described herein.

[0014] Other aspects of this disclosure relate to the therapeutic use of any of the recombinant herpesvirus genomes and / or herpesviruses described herein.

[0015] Other aspects of this disclosure relate to the use of any of the herpesviruses and / or pharmaceutical compositions described herein in the manufacture of drugs for treating one or more forms of congenital ichthyosis.

[0016] Other aspects of this disclosure relate to methods for providing prophylactic, symptomatic, or therapeutic relief of one or more signs or symptoms of congenital ichthyosis in a subject where such relief is needed, the methods comprising administering an effective amount of any of the herpesviruses and / or pharmaceutical compositions described herein to a subject. In some embodiments, congenital ichthyosis is defined as harlequin ichthyosis (HI), autosomal recessive congenital ichthyosis (ARCI), lobed ichthyosis (LI), congenital ichthyoid erythroderma (CIE), Shanarin-Dorfmann syndrome (CDS), Sjögren-Larsson syndrome (SLS), intellectual disability, intestinal disease, hearing loss, peripheral neuropathy, ichthyosis, and keratosis (MEDNIK) syndrome, chondrodysplasia punctata 1 (CDPX1), chondrodysplasia punctata 2 (CDPX2), peeling skin syndrome (PSS), neonatal ichthyosis sclerosing cholangitis (NISCH) syndrome, ichthyosis vulgaris, keratitis-ichthyosis-hearing loss (KID) syndrome, palmoplantar keratosis (PPK), palmoplantar keratosis with sensorineural hearing loss (PPK / SNHL), epidermolytic palmoplantar keratosis ( The following are selected from EPPK, fluctuating erythema keratoderma (EKV), Crowston syndrome, progressive symmetrical erythema keratoderma, epidermolytic ichthyosis (EI), superficial epidermolytic ichthyosis (SEI), loricrin keratoderma, follicular ichthyosis, alopecia, and photophobia (IFAP) syndrome, Olmsted syndrome, ichthyoid erythroderma and congenital unilateral dysplasia (CHILD) syndrome with limb defects, Refsum disease, Neu-Laksowa syndrome, linear keratosis with congenital ichthyosis and sclerosing keratosis (KLICK) syndrome, ichthyosis prematurity syndrome (IPS), cerebral malformations, neurological disorders, ichthyosis, and palmoplantar keratosis (CEDNIK) syndrome, X-linked ichthyosis, arthral contracture-renal dysfunction-cholestasis (ARC) syndrome, and restrictive skin disorders. See, for example, U.S. Patent No. 10,525,090, which is incorporated herein by reference in its entirety for all purposes.

[0017] Other aspects of this disclosure relate to methods for providing preventive, symptomatic, or therapeutic relief of one or more signs or symptoms of clown-like (HI) in a subject where such relief is needed, the methods comprising administering an effective amount of any of the herpesviruses and / or pharmaceutical compositions described herein to a subject. In some embodiments, the recombinant herpesvirus genome comprises one or more polynucleotides encoding the ABCA12 polypeptide.

[0018] Other aspects of this disclosure relate to methods for providing prophylactic, symptomatic, or therapeutic relief of one or more signs or symptoms of Shanarin-Dorfmann syndrome (CDS) in a subject where such relief is needed, the methods comprising administering an effective amount of any of the viruses and / or pharmaceutical compositions described herein to a subject. In some embodiments, the recombinant herpesvirus genome comprises one or more polynucleotides encoding the ABHD5 polypeptide.

[0019] Other aspects of this disclosure relate to methods for providing prophylactic, symptomatic, or therapeutic relief of one or more signs or symptoms of Sjögren-Larsson syndrome in a subject where such relief is needed, the methods comprising administering an effective amount of any of the viruses and / or pharmaceutical compositions described herein to the subject. In some embodiments, the recombinant herpesvirus genome comprises one or more polynucleotides encoding the ALDH3A2 polypeptide.

[0020] Other aspects of the present disclosure relate to methods for providing prophylactic, symptomatic, or therapeutic relief of one or more signs or symptoms of autosomal recessive congenital ichthyosis (ARCI) in subjects where such relief is needed, the methods comprising administering an effective amount of any of the herpesviruses and / or pharmaceutical compositions described herein to a subject. In some embodiments, the recombinant herpesvirus genome comprises one or more polynucleotides encoding polypeptides selected from ALOX12B, ALOXE3, CASP14, CERS3, CYP4F22, LIPN, NIPAL4, PNPLA1, SDR9C7, SLC27A4, ST14, and SULT2B1.

[0021] Other aspects of this disclosure relate to methods for providing prophylactic, symptomatic, or therapeutic relief of one or more signs or symptoms of intellectual disability, intestinal disease, hearing loss, peripheral neuropathy, ichthyosis, and keratosis (MEDNIK) syndrome in subjects where such relief is needed, the methods comprising administering an effective amount of any of the herpesviruses and / or pharmaceutical compositions described herein to a subject. In some embodiments, the recombinant herpesvirus genome comprises one or more polynucleotides encoding the AP1S1 polypeptide.

[0022] Other aspects of this disclosure relate to methods for providing prophylactic, symptomatic, or therapeutic relief of one or more signs or symptoms of chondrodysplasia punctate 1 (CDPX1) in subjects where such relief is needed, the methods comprising administering an effective amount of any of the viruses and / or pharmaceutical compositions described herein to a subject. In some embodiments, the recombinant herpesvirus genome comprises one or more polynucleotides encoding an ARSE polypeptide.

[0023] Other aspects of this disclosure relate to methods for providing prophylactic, symptomatic, or therapeutic relief of one or more signs or symptoms of chondrodysplasia punctate 2 (CDPX2) in subjects where such relief is needed, the methods comprising administering an effective amount of any of the viruses and / or pharmaceutical compositions described herein to a subject. In some embodiments, the recombinant herpesvirus genome comprises one or more polynucleotides encoding an EBP polypeptide.

[0024] Other aspects of the present disclosure relate to methods for providing prophylactic, symptomatic, or therapeutic relief of one or more signs or symptoms of peeling skin syndrome (PSS) in a subject where such relief is needed, the methods comprising administering an effective amount of any of the viruses and / or pharmaceutical compositions described herein to the subject. In some embodiments, the recombinant herpesvirus genome comprises one or more polynucleotides encoding polypeptides selected from CDSN, CHST8, CSTA, FLG2, and SERPINB8.

[0025] Other aspects of the present disclosure relate to methods for providing prophylactic, symptomatic, or therapeutic relief of one or more signs or symptoms of neonatal ichthyosis sclerosing cholangitis (NISCH) syndrome in subjects where such relief is needed, the methods comprising administering an effective amount of any of the herpesviruses and / or pharmaceutical compositions described herein to a subject. In some embodiments, the recombinant herpesvirus genome comprises one or more polynucleotides encoding the CLDN1 polypeptide.

[0026] Other aspects of the present disclosure relate to methods for providing prophylactic, symptomatic, or therapeutic relief of one or more signs or symptoms of ichthyosis vulgaris in a subject where such relief is needed, the methods comprising administering an effective amount of any of the herpesviruses and / or pharmaceutical compositions described herein to a subject. In some embodiments, the recombinant herpesvirus genome comprises one or more polynucleotides encoding an FLG polypeptide.

[0027] Other aspects of the present disclosure relate to methods for providing prophylactic, symptomatic, or therapeutic relief of one or more signs or symptoms of keratitis-ichthyosis-hearing loss (KID) syndrome, Crowston syndrome, and / or palmoplantar keratosis with sensorineural hearing loss (PPK / SNHL) in subjects where such relief is needed, the methods comprising administering an effective amount of any of the herpesviruses and / or pharmaceutical compositions described herein to a subject. In some embodiments, the recombinant herpesvirus genome comprises one or more polynucleotides encoding polypeptides selected from GJB2 and GJB6.

[0028] Other aspects of the present disclosure relate to methods for providing prophylactic, symptomatic, or therapeutic relief of one or more signs or symptoms of variable erythema keratoderma (EKV) in a subject where such relief is needed, the methods comprising administering an effective amount of any of the herpesviruses and / or pharmaceutical compositions described herein to a subject. In some embodiments, the recombinant herpesvirus genome comprises one or more polynucleotides encoding polypeptides selected from GJB3 and GJB4.

[0029] Other aspects of the present disclosure relate to methods for providing prophylactic, symptomatic, or therapeutic relief of one or more signs or symptoms of progressive symmetric erythematous keratoderma in a subject where such relief is needed, the methods comprising administering an effective amount of any of the herpesviruses and / or pharmaceutical compositions described herein to a subject. In some embodiments, the recombinant herpesvirus genome comprises one or more polynucleotides encoding a KDSR polypeptide.

[0030] Other aspects of the present disclosure relate to methods for providing prophylactic, symptomatic, or therapeutic relief of one or more signs or symptoms of epidermolytic ichthyosis (EI) and / or superficial epidermolytic ichthyosis (SEI) in subjects where such relief is needed, the methods comprising administering an effective amount of any of the herpesviruses and / or pharmaceutical compositions described herein to a subject. In some embodiments, the recombinant herpesvirus genome comprises one or more polynucleotides encoding polypeptides selected from KRT1, KRT2, and KRT10.

[0031] Other aspects of the present disclosure relate to methods for providing prophylactic, symptomatic, or therapeutic relief of one or more signs or symptoms of epidermolytic palmoplantar keratoderma (EPPK) in a subject where such relief is needed, the methods comprising administering an effective amount of any of the herpesviruses and / or pharmaceutical compositions described herein to a subject. In some embodiments, the recombinant herpesvirus genome comprises one or more polynucleotides encoding a KRT9 polypeptide.

[0032] Other aspects of this disclosure relate to methods for providing prophylactic, symptomatic, or therapeutic relief of one or more signs or symptoms of loricrin keratosis in a subject where such relief is needed, the methods comprising administering an effective amount of any of the herpesviruses and / or pharmaceutical compositions described herein to a subject. In some embodiments, the recombinant herpesvirus genome comprises one or more polynucleotides encoding a LOR polypeptide.

[0033] Other aspects of the present disclosure relate to methods for providing prophylactic, symptomatic, or therapeutic relief of one or more signs or symptoms of follicular ichthyosis, alopecia, and photophobia (IFAP) syndrome in subjects where such relief is needed, the methods comprising administering an effective amount of any of the herpesviruses and / or pharmaceutical compositions described herein to a subject. In some embodiments, the recombinant herpesvirus genome comprises one or more polynucleotides encoding the MBTPS2 polypeptide.

[0034] Other aspects of the present disclosure relate to methods for providing prophylactic, symptomatic, or therapeutic relief of one or more signs or symptoms of ichthyosis-like erythroderma and unilateral dysplasia (CHILD) syndrome with limb defects in subjects in need, the methods comprising administering an effective amount of any of the herpesviruses and / or pharmaceutical compositions described herein to a subject. In some embodiments, the recombinant herpesvirus genome comprises one or more polynucleotides encoding an NSDHL polypeptide.

[0035] Other aspects of the present disclosure relate to methods for providing prophylactic, symptomatic, or therapeutic relief of one or more signs or symptoms of Refsum disease in a subject where such relief is needed, the methods comprising administering an effective amount of any of the herpesviruses and / or pharmaceutical compositions described herein to a subject. In some embodiments, the recombinant herpesvirus genome comprises one or more polynucleotides encoding polypeptides selected from PEX7 and PHYH.

[0036] Other aspects of the present disclosure relate to methods for providing prophylactic, symptomatic, or therapeutic relief of one or more signs or symptoms of Neu-Laksowa disease in a subject in need, the methods comprising administering an effective amount of any of the herpesviruses and / or pharmaceutical compositions described herein to a subject. In some embodiments, the recombinant herpesvirus genome comprises one or more polynucleotides encoding polypeptides selected from PHGDH and PSAT1.

[0037] Other aspects of the present disclosure relate to methods for providing prophylactic, symptomatic, or therapeutic relief of one or more signs or symptoms of linear keratosis (KLICK) syndrome with congenital ichthyosis and sclerosing keratosis in subjects where such relief is needed, the methods comprising administering an effective amount of any of the herpesviruses and / or pharmaceutical compositions described herein to a subject. In some embodiments, the recombinant herpesvirus genome comprises one or more polynucleotides encoding a POMP polypeptide.

[0038] Other aspects of this disclosure relate to methods for providing prophylactic, symptomatic, or therapeutic relief of one or more signs or symptoms of ichthyosis prematurity syndrome (IPS) in subjects where such relief is needed, the methods comprising administering an effective amount of any of the herpesviruses and / or pharmaceutical compositions described herein to a subject. In some embodiments, the recombinant herpesvirus genome comprises one or more polynucleotides encoding the SLC27A4 polypeptide.

[0039] Other aspects of the present disclosure relate to methods for providing prophylactic, symptomatic, or therapeutic relief of one or more signs or symptoms of cerebral malformations, neurological disorders, ichthyosis, and palmoplantar keratoderma (CEDNIK) syndrome in subjects where such relief is needed, the methods comprising administering an effective amount of any of the herpesviruses and / or pharmaceutical compositions described herein to a subject. In some embodiments, the recombinant herpesvirus genome comprises one or more polynucleotides encoding the SNAP29 polypeptide.

[0040] Other aspects of this disclosure relate to methods for providing prophylactic, symptomatic, or therapeutic relief of one or more signs or symptoms of X-linked ichthyosis in a subject where such relief is needed, the methods comprising administering an effective amount of any of the herpesviruses and / or pharmaceutical compositions described herein to a subject. In some embodiments, the recombinant herpesvirus genome comprises one or more polynucleotides encoding an STS polypeptide.

[0041] Other aspects of the present disclosure relate to methods for providing prophylactic, symptomatic, or therapeutic relief of one or more signs or symptoms of arthritis-renal dysfunction-cholestasis (ARC) syndrome in subjects where such relief is needed, the methods comprising administering an effective amount of any of the viruses and / or pharmaceutical compositions described herein to a subject. In some embodiments, the recombinant herpesvirus genome comprises one or more polynucleotides encoding the VPS33B polypeptide.

[0042] Other aspects of this disclosure relate to methods for providing prophylactic, symptomatic, or therapeutic relief of one or more signs or symptoms of restrictive skin disorders in subjects where such relief is needed, the methods comprising administering an effective amount of any of the herpesviruses and / or pharmaceutical compositions described herein to a subject. In some embodiments, the recombinant herpesvirus genome comprises one or more polynucleotides encoding the ZMPSTE24 polypeptide.

[0043] In some embodiments, which can be combined with any of the prior embodiments, the subject is human. In some embodiments, which can be combined with any of the prior embodiments, the subject genome includes pathogenic variants of ichthyosis-related genes. In some embodiments, which can be combined with any of the prior embodiments, the subject genome includes loss-of-function mutations of ichthyosis-related genes.

[0044] In some embodiments, which can be combined with any of the prior embodiments, the herpes virus or pharmaceutical composition is administered to the subject topically, percutaneously, subcutaneously, on the skin, intradermally, orally, sublingually, buccally, rectally, vaginally, intravenously, intraarterially, intramuscularly, intrabonely, intracardiacly, intraperitoneally, transmucosally, intravitreously, subretinally, intraarticularly, periarticularly, locally, or by inhalation. In some embodiments, the herpes virus or pharmaceutical composition is administered to the subject topically, percutaneously, subcutaneously, intradermally, or transmucosally. In some embodiments, the herpes virus or pharmaceutical composition is administered to the subject topically, percutaneously, or intradermally. In some embodiments, the herpes virus or pharmaceutical composition is administered to the subject topically. In some embodiments, which can be combined with any of the prior embodiments, the skin of the subject is rubbed or made more permeable before administration. [Brief explanation of the drawing]

[0045] [Figure 1-1]Figures 1A-1I show schematic diagrams of wild-type and modified herpes simplex virus genomes. Figure 1A shows the wild-type herpes simplex virus genome. Figure 1B shows the modified herpes simplex virus genome, which includes deletions of the coding sequences for both copies of ICP4, and has an expression cassette containing polynucleotides encoding ichthyosis-related polypeptides integrated into each ICP4 locus. Figure 1C shows the modified herpes simplex virus genome, which includes deletions of the coding sequences for both copies of ICP4 and UL41, and has an expression cassette containing polynucleotides encoding ichthyosis-related polypeptides integrated into each ICP4 locus. Figure 1D shows the modified herpes simplex virus genome, which includes deletions of the coding sequences for both copies of ICP4 and UL41, and has an expression cassette containing polynucleotides encoding ichthyosis-related polypeptides integrated into the UL41 locus. Figure 1E shows a modified herpes simplex virus genome containing deletions of the coding sequences for ICP4 (both copies) and ICP22, and includes an expression cassette containing a polynucleotide encoding an ichthyosis-related polypeptide integrated into each ICP4 locus. Figure 1F shows a modified herpes simplex virus genome containing deletions of the coding sequences for ICP4 (both copies) and ICP22, and includes an expression cassette containing a polynucleotide encoding an ichthyosis-related polypeptide integrated into the ICP22 locus. Figure 1G shows a modified herpes simplex virus genome containing deletions of the coding sequences for ICP4 (both copies), UL41, and ICP22, and includes an expression cassette containing a polynucleotide encoding an ichthyosis-related polypeptide integrated into each ICP4 gene. Figure 1H shows a modified herpes simplex virus genome containing deletions of the coding sequences for ICP4 (both copies), UL41, and ICP22, and includes an expression cassette containing a polynucleotide encoding an ichthyosis-related polypeptide integrated into the UL41 locus. Figure 1I shows a modified herpes simplex virus genome containing deletions of the coding sequences for ICP4 (both copies), UL41, and ICP22, and having an expression cassette containing a polynucleotide encoding an ichthyosis-related polypeptide integrated into the ICP22 locus. [Figure 1-2]Please refer to the explanation in Figure 1-1. [Figure 1-3] Please refer to the explanation in Figure 1-1. [Figure 1-4] Please refer to the explanation in Figure 1-1. [Figure 1-5] Please refer to the explanation in Figure 1-1. [Figure 2-1] Figures 2A-2G show the in vitro evaluation of HSV-TGM1 in immortalized and primary TGM1-deficient human ARCI keratinocytes grown in low-calcium cell culture medium. Figure 2A shows the dose-dependent detection of human TGM1 DNA copies in response to the increase in MOI of HSV-TGM1 in immortalized keratinocytes, as evaluated by qPCR. Data are shown as the mean ± SEM of two repeats. Figure 2B shows the dose-dependent expression of human TGM1 transcripts in response to the increase in MOI of HSV-TGM1 in immortalized keratinocytes, as evaluated by qRT-PCR. Data are shown as the mean ± SEM of two repeats. Figure 2C shows HSV-TGM1-mediated TGM1 protein expression in infected immortalized keratinocytes as measured by Western blot. Figure 2D shows a representative immunofluorescence image of human TGM1 protein expression in immortalized keratinocytes upon HSV-TGM1 infection. Figure 2E shows a representative immunofluorescence image of HSV-TGM1-dependent TGM1 enzyme activity in immortalized keratinocytes. Figure 2F shows HSV-TGM1-mediated TGM1 protein expression in infected primary cells, as determined by Western blot analysis. Figure 2G shows a representative immunofluorescence image of human TGM1 protein expression in primary cells upon HSV-TGM1 infection. In these experiments, uninfected (pseudo) and HSV-mCherry-infected (mCherry) cells were used as negative controls. Normal primary keratinocytes (NPK) were used as a positive control. Nuclei were visualized using DAPI staining. GAPDH was used as a loading control. Western blot and immunofluorescence analysis provide quantification of protein levels and fluorescence intensity for each condition. Bar: 130 μm. [Figure 2-2] Please refer to the explanation in Figure 2-1. [Figure 3]Figures 3A-3B show the in vitro evaluation of HSV-TGM1 in immortalized TGM1-deficient human ARCI keratinocytes grown in high-calcium cell culture medium. Figure 3A shows a representative immunofluorescence image of human TGM1 protein expression in immortalized keratinocytes upon HSV-TGM1 infection. Figure 3B shows a representative immunofluorescence image of HSV-TGM1-dependent TGM1 enzyme activity in immortalized keratinocytes. Uninfected (pseudo) cells were used as a negative control. Normal primary keratinocytes (NPKs) were used as a positive control. Nuclei were visualized using DAPI staining. Quantification of fluorescence intensity is provided for each condition. Bar: 130 μm. [Figure 4] This report shows the in vitro evaluation of HSV-TGM1 in primary TGM1-deficient human ARCI keratinocytes grown in high-calcium cell culture medium. Representative immunofluorescence images of human TGM1 protein expression in primary keratinocytes infected with HSV-TGM1 are shown. Uninfected (pseudo) cells were used as a negative control. Normal primary keratinocytes (NPK) were used as a positive control. Nuclei were visualized using DAPI staining. Quantification of fluorescence intensity is provided for each condition. Bar: 130 μm. [Figure 5] Figures 5A–5B show the survival rates of primary TGM1-deficient human ARCI keratinocytes grown in low- and high-calcium cell culture media after HSV-TGM1 infection. Figure 5A shows representative bright-field images of primary keratinocytes grown in low- or high-calcium cell culture media 48 hours after infection with HSV-TGM1 at the indicated MOI. Uninfected (pseudo) cells were used as negative controls. Figure 5B shows the survival rates of HSV-TGM1-infected primary LI patient keratinocytes 48 hours post-infection as determined by the MTS assay. For each condition, data are shown as mean ± SEM from three separate experiments (using triple wells). Bar: 370 μm. [Figure 6-1]Figures 6A–6D show the in vivo evaluation of HSV-TGM1 via local delivery routes to BALB / c mice. Figure 6A shows representative hematoxylin and eosin (H&E) stained samples collected by tape stripping or permeabilization with acetone from the skin of BALB / c mice locally treated with either HSV-TGM1 (low or high dose) or a negative control (vehicle). Figure 6B shows dose-dependent detection of human TGM1 DNA copies in mouse skin biopsies collected 48 hours after tape stripping or permeabilization with acetone and application of HSV-TGM1 (low or high dose) or a negative control (vehicle), as evaluated by qPCR. Figure 6C shows dose-dependent expression of human TGM1 transcripts in mouse skin biopsies collected 48 hours after tape stripping or permeabilization with acetone and application of HSV-TGM1 (low or high dose) or a negative control (vehicle), as evaluated by qRT-PCR. For each vehicle control condition of qPCR and qRT-PCR analysis, data are shown as the mean of two tissue samples (two replicate tests / tissue samples) ± SEM. For each HSV-TGM1 condition, data are shown as the mean of four tissue samples (two replicate tests / tissue samples) ± SEM. Figure 6D shows representative immunofluorescence images of human TGM1, mouse loricrin, and mouse integrin α-6 protein localization in mouse skin biopsies collected 48 hours after skin barrier disruption by acetone treatment or tape stripping, and application of HSV-TGM1 (low or high dose) or negative control (vehicle). Nuclei were visualized using DAPI staining. Bar: 50 μm. [Figure 6-2] Please refer to the explanation in Figure 6-1. [Figure 7]This study presents the in vivo evaluation of mouse TGM1 during HSV-TGM1 infection via multiple local delivery routes to BALB / c mice. It shows the magnitude change in mouse TGM1 RNA copies in mouse skin biopsies collected 48 hours after permeabilization by tape stripping or acetone treatment, and application of the vehicle alone to HSV-TGM1 (low or high dose) or untreated control skin, as evaluated by qPCR. For each vehicle condition, data are presented as the mean of two tissue samples (two replicate tests / tissue samples) ± SEM. For each HSV-TGM1 condition, data are presented as the mean of four tissue samples (two replicate tests / tissue samples) ± SEM. As determined by a two-sided Student's t-test, ns: not significant (p>0.05). Bar: 50 μm. [Figure 8] Figures 8A-8C show the in vivo short-term pharmacokinetics of HSV-TGM1 upon local delivery to BALB / c mice. Figure 8A shows the detection of human TGM1 DNA copies in skin biopsies collected at the indicated time point from BALB / c mice locally treated with either HSV-TGM1 or a negative control (vehicle). Figure 8B shows the detection of human TGM1 transcripts in skin biopsies collected at the indicated time point from BALB / c mice locally treated with either HSV-TGM1 or a negative control (vehicle). For each vehicle-control condition of qPCR and qRT-PCR analysis, data are shown as the mean of two tissue samples (two replicate tests / tissue samples) ± SEM. For each HSV-TGM1 condition, data are shown as the mean of four tissue samples (two replicate tests / tissue samples) ± SEM. Figure 8C shows representative immunofluorescence images of human TGM1 and mouse loricrinprotein localization in mouse skin biopsies taken at the indicated time point from BALB / c mice locally treated with either HSV-TGM1 or a negative control (vehicle). Nuclei were visualized using DAPI staining. Bar: 50 μm. [Figure 9-1]Figures 9A–9D show the in vivo pharmacokinetics of HSV-TGM1 after single and multiple local delivery to BALB / c mice. Figure 9A shows H&E-stained skin biopsies taken from BALB / c mice treated and collected at the indicated time after single or multiple local administration of either HSV-TGM1 or a negative control (vehicle). Figure 9B shows the detection of human TGM1 DNA copies in skin biopsies taken from BALB / c mice treated and collected at the indicated time after single or multiple local administration of either HSV-TGM1 or a negative control (vehicle). Figure 9C shows the detection of human TGM1 transcripts in skin biopsies taken from BALB / c mice treated and collected at the indicated time after single or multiple local administration of either HSV-TGM1 or a negative control (vehicle). For each vehicle-control condition of qPCR and qRT-PCR analysis, data are shown as the mean of two tissue samples (two replicate tests / tissue sample) ± SEM. For each HSV-TGM1 condition, data are shown as the mean (2 replicate tests / tissue sample) ± SEM of 4 or 6 tissue samples. Figure 9D shows representative immunofluorescence images of human TGM1 and mouse loricrinprotein localization in skin biopsies taken from BALB / c mice treated and collected at the indicated time points after single or multiple local administrations of either HSV-TGM1 or a negative control (vehicle). Nuclei were visualized using DAPI staining. Bar: 50 μm. [Figure 9-2] Please refer to the explanation in Figure 9-1. [Modes for carrying out the invention]

[0046] Detailed explanation In some embodiments, this disclosure relates to the use of recombinant nucleic acids (e.g., recombinant herpesvirus genomes) and / or viruses (e.g., herpesviruses) in which one or more polynucleotides encode one or more ichthyosis-related polypeptides (e.g., wild-type and / or functional ichthyosis-related polypeptides), to supplement or treat endogenous ichthyosis-related gene deficiencies (e.g., subjects whose genomes are congenitally carrying pathogenic variants of ichthyosis-related genes(s)). Not limited to theory, the recombinant nucleic acids, viruses, compositions, formulations, pharmaceuticals and / or methods described herein are thought to be useful in treating existing skin abnormalities in individuals with congenital ichthyosis (such as individuals with X-linked ichthyosis) and in preventing or delaying the recurrence of wounds and skin abnormalities in treated subjects.

[0047] The following description includes exemplary methods, parameters, etc. However, it should be noted that such descriptions are not intended to limit the scope of this disclosure, but rather are provided as descriptions of exemplary embodiments.

[0048] I. General techniques The techniques and procedures described or referenced herein are generally well understood by those skilled in the art and refer to conventional methodologies, such as Sambrook et al., Molecular Cloning: A Laboratory Manual 3d edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Current Protocols in Molecular Biology (FMAusubel, et al. eds., (2003)); the series Methods in Enzymology (Academic Press, Inc.): PCR 2: A Practical Approach (MJ MacPherson, BD Hames and GRTaylor eds. (1995)), Harlow and Lane, eds. (1988); Oligonucleotide Synthesis (MJ Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (JE Cellis, ed., 1998) Academic Press; Animal Cell Culture (RIFreshney), ed., 1987), Introduction to Cell and Tissue Culture (JP Mather and PE Roberts, 1998) Plenum Press, Cell and Tissue Culture: Laboratory Procedures (A. Doyle, JBGriffiths, and DG Newell, eds., 1993-8) J. Wiley and Sons, Gene Transfer Vectors for Mammalian Cells (JMMiller and MP Calos, eds., 1987), PCR: The Polymerase Chain Reaction, (Mullis et al., eds.It is commonly used with widely adopted methodologies, such as those described in *Short Protocols in Molecular Biology* (Wiley and Sons, 1994) and *Short Protocols in Molecular Biology* (Wiley and Sons, 1999).

[0049] II. Definition Before describing this disclosure in detail, it should be understood that this disclosure is not limited to any particular composition or biological system and is, needless to say, subject to change. It should also be understood that the terms used herein are solely for the purpose of describing specific embodiments and are not intended to be limiting.

[0050] As used herein, unless the context clearly indicates otherwise, the singular forms "a," "an," and "the" refer to multiple objects. Therefore, for example, a reference to "molecule" may optionally include combinations of two or more such molecules.

[0051] As used herein, the term "and / or" may include any and all combinations of one or more of the related enumerated items. For example, the term "a and / or b" may refer to "a only," "b only," "a or b," or "a and b," and the term "a, b and / or c" may refer to "a only," "b only," "c only," "a or b," "a or c," "b or c," "a, b or c," "a and b," "a and c," "b and c," or "a, b and c," etc.

[0052] As used herein, the term “approximately” refers to the normal margin of error for each value, as readily understood by those skilled in the art. References to values ​​or parameters “approximately” herein include (and are described) embodiments relating to the value or parameter itself.

[0053] The aspects and embodiments of this disclosure are understood to include "including," "consisting of," and "essentially consisting of."

[0054] As used herein, the terms “polynucleotide,” “nucleic acid sequence,” and “nucleic acid,” and their variations thereto, are a collective term for polydeoxyribonucleotides (containing 2-deoxy-D-ribose), polyribonucleotides (containing D-ribose), any other type of polynucleotide that is an N-glycoside of a purine or pyrimidine base, and other polymers containing a non-nucleotide backbone (but limited to polymers containing nucleic acid bases in a configuration that allows for base pairing and base stacking, as found in DNA and RNA). Therefore, these terms include known types of nucleic acid sequence modifications, such as the substitution of one or more native nucleotides by analogs, and internucleotide modifications.

[0055] As used herein, a nucleic acid is “operatively linked” or “operably linked” when it is placed in a functional relationship with another nucleic acid sequence. For example, a promoter or enhancer is operatively linked to a coding sequence if it affects the transcription of the sequence, or a ribosome binding site is operatively linked to a coding sequence if it is positioned to facilitate translation. Generally, “operatively linked” or “operably linked” means that the linked DNA or RNA sequences are adjacent to each other.

[0056] As used herein, the term “vector” refers to individual elements used to introduce heterologous nucleic acids into cells for either their expression or replication. Expression vectors include vectors capable of expressing nucleic acids operably linked to a regulatory sequence, such as a promoter region, which can result in the expression of such nucleic acids. Thus, expression vectors may refer to DNA constructs or RNA constructs such as plasmids, phages, recombinant viruses, or other vectors that, when introduced into a suitable host cell, result in the expression of nucleic acids. Suitable expression vectors are well known to those skilled in the art and include those that are replicable in eukaryotic cells, and those that remain in the episome or are integrated into the host cell genome.

[0057] As used herein, “open reading frame” or “ORF” refers to a continuous segment of nucleic acid, either DNA or RNA, that codes for a protein or polypeptide. Typically, nucleic acids include a translation start signal or start codon, such as ATG or AUG, and a stop codon.

[0058] As used herein, “untranslated region” or “UTR” refers to the untranslated nucleic acid located at the 5' and / or 3' ends of an open reading frame. The inclusion of one or more UTRs in a polynucleotide may affect the post-transcriptional regulation, mRNA stability, and / or translation of the polynucleotide.

[0059] As used herein, the term “transgene” refers to a polynucleotide that, after being introduced into a cell, can be transcribed into RNA, translated, and / or expressed under appropriate conditions. In some embodiments, the transgene confers a desired characteristic to the cell into which it is introduced, or otherwise produces a desired therapeutic or diagnostic outcome.

[0060] As used herein, the terms “polypeptide,” “protein,” and “peptide” are interchangeable and may refer to polymers of two or more amino acids.

[0061] As used herein, “subject,” “host,” or “individual” refers to any animal classified as such, including humans, mammals including domesticated animals and livestock, as well as zoo animals, sports animals or pets such as dogs, horses, cats, and cows, and animals used in research such as mice, rats, hamsters, rabbits, and non-human primates. In some embodiments, mammal is human.

[0062] As used herein, the terms “pharmaceutical preparation” or “pharmaceutical composition” refer to a preparation in which the biological activity of the active ingredient(s) is effective and which does not contain additional ingredients that are unacceptably toxic to the subject to which the composition or preparation is administered. A “pharmaceutically acceptable” excipient (e.g., vehicle, additive) is one that can provide an effective dose of the active ingredient(s) that is appropriately administered to and used by the target mammal.

[0063] As used herein, “cutaneous administration” or “administering cutaneously” refers to the delivery of a composition to a subject by directly or otherwise bringing a formulation containing the composition into contact with the entire ("whole body") or a portion ("topical") skin of a patient. This term encompasses several routes of administration, including but not limited to topical and transdermal. Topical administration may be used as a means of delivering the composition to the epidermis or dermis, or specific layers thereof, of a subject.

[0064] As used herein, “effective dose” means the minimum amount necessary to produce a measurable improvement or prevention of one or more symptoms of a particular disorder. “Effective dose” may vary depending on factors such as the patient’s condition, age, sex, and weight. An effective dose is also the amount at which the therapeutic benefit outweighs any toxic or adverse effects of the treatment. In the case of prophylactic use, beneficial or desired outcomes include the elimination or reduction of the risk of disease, a reduction in the severity of the disease, or a delay in the onset of the disease, its complications, and intermediate pathological phenotypes that appear during the onset of the disease. In the case of therapeutic use, beneficial or desired outcomes include clinical outcomes such as the reduction of one or more symptoms caused by the disease, an improvement in the quality of life of the person suffering from the disease, a reduction in the dose of other drug therapies used to treat the symptoms of the disease, a delay in disease progression, and / or an extension of survival. An effective dose may be administered in one or more doses. For the purposes of this disclosure, an effective dose of recombinant nucleic acids, viruses, and / or pharmaceutical compositions is an amount sufficient to achieve a prophylactic or therapeutic treatment, either directly or indirectly. As understood in a clinical context, an effective dose of recombinant nucleic acid, virus, and / or pharmaceutical composition may or may not be achieved in combination with another drug, compound, or pharmaceutical composition. Therefore, “effective dose” may be considered in the context of administration of one or more therapeutic agents, and a single agent may be considered given in an effective dose if, or is achieved, the desired outcome can be achieved when combined with one or more other agents.

[0065] As used herein, “treatment” refers to a clinical intervention designed to alter the natural course of an individual or cell being treated during the course of a clinical condition. Desired effects of treatment include slowing the rate of disease / disorder / abnormality progression, improvement or mitigation of the disease / disorder / abnormal condition, and remission or improved prognosis. For example, an individual is considered successfully “treated” if one or more symptoms associated with congenital ichthyosis (e.g., X-linked ichthyosis, LI, CIE, HI, etc.) are reduced or eliminated.

[0066] As used herein, the term “delaying the progression of disease / disorder / abnormality” means delaying, interfering with, slowing, suppressing, stabilizing, and / or delaying the onset of disease / disorder / abnormality. This delay may be of varying length or duration depending on the disease / disorder / abnormality history and / or the individual being treated. As will be apparent to those skilled in the art, a sufficient or substantial delay may encompass prevention in that the individual effectively does not develop the disease.

[0067] III. Recombinant Nucleic Acids Certain aspects of this disclosure relate to recombinant nucleic acids (e.g., isolated recombinant nucleic acids) comprising one or more polynucleotides (e.g., one or more, two or more, three or more, four or more, five or more, ten or more, etc.) encoding ichthyosis-related polypeptides (e.g., human ichthyosis-related polypeptides such as steryl sulfatase). In some embodiments, this disclosure relates to recombinant nucleic acids (e.g., isolated recombinant nucleic acids) comprising one or more polynucleotides (e.g., one or more, two or more, three or more, four or more, five or more, ten or more, etc.) encoding two or more ichthyosis-related polypeptides. In some embodiments, the recombinant nucleic acid comprises one or more polynucleotides encoding two or more identical ichthyosis-related polypeptides. In some embodiments, the recombinant nucleic acid comprises one or more polynucleotides encoding two or more different ichthyosis-related polypeptides.

[0068] 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 herpesvirus 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 herpes simplex virus genome is a recombinant herpes simplex virus type 1 (HSV-1) genome.

[0069] Polynucleotides encoding ichthyosis-related polypeptides In some embodiments, the disclosure relates to recombinant nucleic acids comprising one or more polynucleotides containing the coding sequence of an ichthyosis-related gene. In some embodiments, the ichthyosis-related gene is a pathogenic variant and / or loss-of-function mutation that correlates with, causes, or contributes to one or more forms of congenital ichthyosis (e.g., harlequin ichthyosis (HI), autosomal recessive congenital ichthyosis (ARCI), phyllodes ichthyosis (LI), congenital ichthyosis-like erythroderma (CIE), Shanarin-Dorfmann syndrome (CDS), Sjögren-Larsson syndrome (SLS), intellectual disability, intestinal Diseases, hearing loss, peripheral neuropathy, ichthyosis, and keratosis (MEDNIK) syndrome, chondrodysplasia punctate 1 (CDPX1), chondrodysplasia punctate 2 (CDPX2), peeling skin syndrome (PSS), neonatal ichthyosis sclerosing cholangitis (NISCH) syndrome, ichthyosis vulgaris, keratitis-ichthyosis-hearing loss (KID) syndrome, palmoplantar keratosis (PPK), palmoplantar keratosis with sensorineural hearing loss (PPK / SNHL), epidermal lysis palmoplantar keratosis (EPPK), Variable erythema keratoderma (EKV), Crowston syndrome, progressive symmetrical erythema keratoderma, epidermolytic ichthyosis (EI), superficial epidermolytic ichthyosis (SEI), loricrin keratoderma, follicular ichthyosis, alopecia, and photophobia (IFAP) syndrome, Olmsted syndrome, ichthyoid erythroderma and congenital unilateral dysplasia (CHILD) syndrome with limb defects, Refsum disease, Neu-Laksoa syndrome, linear keratosis with congenital ichthyosis and sclerosing keratosis. These are the wild-type and / or functional versions of genes identified as including pathogenic variants and / or loss-of-function mutations of genes identified in patients with one or more of the following conditions: KLICK syndrome, ichthyosis prematurity syndrome (IPS), cerebral malformation, neurological disorders, ichthyosis, and palmoplantar keratoderma (CEDNIK) syndrome, X-linked ichthyosis, arthral contracture-renal dysfunction-cholestasis (ARC) syndrome, and restrictive skin disorders.Genes containing pathogenic variants and / or loss-of-function mutations that correlate with, cause, or contribute to one or more forms of congenital ichthyosis include, for example, ABCA12, ABHD5, ALDH3A2, ALOX12B, ALOXE3, AP1S1, ARSE, CASP14, CDSN, CERS3, CHST8, CLDN1, CSTA, CYP4F22, EBP, ELOVL4, FLG, FLG2, Includes GJB2, GJB3, GJB4, GJB6, KDSR, KRT1, KRT2, KRT9, KRT10, LIPN, LOR, MBTPS2, NIPAL4, NSDHL, PEX7, PHGDH, PHYH, PNPLA1, POMP, PSAT1, SDR9C7, SERPINB8, SLC27A4, SNAP29, ST14, STS, SULT2B1, VPS33B, and ZMPSTE24.

[0070] The coding sequences of any suitable ichthyosis-related gene known in the art (including any isoform thereof) are, for example, the ABCA12 gene (e.g., the human ABCA12 gene disclosed as NCBI gene ID: 26154), the ABHD5 gene (e.g., the human ABHD5 gene disclosed as NCBI gene ID: 51099), the ALDH3A2 gene (e.g., the human ALDH3A2 gene disclosed as NCBI gene ID: 224), and the ALOX12B gene (e.g., the human A12 gene disclosed as NCBI gene ID: 242). LOX12B gene), ALOXE3 gene (e.g., human ALOXE3 gene disclosed as NCBI gene ID: 59344), AP1S1 gene (e.g., human AP1S1 gene disclosed as NCBI gene ID: 1174), ARSE gene (e.g., human ARSE gene disclosed as NCBI gene ID: 415), CASP14 gene (e.g., human CASP14 gene disclosed as NCBI gene ID: 23581), CDSN gene (e.g., human CDSN gene disclosed as NCBI gene ID: 1041) (e.g., the human CERS3 gene disclosed as NCBI gene ID: 204219), the CHST8 gene (e.g., the human CHST8 gene disclosed as NCBI gene ID: 64377), the CLDN1 gene (e.g., the human CLDN1 gene disclosed as NCBI gene ID: 9076), the CSTA gene (e.g., the human CSTA gene disclosed as NCBI gene ID: 1475), the CYP4F22 gene (e.g., the human CYP4F22 gene disclosed as NCBI gene ID: 126410) Child), EBP gene (e.g., human EBP gene disclosed as NCBI gene ID: 10682), ELOVL4 gene (e.g., human ELOVL4 gene disclosed as NCBI gene ID: 6785), FLG gene (e.g., human FLG gene disclosed as NCBI gene ID: 2312), FLG2 gene (e.g., human FLG2 gene disclosed as NCBI gene ID: 388698), GJB2 gene (e.g., human GJB2 gene disclosed as NCBI gene ID: 2706), GJB3 gene (e.g.,Human GJB3 gene (disclosed as NCBI gene ID: 2707), GJB4 gene (e.g., human GJB4 gene disclosed as NCBI gene ID: 127534), GJB6 gene (e.g., human GJB6 gene disclosed as NCBI gene ID: 10804), KDSR gene (e.g., human KDSR gene disclosed as NCBI gene ID: 2531), KRT1 gene (e.g., human KRT1 gene disclosed as NCBI gene ID: 3848), KRT2 gene (e.g., human GJB3 gene disclosed as NCBI gene ID: 3849) Human KRT2 gene, KRT9 gene (e.g., human KRT9 gene disclosed as NCBI gene ID: 3857), KRT10 gene (e.g., human KRT10 gene disclosed as NCBI gene ID: 3858), LIPN gene (e.g., human LIPN gene disclosed as NCBI gene ID: 643418), LOR gene (e.g., human LOR gene disclosed as NCBI gene ID: 4014), MBTPS2 gene (e.g., human MBTPS2 gene disclosed as NCBI gene ID: 51360), NIPA L4 gene (e.g., human NIPAL4 gene disclosed as NCBI gene ID: 348938), NSDHL gene (e.g., human NSDHL gene disclosed as NCBI gene ID: 50814), PEX7 gene (e.g., human PEX7 gene disclosed as NCBI gene ID: 5191), PHGDH gene (e.g., human PHGDH gene disclosed as NCBI gene ID: 26227), PHYH gene (e.g., human PHYH gene disclosed as NCBI gene ID: 5264), PNPLA1 gene (e.g., N Human PNPLA1 gene disclosed as CBI gene ID: 285848), POMP gene (e.g., human POMP gene disclosed as NCBI gene ID: 51371), PSAT1 gene (e.g., human PSAT1 gene disclosed as NCBI gene ID: 29968), SDR9C7 gene (e.g., human SDR9C7 gene disclosed as NCBI gene ID: 121214), SERPINB8 gene (e.g., human SERPINB8 gene disclosed as NCBI gene ID: 5271), SLC27A4 gene (e.g.,These genes may be encoded by polynucleotides of the present disclosure, including the human SLC27A4 gene (disclosed as NCBI gene ID: 10999), the SNAP29 gene (e.g., the human SNAP29 gene disclosed as NCBI gene ID: 9342), the ST14 gene (e.g., the human ST14 gene disclosed as NCBI gene ID: 6768), the STS gene (e.g., the human STS gene disclosed as NCBI gene ID: 412), the SULT2B1 gene (e.g., the human SULT2B1 gene disclosed as NCBI gene ID: 6820), the VPS33B gene (e.g., the human VPS33B gene disclosed as NCBI gene ID: 26276), and the ZMPSTE24 gene (e.g., the human ZMPSTE24 gene disclosed as NCBI gene ID: 10269). Methods for identifying ichthyosis-related gene homologs / orthologs from additional species are known to those skilled in the art, including the use of nucleic acid sequence alignment programs such as BLAST® Blastn Suite. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity to any of the sequences (and / or coding sequences) of the ichthyosis-related genes described herein. In some embodiments, the polynucleotides of the Disclosure include coding sequences of human ichthyosis-related genes.

[0071] In some embodiments, the polynucleotides of this disclosure include codon-optimized variants of the coding sequences of any ichthyosis-related genes described herein or known in the art. In some embodiments, the use of codon-optimized variants of the coding sequences of ichthyosis-related genes increases the stability and / or yield of heterologous expression (RNA and / or protein) of the encoded polypeptide in target cells compared to the stability and / or yield of heterologous expression of the corresponding non-codon-optimized wild type. Any suitable method known in the art to optimize the codon sequences for expression in one or more target cells (e.g., one or more human cells), including the method described by Fath et al., can be used (PLoS One. 2011 Mar 3; 6(3): e17596).

[0072] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human ABCA12 gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with a sequence selected from SEQ ID NOs: 1 to 4. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 1 or SEQ ID NO: 2.

[0073] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 1 or SEQ ID NO: 2 are polynucleotides 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 2000, at least 3000, at least 4000, at least 5000, at least 6000, at least 7000, but less than 7788 consecutive nucleotides of SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1-7785 of SEQ ID NO: 1 or SEQ ID NO: 2.

[0074] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 3 or SEQ ID NO: 4. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 3 or SEQ ID NO: 4 are polynucleotides 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 2000, at least 3000, at least 4000, at least 5000, at least 6000, but less than 6834 consecutive nucleotides of SEQ ID NO: 3 or SEQ ID NO: 4. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1-6831 of SEQ ID NO: 3 or SEQ ID NO: 4.

[0075] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human ABHD5 gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 5 or SEQ ID NO: 6. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 5 or SEQ ID NO: 6.

[0076] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 5 or SEQ ID NO: 6. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 5 or SEQ ID NO: 6 are polynucleotides 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, but less than 1050 consecutive nucleotides of SEQ ID NO: 5 or SEQ ID NO: 6. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1-1047 of SEQ ID NO: 5 or SEQ ID NO: 6.

[0077] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human ALDH3A2 gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 7 or SEQ ID NO: 8. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 7 or SEQ ID NO: 8.

[0078] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 7 or SEQ ID NO: 8. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 7 or SEQ ID NO: 8 are polynucleotides 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, but less than 1527 consecutive nucleotides of SEQ ID NO: 7 or SEQ ID NO: 8. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1 to 1524 of SEQ ID NO: 7 or SEQ ID NO: 8.

[0079] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human ALOX12B gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 9 or SEQ ID NO: 10. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 9 or SEQ ID NO: 10.

[0080] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 9 or SEQ ID NO: 10. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 9 or SEQ ID NO: 10 are polynucleotides 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, but less than 2106 consecutive nucleotides of SEQ ID NO: 9 or SEQ ID NO: 10. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1 to 2103 of SEQ ID NO: 9 or SEQ ID NO: 10. In some embodiments, the polynucleotides of the Disclosure include sequences of nucleic acids 1 to 2106 of SEQ ID NO: 9 or SEQ ID NO: 10.

[0081] In some embodiments, the polynucleotides of the Disclosure include a coding sequence of the human ALOXE3 gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with a sequence selected from SEQ ID NOs.

[0082] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 11 or SEQ ID NO: 12. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 11 or SEQ ID NO: 12 are polynucleotides 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, but less than 2136 consecutive nucleotides of SEQ ID NO: 11 or SEQ ID NO: 12. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1 to 2133 of SEQ ID NO: 11 or SEQ ID NO: 12.

[0083] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 13 or SEQ ID NO: 14. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 13 or SEQ ID NO: 14 are polynucleotides 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, but less than 2532 consecutive nucleotides of SEQ ID NO: 13 or SEQ ID NO: 14. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequence of nucleic acids 1-2529 of SEQ ID NO: 13 or SEQ ID NO: 14.

[0084] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human AP1S1 gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 15 or SEQ ID NO: 16. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 15 or SEQ ID NO: 16.

[0085] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 15 or SEQ ID NO: 16. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 15 or SEQ ID NO: 16 are polynucleotides 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, but less than 477 consecutive nucleotides of SEQ ID NO: 15 or SEQ ID NO: 16. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1-474 of SEQ ID NO: 15 or SEQ ID NO: 16.

[0086] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human ARSE gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 17 or SEQ ID NO: 18. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 17 or SEQ ID NO: 18.

[0087] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 17 or SEQ ID NO: 18. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 17 or SEQ ID NO: 18 are polynucleotides 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, but less than 1770 consecutive nucleotides of SEQ ID NO: 17 or SEQ ID NO: 18. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1 to 1767 of SEQ ID NO: 17 or SEQ ID NO: 18.

[0088] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human CASP14 gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 19 or SEQ ID NO: 20. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 19 or SEQ ID NO: 20.

[0089] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 19 or SEQ ID NO: 20. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 19 or SEQ ID NO: 20 are polynucleotides 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, but less than 729 consecutive nucleotides of SEQ ID NO: 19 or SEQ ID NO: 20. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequence of nucleic acids 1-726 of SEQ ID NO: 19 or SEQ ID NO: 20.

[0090] In some embodiments, the polynucleotides of the Disclosure include a coding sequence of the human CDSN gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 21 or SEQ ID NO: 22. In some embodiments, the polynucleotides of the Disclosure include a sequence of SEQ ID NO: 21 or SEQ ID NO: 22.

[0091] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 21 or SEQ ID NO: 22. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 21 or SEQ ID NO: 22 are polynucleotides 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, but less than 1590 consecutive nucleotides of SEQ ID NO: 21 or SEQ ID NO: 22. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with the nucleic acid sequences 1-1587 of SEQ ID NO: 21 or SEQ ID NO: 22.

[0092] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human CERS3 gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 23 or SEQ ID NO: 24. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 23 or SEQ ID NO: 24.

[0093] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 23 or SEQ ID NO: 24. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 23 or SEQ ID NO: 24 are polynucleotides 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, but less than 1152 consecutive nucleotides of SEQ ID NO: 23 or SEQ ID NO: 24. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1 to 1149 of SEQ ID NO: 23 or SEQ ID NO: 24.

[0094] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human CHST8 gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 25 or SEQ ID NO: 26. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 25 or SEQ ID NO: 26.

[0095] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 25 or SEQ ID NO: 26. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 25 or SEQ ID NO: 26 are polynucleotides 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, but less than 1275 consecutive nucleotides of SEQ ID NO: 25 or SEQ ID NO: 26. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1 to 272 of SEQ ID NO: 25 or SEQ ID NO: 26.

[0096] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human CLDN1 gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 27 or SEQ ID NO: 28. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 27 or SEQ ID NO: 28.

[0097] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 27 or SEQ ID NO: 28. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 27 or SEQ ID NO: 28 are polynucleotides 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, but less than 636 consecutive nucleotides of SEQ ID NO: 27 or SEQ ID NO: 28. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1-633 of SEQ ID NO: 27 or SEQ ID NO: 28.

[0098] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human CSTA gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 29 or SEQ ID NO: 30. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 29 or SEQ ID NO: 30.

[0099] In some embodiments, the polynucleotides of the Disclosure include a 5' cut, a 3' cut, or a fragment of the sequence of SEQ ID NO: 29 or SEQ ID NO: 30. In some embodiments, the 5' cut, a 3' cut, or a fragment of the sequence of SEQ ID NO: 29 or SEQ ID NO: 30 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, but less than 297 consecutive nucleotides of SEQ ID NO: 29 or SEQ ID NO: 30. In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of nucleic acids 1-294 of SEQ ID NO: 29 or SEQ ID NO: 30. In some embodiments, the polynucleotides of this disclosure include the sequence of nucleic acids 1 to 294 of SEQ ID NO: 29 or SEQ ID NO: 30.

[0100] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human CYP4F22 gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 31 or SEQ ID NO: 32. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 31 or SEQ ID NO: 32.

[0101] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 31 or SEQ ID NO: 32. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 31 or SEQ ID NO: 32 are polynucleotides 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, but less than 1596 consecutive nucleotides of SEQ ID NO: 31 or SEQ ID NO: 32. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1 to 1593 of SEQ ID NO: 31 or SEQ ID NO: 32.

[0102] In some embodiments, the polynucleotides of the Disclosure include a coding sequence of the human EBP gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 33 or SEQ ID NO: 34. In some embodiments, the polynucleotides of the Disclosure include a sequence of SEQ ID NO: 33 or SEQ ID NO: 34.

[0103] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 33 or SEQ ID NO: 34. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 33 or SEQ ID NO: 34 are polynucleotides 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, but less than 693 consecutive nucleotides of SEQ ID NO: 33 or SEQ ID NO: 34. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequence of nucleic acids 1-690 of SEQ ID NO: 33 or SEQ ID NO: 34.

[0104] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human ELOVL4 gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 35 or SEQ ID NO: 36. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 35 or SEQ ID NO: 36.

[0105] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 35 or SEQ ID NO: 36. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 35 or SEQ ID NO: 36 are polynucleotides 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, but less than 945 consecutive nucleotides of SEQ ID NO: 35 or SEQ ID NO: 36. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1-942 of SEQ ID NO: 35 or SEQ ID NO: 36.

[0106] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human FLG gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 37 or SEQ ID NO: 38. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 37 or SEQ ID NO: 38.

[0107] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 37 or SEQ ID NO: 38. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 37 or SEQ ID NO: 38 are polynucleotides 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 3000, at least 4000, at least 5000, at least 6000, at least 7000, at least 8000, at least 9000, at least 10000, at least 11000, at least 12000, but less than 12186 consecutive nucleotides of SEQ ID NO: 37 or SEQ ID NO: 38. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1 to 12183 of SEQ ID NO: 37 or SEQ ID NO: 38.

[0108] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human FLG2 gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 39. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 39.

[0109] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 39. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 39 are polynucleotides 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 3000, at least 4000, at least 5000, at least 6000, at least 7000, but less than 7176 consecutive nucleotides of SEQ ID NO: 39. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1 to 7173 of SEQ ID NO: 39.

[0110] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human GJB2 gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 40 or SEQ ID NO: 41. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 40 or SEQ ID NO: 41.

[0111] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 40 or SEQ ID NO: 41. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 40 or SEQ ID NO: 41 are polynucleotides 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, but less than 681 consecutive nucleotides of SEQ ID NO: 40 or SEQ ID NO: 41. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1-678 of SEQ ID NO: 40 or SEQ ID NO: 41.

[0112] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human GJB3 gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 42 or SEQ ID NO: 43. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 42 or SEQ ID NO: 43.

[0113] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 42 or SEQ ID NO: 43. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 42 or SEQ ID NO: 43 are polynucleotides 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, but less than 813 consecutive nucleotides of SEQ ID NO: 42 or SEQ ID NO: 43. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequence of nucleic acids 1-810 of SEQ ID NO: 42 or SEQ ID NO: 43.

[0114] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human GJB4 gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 44 or SEQ ID NO: 45. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 44 or SEQ ID NO: 45.

[0115] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 44 or SEQ ID NO: 45. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 44 or SEQ ID NO: 45 are polynucleotides 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, but less than 801 consecutive nucleotides of SEQ ID NO: 44 or SEQ ID NO: 45. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1-798 of SEQ ID NO: 44 or SEQ ID NO: 45.

[0116] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human GJB6 gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 46 or SEQ ID NO: 47. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 46 or SEQ ID NO: 47.

[0117] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 46 or SEQ ID NO: 47. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 46 or SEQ ID NO: 47 are polynucleotides 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, but less than 786 consecutive nucleotides of SEQ ID NO: 46 or SEQ ID NO: 47. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1-783 of SEQ ID NO: 46 or SEQ ID NO: 47.

[0118] In some embodiments, the polynucleotides of the Disclosure include a coding sequence of a human KDSR gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 48 or SEQ ID NO: 49. In some embodiments, the polynucleotides of the Disclosure include a sequence of SEQ ID NO: 48 or SEQ ID NO: 49.

[0119] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 48 or SEQ ID NO: 49. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 48 or SEQ ID NO: 49 are polynucleotides 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, but less than 999 consecutive nucleotides of SEQ ID NO: 48 or SEQ ID NO: 49. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequence of nucleic acids 1-996 of SEQ ID NO: 48 or SEQ ID NO: 49.

[0120] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human KRT1 gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 50 or SEQ ID NO: 51. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 50 or SEQ ID NO: 51.

[0121] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 50 or SEQ ID NO: 51. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 50 or SEQ ID NO: 51 are polynucleotides 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, but less than 1935 consecutive nucleotides of SEQ ID NO: 50 or SEQ ID NO: 51. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1 to 1932 of SEQ ID NO: 50 or SEQ ID NO: 51.

[0122] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human KRT2 gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 52 or SEQ ID NO: 53. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 52 or SEQ ID NO: 53.

[0123] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 52 or SEQ ID NO: 53. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 52 or SEQ ID NO: 53 are polynucleotides 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, but less than 1920 consecutive nucleotides of SEQ ID NO: 52 or SEQ ID NO: 53. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1 to 1917 of SEQ ID NO: 52 or SEQ ID NO: 53.

[0124] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human KRT9 gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 54 or SEQ ID NO: 55. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 54 or SEQ ID NO: 55.

[0125] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 54 or SEQ ID NO: 55. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 54 or SEQ ID NO: 55 are polynucleotides 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, but less than 1872 consecutive nucleotides of SEQ ID NO: 54 or SEQ ID NO: 55. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequence of nucleic acids 1-1869 of SEQ ID NO: 54 or SEQ ID NO: 55.

[0126] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human KRT10 gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 56 or SEQ ID NO: 57. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 56 or SEQ ID NO: 57.

[0127] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 56 or SEQ ID NO: 57. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 56 or SEQ ID NO: 57 are polynucleotides 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, but less than 1755 consecutive nucleotides of SEQ ID NO: 56 or SEQ ID NO: 57. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1 to 1752 of SEQ ID NO: 56 or SEQ ID NO: 57.

[0128] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human LIPN gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 58 or SEQ ID NO: 59. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 58 or SEQ ID NO: 59.

[0129] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 58 or SEQ ID NO: 59. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 58 or SEQ ID NO: 59 are polynucleotides 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, but less than 1197 consecutive nucleotides of SEQ ID NO: 58 or SEQ ID NO: 59. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1 to 1194 of SEQ ID NO: 58 or SEQ ID NO: 59.

[0130] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human LOR gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 60 or SEQ ID NO: 61. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 60 or SEQ ID NO: 61.

[0131] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 60 or SEQ ID NO: 61. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 60 or SEQ ID NO: 61 are polynucleotides 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, but less than 939 consecutive nucleotides of SEQ ID NO: 60 or SEQ ID NO: 61. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1-936 of SEQ ID NO: 60 or SEQ ID NO: 61.

[0132] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human MBTPS2 gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 62 or SEQ ID NO: 63. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 62 or SEQ ID NO: 63.

[0133] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 62 or SEQ ID NO: 63. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 62 or SEQ ID NO: 63 are polynucleotides 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, but less than 1560 consecutive nucleotides of SEQ ID NO: 62 or SEQ ID NO: 63. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1 to 1557 of SEQ ID NO: 62 or SEQ ID NO: 63.

[0134] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human NIPAL4 gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with a sequence selected from SEQ ID NOs. In some embodiments, the polynucleotides of the Disclosure include a sequence selected from SEQ ID NOs. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NOs.

[0135] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 64 or SEQ ID NO: 65. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 64 or SEQ ID NO: 65 are polynucleotides 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, but less than 1401 consecutive nucleotides of SEQ ID NO: 64 or SEQ ID NO: 65. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1 to 1398 of SEQ ID NO: 64 or SEQ ID NO: 65.

[0136] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 66 or SEQ ID NO: 67. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 66 or SEQ ID NO: 67 are polynucleotides 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, but less than 1344 consecutive nucleotides of SEQ ID NO: 66 or SEQ ID NO: 67. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1 to 1341 of SEQ ID NO: 66 or SEQ ID NO: 67.

[0137] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human NSDHL gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 68 or SEQ ID NO: 69. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 68 or SEQ ID NO: 69.

[0138] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 68 or SEQ ID NO: 69. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 68 or SEQ ID NO: 69 are polynucleotides 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, but less than 1122 consecutive nucleotides of SEQ ID NO: 68 or SEQ ID NO: 69. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1 to 1119 of SEQ ID NO: 68 or SEQ ID NO: 69.

[0139] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human PEX7 gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 70 or SEQ ID NO: 71. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 70 or SEQ ID NO: 71.

[0140] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 70 or SEQ ID NO: 71. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 70 or SEQ ID NO: 71 are polynucleotides 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, but less than 972 consecutive nucleotides of SEQ ID NO: 70 or SEQ ID NO: 71. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with the sequences of nucleic acids 1 to 969 of SEQ ID NO: 70 or SEQ ID NO: 71.

[0141] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human PHGDH gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 72 or SEQ ID NO: 73. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 72 or SEQ ID NO: 73.

[0142] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 72 or SEQ ID NO: 73. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 72 or SEQ ID NO: 73 are polynucleotides 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, but less than 1602 consecutive nucleotides of SEQ ID NO: 72 or SEQ ID NO: 73. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequence of nucleic acids 1 to 1599 of SEQ ID NO: 72 or SEQ ID NO: 73.

[0143] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human PHYH gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 74 or SEQ ID NO: 75. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 74 or SEQ ID NO: 75.

[0144] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 74 or SEQ ID NO: 75. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 74 or SEQ ID NO: 75 are polynucleotides 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, but less than 1017 consecutive nucleotides of SEQ ID NO: 74 or SEQ ID NO: 75. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1 to 10¹⁴ of SEQ ID NO: 74 or SEQ ID NO: 75.

[0145] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human PNPLA1 gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with a sequence selected from SEQ ID NOs.

[0146] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 76 or SEQ ID NO: 77. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 76 or SEQ ID NO: 77 are polynucleotides 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, but less than 1599 consecutive nucleotides of SEQ ID NO: 76 or SEQ ID NO: 77. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequence of nucleic acids 1 to 1596 of SEQ ID NO: 76 or SEQ ID NO: 77.

[0147] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 78 or SEQ ID NO: 79. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 78 or SEQ ID NO: 79 are polynucleotides 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, but less than 1314 consecutive nucleotides of SEQ ID NO: 78 or SEQ ID NO: 79. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1 to 1311 of SEQ ID NO: 78 or SEQ ID NO: 79.

[0148] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 80 or SEQ ID NO: 81. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 80 or SEQ ID NO: 81 are polynucleotides 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, but less than 1341 consecutive nucleotides of SEQ ID NO: 80 or SEQ ID NO: 81. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1 to 1338 of SEQ ID NO: 80 or SEQ ID NO: 81.

[0149] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human POMP gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 82 or SEQ ID NO: 83. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 82 or SEQ ID NO: 83.

[0150] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 82 or SEQ ID NO: 83. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 82 or SEQ ID NO: 83 are polynucleotides 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, but less than 426 consecutive nucleotides of SEQ ID NO: 82 or SEQ ID NO: 83. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1 to 423 of SEQ ID NO: 82 or SEQ ID NO: 83.

[0151] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human PSAT1 gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 84 or SEQ ID NO: 85. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 84 or SEQ ID NO: 85.

[0152] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 84 or SEQ ID NO: 85. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 84 or SEQ ID NO: 85 are polynucleotides 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, but less than 1113 consecutive nucleotides of SEQ ID NO: 84 or SEQ ID NO: 85. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1 to 1110 of SEQ ID NO: 84 or SEQ ID NO: 85.

[0153] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human SDR9C7 gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 86 or SEQ ID NO: 87. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 86 or SEQ ID NO: 87.

[0154] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 86 or SEQ ID NO: 87. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 86 or SEQ ID NO: 87 are polynucleotides 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, but less than 942 consecutive nucleotides of SEQ ID NO: 86 or SEQ ID NO: 87. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1-939 of SEQ ID NO: 86 or SEQ ID NO: 87.

[0155] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human SERPINB8 gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 88 or SEQ ID NO: 89. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 88 or SEQ ID NO: 89.

[0156] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 88 or SEQ ID NO: 89. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 88 or SEQ ID NO: 89 are polynucleotides 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, but less than 1125 consecutive nucleotides of SEQ ID NO: 88 or SEQ ID NO: 89. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1 to 1122 of SEQ ID NO: 88 or SEQ ID NO: 89. In some embodiments, the polynucleotides of the Disclosure include sequences of nucleic acids 1 to 1125 of SEQ ID NO: 88 or SEQ ID NO: 89.

[0157] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human SLC27A4 gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 90 or SEQ ID NO: 91. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 90 or SEQ ID NO: 91.

[0158] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 90 or SEQ ID NO: 91. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 90 or SEQ ID NO: 91 are polynucleotides 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, but less than 1932 consecutive nucleotides of SEQ ID NO: 90 or SEQ ID NO: 91. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1 to 1929 of SEQ ID NO: 90 or SEQ ID NO: 91.

[0159] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human SNAP29 gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 92 or SEQ ID NO: 93. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 92 or SEQ ID NO: 93.

[0160] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 92 or SEQ ID NO: 93. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 92 or SEQ ID NO: 93 are polynucleotides 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, but less than 777 consecutive nucleotides of SEQ ID NO: 92 or SEQ ID NO: 93. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1 to 774 of SEQ ID NO: 92 or SEQ ID NO: 93.

[0161] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human ST14 gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 94 or SEQ ID NO: 95. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 94 or SEQ ID NO: 95.

[0162] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 94 or SEQ ID NO: 95. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 94 or SEQ ID NO: 95 are polynucleotides 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 2500, but less than 2568 consecutive nucleotides of SEQ ID NO: 94 or SEQ ID NO: 95. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1 to 2565 of SEQ ID NO: 94 or SEQ ID NO: 95.

[0163] In some embodiments, the polynucleotides of the Disclosure include a coding sequence of a human STS gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 96 or SEQ ID NO: 97. In some embodiments, the polynucleotides of the Disclosure include a sequence of SEQ ID NO: 96 or SEQ ID NO: 97.

[0164] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 96 or SEQ ID NO: 97. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 96 or SEQ ID NO: 97 are polynucleotides 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, but less than 1752 consecutive nucleotides of SEQ ID NO: 96 or SEQ ID NO: 97. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1 to 1749 of SEQ ID NO: 96 or SEQ ID NO: 97.

[0165] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human SULT2B1 gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 153 or SEQ ID NO: 154. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 153 or SEQ ID NO: 154.

[0166] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 153 or SEQ ID NO: 154. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 153 or SEQ ID NO: 154 are polynucleotides 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 600, at least 700, at least 800, at least 900, at least 1000, at least 1050, but less than 1098 consecutive nucleotides of SEQ ID NO: 153 or SEQ ID NO: 154. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1 to 1095 of SEQ ID NO: 153 or SEQ ID NO: 154.

[0167] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human VPS33B gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 98 or SEQ ID NO: 99. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 98 or SEQ ID NO: 99.

[0168] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 98 or SEQ ID NO: 99. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 98 or SEQ ID NO: 99 are polynucleotides 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, but less than 1854 consecutive nucleotides of SEQ ID NO: 98 or SEQ ID NO: 99. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequence of nucleic acids 1-1851 of SEQ ID NO: 98 or SEQ ID NO: 99.

[0169] In some embodiments, the polynucleotides of the Disclosure include the coding sequence of the human ZMPSTE24 gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the Disclosure include 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% sequence identity with respect to the sequence of SEQ ID NO: 100 or SEQ ID NO: 101. In some embodiments, the polynucleotides of the Disclosure include the sequence of SEQ ID NO: 100 or SEQ ID NO: 101.

[0170] In some embodiments, the polynucleotides of the present disclosure include 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 100 or SEQ ID NO: 101. In some embodiments, the 5' cuts, 3' cuts, or fragments of the sequence of SEQ ID NO: 100 or SEQ ID NO: 101 are polynucleotides 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, but less than 1428 consecutive nucleotides of SEQ ID NO: 100 or SEQ ID NO: 101. In some embodiments, the polynucleotides of the Disclosure include sequences 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% sequence identity with respect to the sequences of nucleic acids 1 to 1425 of SEQ ID NO: 100 or SEQ ID NO: 101.

[0171] In some embodiments, the expression of ichthyosis-related genes (e.g., as described above) in one or more cells of subjects requiring expression of ichthyosis-related genes (e.g., subjects harboring one or more pathogenic variants and / or loss-of-function mutations in one or both copies of the corresponding endogenous gene) is beneficial in providing prophylactic, symptomatic, and / or therapeutic relief of one or more signs or symptoms of autosomal dominant, autosomal hemidominant, autosomal recessive, X-linked dominant, and / or X-linked recessive forms of congenital ichthyosis.

[0172] In some embodiments, ichthyosis-related genes (e.g., ABCA12, ABHD5, ALDH3A2, ALOX12B, ALOXE3, AP1S1, ARSE, CASP14, CDSN, CERS3, CHST8, CLDN1, CSTA, CYP4F22, ...) are expressed in one or more cells of subjects requiring expression of ichthyosis-related genes (e.g., subjects possessing one or more pathogenic variants and / or loss-of-function mutations in one or both copies of the corresponding endogenous gene). The expression of ELOVL4, KDSR, LIPN, MBTPS2, NIPAL4, PEX7, PHGDH, PHYH, PNPLA1, POMP, PSAT1, SDR9C7, SERPINB8, SLC27A4, SNAP29, ST14, STS, SULT2B1, VPS33B, ZMPSTE24) is beneficial in providing prophylactic, symptomatic, and / or therapeutic relief of one or more signs or symptoms of autosomal recessive and / or X-linked recessive forms of congenital ichthyosis.

[0173] In some embodiments, the expression of ichthyosis-related genes (e.g., ABCA12, ABHD5, ALDH3A2, ALOX12B, ALOXE3, AP1S1, CASP14, CDSN, CERS3, CHST8, CLDN1, CSTA, CYP4F22, ELOVL4, KDSR, LIPN, NIPAL4, PEX7, PHGDH, PHYH, PNPLA1, POMP, PSAT1, SDR9C7, SERPINB8, SLC27A4, SNAP29, ST14, SULT2B1, VPS33B, ZMPSTE24) in one or more cells of subjects requiring expression of ichthyosis-related genes (e.g., subjects harboring one or more pathogenic variants and / or loss-of-function mutations in one or both copies of the corresponding endogenous gene) is beneficial in providing prophylactic, symptomatic, and / or therapeutic relief of one or more signs or symptoms of the autosomal recessive form of congenital ichthyosis.

[0174] In some embodiments, the expression of ichthyosis-related genes (e.g., ARSE, MBTPS2, STS) in one or more cells of subjects requiring expression of ichthyosis-related genes (e.g., subjects having one or more pathogenic variants and / or loss-of-function mutations in one or both copies of the corresponding endogenous gene) is beneficial in providing prophylactic, symptomatic, and / or therapeutic relief of one or more signs or symptoms of the X-linked recessive form of congenital ichthyosis.

[0175] The polynucleotides of this disclosure (e.g., including coding sequences for ichthyosis-related genes (i.e., encoding ichthyosis-related polypeptides)) 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 (e.g., polypeptide tags in-frame encoded in ichthyosis-related polypeptides to produce fusion proteins), introns (e.g., native introns, modified introns, or heterologous introns), 5'UTR and / or 3'UTR (e.g., native 5'UTR and / or 3'UTR, modified 5'UTR and / or 3'UTR, or heterologous 5'UTR and / or 3'UTR), etc. Examples of suitable polypeptide tags may include, but are not limited to, purification tags (e.g., his tags, flag tags, maltose-binding protein and glutathione-S-transferase tags), detection tags such as photometrically detectable tags (e.g., green fluorescent protein or red fluorescent protein), and tags having detectable enzymatic activity (e.g., alkaline phosphatase), tags containing secretory sequences, signal sequences, reader sequences and / or stabilizing sequences, and any combination of protease cleavage sites (e.g., furin cleavage sites, TEV cleavage sites, thrombin cleavage sites). In some embodiments, the 5'UTR and / or 3'UTR improve the stability, localization and / or translation efficiency of polynucleotides. In some embodiments, the 5'UTR and / or 3'UTR improve the level and / or duration of protein expression. In some embodiments, the 5'UTR and / or 3'UTR include elements (e.g., one or more miRNA binding sites) that can block or reduce off-target expression (e.g., inhibit expression in specific cell types (e.g., neurons) at specific times in the cell cycle, specific developmental stages, etc.). In some embodiments, the 5'UTR and / or 3'UTR include elements (e.g., one or more miRNA binding sites) that can enhance effector protein expression in specific cell types (e.g., human keratinocytes and / or fibroblasts).

[0176] In some embodiments, the polynucleotides of the Disclosure are operably linked to one or more regulatory sequences (e.g., one or more, two or more, three or more, four or more, five or more, ten or more, etc.). The term “regulatory sequence” may include enhancers, insulators, promoters, and other expression regulatory elements (e.g., polyadenylation signals). Any suitable enhancer(s) known in the Art may be used, including, for example, enhancer sequences derived from mammalian genes (e.g., globin, elastase, albumin, α-fetoprotein, insulin, etc.), enhancer sequences derived from eukaryotic viruses (e.g., (bp100-270)SV40 enhancers located behind the origin of replication, cytomegalovirus early promoter enhancers, polyoma enhancers located behind the origin of replication, adenovirus enhancers, etc.) and any combination thereof. Any suitable insulator(s) known in the art may be used, including, for example, the herpes simplex virus (HSV) chromatin boundary (CTRL / CTCF binding / insulator) elements CTRL1 and / or CTRL2, the chicken susceptibility site 4 insulator (cHS4), the human HNRPA2B1-CBX3 ubiquita chromatin opening element (UCOE), the scaffold / matrix binding region (S / MAR) derived from the human interferon beta gene (IFNB1), and any combination thereof.Any suitable promoter known in the art (e.g., a promoter suitable for transcription in mammalian host cells) may be used, including, for example, promoters derived from the genomes of viruses (e.g., polyomavirus, fowlpox virus, adenovirus (e.g., adenovirus 2), bovine papillomavirus, aerosarcoma virus, cytomegalovirus, retrovirus, hepatitis B virus, Simian virus 40 (SV40), etc.), promoters derived from heterologous mammalian genes (e.g., actin promoter (e.g., β-actin promoter), ubiquitin promoter (e.g., ubiquitin C (UbC) promoter), phosphoglycerate kinase (PGK) promoter, immunoglobulin promoter, heat shock protein promoter, etc.), promoters derived from native and / or homologous mammalian genes, synthetic promoters (e.g., CAGG promoter), and any combination thereof (provided that such promoters are compatible with the host cell). Regulatory sequences may include those that direct the constitutive expression of nucleic acids, as well as tissue-specific regulatory sequences and / or inducible or repressive sequences.

[0177] In some embodiments, the polynucleotides of the Disclosure are operably ligated to one or more heterologous promoters. In some embodiments, one or more heterologous promoters are one or more constitutive promoters, tissue-specific promoters, temporal promoters, spatial promoters, inductive promoters, and repressive promoters. In some embodiments, one or more heterologous promoters are one or more of the human cytomegalovirus (HCMV) pre-early promoter, human elongation factor-1 (EF1) promoter, human β-actin promoter, human UbC promoter, human PGK promoter, synthetic CAGG promoter, and any combination thereof. In some embodiments, the polynucleotides of the Disclosure are operably ligated to an HCMV promoter.

[0178] In some embodiments, the recombinant nucleic acids of the Disclosure do not contain polynucleotides containing coding sequences for ichthyosis-related genes (i.e., encoding ichthyosis-related polypeptides) and do not contain coding sequences for transglutaminase genes such as the TGM1 gene or the TGM5 gene (i.e., do not encode transglutaminase polypeptides). In some embodiments, the recombinant nucleic acids of the Disclosure do not contain polynucleotides containing coding sequences for human transglutaminase genes such as the human TGM1 gene or the human TGM5 gene (i.e., do not encode human transglutaminase polypeptides). In some embodiments, the recombinant nucleic acids of the Disclosure do not contain polynucleotides containing coding sequences for filaggrin genes or filaggrin 2 genes such as the human FLG gene or the human FLG2 gene (i.e., do not encode filaggrin or filaggrin 2 polypeptides). In some embodiments, the recombinant nucleic acids of the Disclosure do not contain polynucleotides containing coding sequences for keratin genes such as the KRT1, KRT2, KRT9, KRT10 and / or KRT17 genes (i.e., do not encode keratin polypeptides). In some embodiments, the recombinant nucleic acids of the present disclosure do not contain polynucleotides that encode human keratin genes such as the human KRT1 gene, human KRT2 gene, human KRT9 gene, human KRT10 gene and / or human KRT17 gene (i.e., they do not encode human keratin polypeptides).

[0179] In some embodiments, the recombinant nucleic acids of the Disclosure do not contain polynucleotides comprising the coding sequence of collagen alpha-1(VII) chain polypeptide (COL7) (e.g., the coding sequence of a transgene encoding it). In some embodiments, the recombinant nucleic acids of the Disclosure do not contain polynucleotides comprising the coding sequence of lysyl hydroxylase 3 polypeptide (LH3) (e.g., the coding sequence of a transgene encoding it). In some embodiments, the recombinant nucleic acids of the Disclosure do not contain polynucleotides comprising the coding sequence of keratin type I cytoskeleton 17 polypeptide (KRT17) (e.g., the coding sequence of a transgene encoding it). In some embodiments, the recombinant nucleic acids of the Disclosure do not contain polynucleotides comprising the coding sequence of transglutaminase (TGM) polypeptide (e.g., human transglutaminase polypeptides such as human TGM1 polypeptide and / or human TGM5 polypeptide) (e.g., the coding sequence of a transgene encoding it). In some embodiments, the recombinant nucleic acids of the Disclosure do not contain polynucleotides containing the coding sequence (e.g., the coding sequence of a transgene encoding) of cosmetic proteins (e.g., collagen protein, fibronectin, elastin, lumican, vitronectin / vitronectin receptor, laminin, neuromodulators, fibrillin, additional skin extracellular matrix proteins, etc.). In some embodiments, the recombinant nucleic acids of the Disclosure do not contain polynucleotides containing the coding sequence (e.g., the coding sequence of a transgene encoding) of antibodies (e.g., full-length antibodies, antibody fragments, etc.). In some embodiments, the recombinant nucleic acids of the Disclosure do not contain polynucleotides containing the coding sequence (e.g., the coding sequence of a transgene encoding) of serine protease inhibitor kazal-type (SPINK) polypeptides (e.g., human SPINK polypeptides such as human SPINK5 polypeptide). In some embodiments, the recombinant nucleic acids of the Disclosure do not contain polynucleotides containing the coding sequence (e.g., the coding sequence of a transgene encoding) of laminin polypeptides (e.g., human laminin polypeptides such as human LAMA3, LAMB3, and / or LAMC2 polypeptide).In some embodiments, the recombinant nucleic acids of the Disclosure do not contain polynucleotides comprising the coding sequence of a cystic fibrosis membrane conductance regulator (CFTR) polypeptide (e.g., human CFTR polypeptide) (e.g., the coding sequence of a transgene encoding it). In some embodiments, the recombinant nucleic acids of the Disclosure do not contain polynucleotides comprising the coding sequence of a collagen alpha-1(VII) chain polypeptide, a lysyl hydroxylase 3 polypeptide, a keratin type I cytoskeleton 17 polypeptide, and / or any chimeric polypeptide thereof (e.g., the coding sequence of a transgene encoding them). In some embodiments, the recombinant nucleic acids of the Disclosure do not contain polynucleotides comprising the coding sequence of a collagen alpha-1(VII) chain polypeptide, a lysyl hydroxylase 3 polypeptide, a keratin type I cytoskeleton 17 polypeptide, a transglutaminase (TGM) polypeptide, a filaggrin polypeptide, a SPINK polypeptide, a CFTR polypeptide, a cosmetic protein, an antibody, and / or any chimeric polypeptide thereof (e.g., the coding sequence of a transgene encoding them).

[0180] Ichthyosis-related polypeptides In some embodiments, the disclosure relates to one or more polynucleotides encoding a full-length ichthyosis-related polypeptide or any portion thereof (e.g., a functional fragment). The ichthyosis-related polypeptide may be encoded by any of the ichthyosis-related genes described herein. Any suitable ichthyosis-related polypeptide known in the art is, for example, an ATP-binding cassette subfamily A member 12 polypeptide (e.g., human ATP-binding cassette subfamily A member 12 polypeptide, as disclosed in UniProt accession number Q86UK0), a 1-acylglycerol-3-phosphate O-acyltransferase ABHD5 polypeptide (e.g., human 1-acylglycerol-3-phosphate O-acyltransferase ABHD5 polypeptide, as disclosed in UniProt accession number Q8WTS1), an aldehyde dehydrogenase family 3 member A2 polypeptide (e.g., human aldehyde dehydrogenase family 3 member A2 polypeptide, as disclosed in UniProt accession number P51648), or an arachidonate 12-lipoxygenase 12R polypeptide (e.g., as disclosed in UniProt accession number O75342). (For example, human arachidonate 12-lipoxygenase 12R polypeptide), hydroperoxide isomerase ALOXE3 polypeptide (e.g., human hydroperoxide isomerase ALOXE3 polypeptide as disclosed by UniProt accession number Q9BYJ1), AP-1 complex subunit sigma-1A polypeptide (e.g., human AP-1 complex subunit sigma-1A polypeptide as disclosed by UniProt accession number P61966), arylsulfatase E polypeptide (e.g., human arylsulfatase E polypeptide as disclosed by UniProt accession number P51690), caspase-14 polypeptide (e.g., human caspase-14 polypeptide as disclosed by UniProt accession number P31944), corneodesmosine polypeptide (e.g., as disclosed by UniProt accession number Q15517)Human corneodesmosine polypeptide), ceramide synthase 3 polypeptide (e.g., human ceramide synthase 3 polypeptide as disclosed in UniProt accession number Q8IU89), carbohydrate sulfotransferase 8 polypeptide (e.g., human carbohydrate sulfotransferase 8 polypeptide as disclosed in UniProt accession number Q9H2A9), claudin-1 polypeptide (e.g., human claudin-1 polypeptide as disclosed in UniProt accession number O95832), cystatin-A polypeptide (e.g., human cystatin-A polypeptide as disclosed in UniProt accession number P01040), cytochrome P450 4F22 polypeptide (e.g., human cytochrome P450 polypeptide as disclosed in UniProt accession number Q6NT55) 4F22 polypeptide), 3-β-hydroxysteroid-delta(8),delta(7)-isomerase polypeptide (e.g., human 3-β-hydroxysteroid-delta(8),delta(7)-isomerase polypeptide as disclosed in UniProt accession number Q15125), very long chain fatty acid elongation protein 4 polypeptide (e.g., human very long chain fatty acid elongation protein 4 polypeptide as disclosed in UniProt accession number Q9GZR5), filaggrin polypeptide (e.g., human filaggrin polypeptide as disclosed in UniProt accession number P20930), filaggrin Phosphorus-2 polypeptide (e.g., human filaggrin-2 polypeptide as disclosed in UniProt accession number Q5D862), gap junction β-2 polypeptide (e.g., human gap junction β-2 polypeptide as disclosed in UniProt accession number P29033), gap junction β-3 polypeptide (e.g., human gap junction β-3 polypeptide as disclosed in UniProt accession number O75712), gap junction β-4 polypeptide (e.g., as disclosed in UniProt accession number Q9NTQ9),Human gap junction β-4 polypeptide), gap junction β-6 polypeptide (e.g., human gap junction β-6 polypeptide as disclosed in UniProt accession number O95452), 3-ketodihydrosphingosine reductase polypeptide (e.g., human 3-ketodihydrosphingosine reductase polypeptide as disclosed in UniProt accession number Q06136), keratin type II cytoskeleton 1 polypeptide (e.g., UniProt accession number P042 Human keratin type II cytoskeleton 1 polypeptide (as disclosed in 64), keratin type II cytoskeleton 2 epidermal polypeptide (e.g., human keratin type II cytoskeleton 2 epidermal polypeptide as disclosed in UniProt accession number P35908), keratin type I cytoskeleton 9 polypeptide (e.g., human keratin type I cytoskeleton 9 polypeptide as disclosed in UniProt accession number P35527), keratin type I cytoskeleton 10 polypeptide (e.g., as disclosed in UniProt accession number P13645) (e.g., human keratin type I cytoskeleton 10 polypeptide), lipase member N polypeptide (e.g., human lipase member N polypeptide as disclosed in UniProt accession number Q5VXI9), loricrin polypeptide (e.g., human loricrin polypeptide as disclosed in UniProt accession number P23490), membrane-bound transcription factor site-2 protease polypeptide (e.g., human membrane-bound transcription factor site-2 protease polypeptide as disclosed in UniProt accession number O43462), magnesium transporter NIPA4 polypeptide (e.g., human magnesium transporter NIPA4 polypeptide as disclosed in UniProt accession number Q0D2K0), sterol-4-α-carboxylate 3-dehydrogenase decarboxylase polypeptide (e.g., human sterol-4-α-carboxylate 3-dehydrogenase decarboxylase polypeptide as disclosed in UniProt accession number Q15738), peroxisome targeting signal 2 receptor polypeptide (e.g.,Human peroxisome targeting signal 2 receptor polypeptide (e.g., as disclosed in UniProt accession number O00628), D-3-phosphoglycerate dehydrogenase polypeptide (e.g., human peroxisome targeting signal 2 receptor polypeptide, as disclosed in UniProt accession number O43175), phytanoyl-CoA dioxygenase peroxisome polypeptide (e.g., human phytanoyl-CoA dioxygenase peroxisome polypeptide, as disclosed in UniProt accession number O14832), patatin-like phospholipase domain-containing protein 1 polypeptide (e.g., human patatin-like phospholipase domain-containing protein 1 polypeptide, as disclosed in UniProt accession number Q8N8W4), proteasome mature protein polypeptide (e.g., human proteasome mature protein polypeptide, as disclosed in UniProt accession number Q9Y244), phosphoserine aminotransferase polypeptide (e.g., UniP Human phosphoserine aminotransferase polypeptide (as disclosed in UniProt accession number Q9Y617), short-chain dehydrogenase / reductase family 9C member 7 polypeptide (e.g., human short-chain dehydrogenase / reductase family 9C member 7 polypeptide as disclosed in UniProt accession number Q8NEX9), serpine B8 polypeptide (e.g., human serpine B8 polypeptide as disclosed in UniProt accession number P50452), long-chain fatty acid transport protein 4 polypeptide (e.g., human long-chain fatty acid transport protein 4 polypeptide as disclosed in UniProt accession number Q6P1M0), synaptosome-related protein 29 polypeptide (e.g., human synaptosome-related protein 29 polypeptide as disclosed in UniProt accession number O95721), tumorigenesis inhibitor 14 protein polypeptide (e.g., human tumorigenesis inhibitor 14 protein polypeptide as disclosed in UniProt accession number Q9Y5Y6),These can be encoded by polynucleotides of the Disclosure, including, for example, steryl sulfatase polypeptide (e.g., human steryl sulfatase polypeptide, as disclosed in UniProt accession number P08842), sulfotransferase 2B1 polypeptide (e.g., human sulfotransferase 2B1 polypeptide, as disclosed in UniProt accession number O00204), vacuolar protein sorting-related protein 33B polypeptide (e.g., human vacuolar protein sorting-related protein 33B polypeptide, as disclosed in UniProt accession number Q9H267), and CAAX prenylprotease 1 homolog polypeptide (e.g., human CAAX prenylprotease 1 homolog polypeptide, as disclosed in UniProt accession number O75844). Methods for identifying homologs / orthologues of ichthyosis-related polypeptides from additional species are known to those skilled in the art, for example, by using an amino acid sequence alignment program such as BLAST® blastp suite or OrthoDB. In some embodiments, the ichthyosis-related polypeptides of this disclosure include sequences 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% sequence identity to any of the sequences of ichthyosis-related genes described herein or known in the art.

[0181] In some embodiments, the polynucleotides of the present disclosure encode a human ATP-binding cassette subfamily A member 12 polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the ABCA12 gene as described herein. In some embodiments, the polynucleotide encoding a human ATP-binding cassette subfamily A member 12 polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with the sequence of SEQ ID NO: 102 or SEQ ID NO: 103. In some embodiments, the polynucleotide encoding an ATP-binding cassette subfamily A member 12 polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 102 or SEQ ID NO: 103.

[0182] In some embodiments, the polynucleotide encoding the ATP-binding cassette subfamily A member 12 polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 102. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 200, at least 300, at least 400, at least 500, at least 600, at least 700, at least 800, at least 900, at least 1000, at least 1250, at least 1500, at least 1750, at least 2000, at least 2250, at least 2500, but less than 2595 consecutive amino acids of SEQ ID NO: 102.

[0183] In some embodiments, the polynucleotide encoding the ATP-binding cassette subfamily A member 12 polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 103. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 200, at least 300, at least 400, at least 500, at least 600, at least 700, at least 800, at least 900, at least 1000, at least 1250, at least 1500, at least 1750, at least 2000, but less than 2277 consecutive amino acids of SEQ ID NO: 103.

[0184] In some embodiments, the polynucleotides of the present disclosure encode the human 1-acylglycerol-3-phosphate O-acyltransferase ABHD5 polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the ABHD5 gene as described herein. In some embodiments, the polynucleotide encoding the 1-acylglycerol-3-phosphate O-acyltransferase ABHD5 polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with respect to the sequence of SEQ ID NO: 104. In some embodiments, the polynucleotide encoding the 1-acylglycerol-3-phosphate O-acyltransferase ABHD5 polypeptide is a polynucleotide encoding a polypeptide containing the amino acid sequence of SEQ ID NO: 104.

[0185] In some embodiments, the polynucleotide encoding the 1-acylglycerol-3-phosphate O-acyltransferase ABHD5 polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 104. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 200, at least 300, but less than 349 consecutive amino acids of SEQ ID NO: 104.

[0186] In some embodiments, the polynucleotides of the present disclosure encode the human aldehyde dehydrogenase family 3 member A2 polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the ALDH3A2 gene as described herein. In some embodiments, the polynucleotide encoding the aldehyde dehydrogenase family 3 member A2 polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with respect to the sequence of SEQ ID NO: 105. In some embodiments, the polynucleotide encoding the aldehyde dehydrogenase family 3 member A2 polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 105.

[0187] In some embodiments, the polynucleotide encoding the aldehyde dehydrogenase family 3 member A2 polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 105. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 200, at least 300, at least 400, at least 500, but less than 508 consecutive amino acids of SEQ ID NO: 105.

[0188] In some embodiments, the polynucleotides of the present disclosure encode human arachidonic acid 12-lipoxygenase 12R polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the ALOX12B gene as described herein. In some embodiments, the polynucleotide encoding arachidonic acid 12-lipoxygenase 12R polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with respect to the sequence of SEQ ID NO: 106. In some embodiments, the polynucleotide encoding arachidonic acid 12-lipoxygenase 12R polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 106.

[0189] In some embodiments, the polynucleotide encoding the arachidonic acid 12-lipoxygenase 12R type polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 106. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 200, at least 300, at least 400, at least 500, at least 600, at least 700, but less than 701 consecutive amino acids of SEQ ID NO: 106.

[0190] In some embodiments, the polynucleotides of the present disclosure encode the human hydroperoxide isomerase ALOXE3 polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the ALOXE3 gene as described herein. In some embodiments, the polynucleotide encoding the hydroperoxide isomerase ALOXE3 polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with the sequence of SEQ ID NO: 107 or SEQ ID NO: 108. In some embodiments, the polynucleotide encoding the hydroperoxide isomerase ALOXE3 polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 107 or SEQ ID NO: 108.

[0191] In some embodiments, the polynucleotide encoding the hydroperoxide isomerase ALOXE3 polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 107. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 200, at least 300, at least 400, at least 500, at least 600, at least 700, but less than 711 consecutive amino acids of SEQ ID NO: 107.

[0192] In some embodiments, the polynucleotide encoding the hydroperoxide isomerase ALOXE3 polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 108. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 200, at least 300, at least 400, at least 500, at least 600, at least 700, at least 800, but less than 843 consecutive amino acids of SEQ ID NO: 108.

[0193] In some embodiments, the polynucleotides of the Disclosure encode the human AP-1 complex subunit sigma-1A polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the AP1S1 gene as described herein. In some embodiments, the polynucleotide encoding the AP-1 complex subunit sigma-1A polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with respect to the sequence of SEQ ID NO: 109. In some embodiments, the polynucleotide encoding the AP-1 complex subunit sigma-1A polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 109.

[0194] In some embodiments, the polynucleotide encoding the AP-1 complex subunit sigma-1A polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 109. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, but less than 158, consecutive amino acids of SEQ ID NO: 109.

[0195] In some embodiments, the polynucleotides of this disclosure encode human arylsulfatase E polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the ARSE gene as described herein. In some embodiments, the polynucleotide encoding arylsulfatase E polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with respect to the sequence of SEQ ID NO: 110. In some embodiments, the polynucleotide encoding arylsulfatase E polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 110.

[0196] In some embodiments, the polynucleotide encoding the arylsulfatase E polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 110. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 200, at least 300, at least 400, at least 500, but less than 589 consecutive amino acids of SEQ ID NO: 110.

[0197] In some embodiments, the polynucleotides of the Disclosure encode human caspase-14 polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the CASP14 gene as described herein. In some embodiments, the polynucleotide encoding caspase-14 polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with the sequence of SEQ ID NO: 111. In some embodiments, the polynucleotide encoding caspase-14 polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 111.

[0198] In some embodiments, the polynucleotide encoding the caspase-14 polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 111. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 200, but less than 242 consecutive amino acids of SEQ ID NO: 111.

[0199] In some embodiments, the polynucleotides of the Disclosure encode human corneodesmosine polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the CDSN gene as described herein. In some embodiments, the polynucleotide encoding corneodesmosine polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with the sequence of SEQ ID NO: 112. In some embodiments, the polynucleotide encoding corneodesmosine polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 112.

[0200] In some embodiments, the polynucleotide encoding the cornodesmosin polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 112. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 200, at least 300, at least 400, at least 500, but less than 529 consecutive amino acids of SEQ ID NO: 112.

[0201] In some embodiments, the polynucleotides of the Disclosure encode human ceramide synthase 3 polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the CERS3 gene as described herein. In some embodiments, the polynucleotide encoding ceramide synthase 3 polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with the sequence of SEQ ID NO: 113. In some embodiments, the polynucleotide encoding ceramide synthase 3 polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 113.

[0202] In some embodiments, the polynucleotide encoding the ceramide synthase 3 polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 113. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 200, at least 300, but less than 383 consecutive amino acids of SEQ ID NO: 113.

[0203] In some embodiments, the polynucleotides of this disclosure encode human carbohydrate sulfotransferase 8 polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the CHST8 gene as described herein. In some embodiments, the polynucleotide encoding carbohydrate sulfotransferase 8 polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with the sequence of SEQ ID NO: 114. In some embodiments, the polynucleotide encoding carbohydrate sulfotransferase 8 polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 114.

[0204] In some embodiments, the polynucleotide encoding the carbohydrate sulfotransferase 8 polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 114. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 150, at least 200, at least 250, at least 300, at least 350, at least 400, but less than 424 consecutive amino acids of SEQ ID NO: 114.

[0205] In some embodiments, the polynucleotides of this disclosure encode human claudin-1 polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the CLDN1 gene as described herein. In some embodiments, the polynucleotide encoding claudin-1 polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with respect to the sequence of SEQ ID NO: 115. In some embodiments, the polynucleotide encoding claudin-1 polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 115.

[0206] In some embodiments, the polynucleotide encoding the claudin-1 polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 115. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 200, but less than 211 consecutive amino acids of SEQ ID NO: 115.

[0207] In some embodiments, the polynucleotides of this disclosure encode human cystatin-A polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the CSTA gene as described herein. In some embodiments, the polynucleotide encoding cystatin-A polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with respect to the sequence of SEQ ID NO: 116. In some embodiments, the polynucleotide encoding cystatin-A polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 116.

[0208] In some embodiments, the polynucleotide encoding the cystatin-A polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 116. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, but less than 98 consecutive amino acids of SEQ ID NO: 116.

[0209] In some embodiments, the polynucleotides of this disclosure encode the human cytochrome P450 4F22 polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the CYP4F22 gene as described herein. In some embodiments, the polynucleotide encoding the cytochrome P450 4F22 polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with respect to the sequence of SEQ ID NO: 117. In some embodiments, the polynucleotide encoding the cytochrome P450 4F22 polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 117.

[0210] In some embodiments, the polynucleotide encoding the cytochrome P450 4F22 polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 117. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 200, at least 300, at least 400, at least 500, but less than 531 consecutive amino acids of SEQ ID NO: 117.

[0211] In some embodiments, the polynucleotides of the present disclosure encode human 3-β-hydroxysteroid-delta(8),delta(7)-isomerase polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the EBP gene as described herein. In some embodiments, the polynucleotide encoding the 3-β-hydroxysteroid-delta(8),delta(7)-isomerase polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with respect to the sequence of SEQ ID NO: 118. In some embodiments, the 3-β-hydroxysteroid-delta(8),delta(7)-isomerase polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 118.

[0212] In some embodiments, the polynucleotide encoding the 3-β-hydroxysteroid-delta(8),delta(7)-isomerase polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 118. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 125, at least 150, at least 175, at least 200, at least 225, but less than 230 consecutive amino acids of SEQ ID NO: 118.

[0213] In some embodiments, the polynucleotides of the present disclosure encode human extra-long chain fatty acid elongation protein 4 polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the ELOVL4 gene as described herein. In some embodiments, the polynucleotide encoding the extra-long chain fatty acid elongation protein 4 polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with respect to the sequence of SEQ ID NO: 119. In some embodiments, the polynucleotide encoding the extra-long chain fatty acid elongation protein 4 polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 119.

[0214] In some embodiments, the polynucleotide encoding the extra-long-chain fatty acid elongation protein 4 polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 119. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 200, at least 300, but less than 314 consecutive amino acids of SEQ ID NO: 119.

[0215] In some embodiments, the polynucleotides of this disclosure encode human filaggrin polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the FLG gene as described herein. In some embodiments, the polynucleotide encoding filaggrin polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with respect to the sequence of SEQ ID NO: 120. In some embodiments, the polynucleotide encoding filaggrin polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 120.

[0216] In some embodiments, the polynucleotide encoding filaggrin polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 120. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 200, at least 300, at least 400, at least 500, at least 1000, at least 1500, at least 2000, at least 2500, at least 3000, at least 3500, at least 4000, but less than 4061 consecutive amino acids of SEQ ID NO: 120.

[0217] In some embodiments, the polynucleotides of the present disclosure encode human filaggrin 2 polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the FLG2 gene as described herein. In some embodiments, the polynucleotide encoding filaggrin 2 polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with the sequence of SEQ ID NO: 121. In some embodiments, the polynucleotide encoding filaggrin 2 polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 121.

[0218] In some embodiments, the polynucleotide encoding filaggrin 2 polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 121. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 200, at least 300, at least 400, at least 500, at least 750, at least 1000, at least 1250, at least 1500, at least 1750, at least 2000, at least 2250, but less than 2391 consecutive amino acids of SEQ ID NO: 121.

[0219] In some embodiments, the polynucleotides of the present disclosure encode human gap-junction β-2 polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the GJB2 gene as described herein. In some embodiments, the polynucleotide encoding the gap-junction β-2 polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with the sequence of SEQ ID NO: 122. In some embodiments, the polynucleotide encoding the gap-junction β-2 polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 122.

[0220] In some embodiments, the polynucleotide encoding the gap-junction β-2 polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 122. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 125, at least 150, at least 175, at least 200, but less than 226, consecutive amino acids of SEQ ID NO: 122.

[0221] In some embodiments, the polynucleotides of the present disclosure encode human gap-junction β-3 polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the GJB3 gene as described herein. In some embodiments, the polynucleotide encoding the gap-junction β-3 polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with respect to the sequence of SEQ ID NO: 123. In some embodiments, the polynucleotide encoding the gap-junction β-3 polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 123.

[0222] In some embodiments, the polynucleotide encoding the gap-junction β-3 polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 123. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 150, at least 200, at least 250, but less than 270 consecutive amino acids of SEQ ID NO: 123.

[0223] In some embodiments, the polynucleotides of the present disclosure encode human gap-junction β-4 polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the GJB4 gene as described herein. In some embodiments, the polynucleotide encoding the gap-junction β-4 polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with respect to the sequence of SEQ ID NO: 124. In some embodiments, the polynucleotide encoding the gap-junction β-4 polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 124.

[0224] In some embodiments, the polynucleotide encoding the gap-junction β-4 polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 124. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 150, at least 200, at least 250, but less than 266, consecutive amino acids of SEQ ID NO: 124.

[0225] In some embodiments, the polynucleotides of the present disclosure encode human gap-junction β-6 polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the GJB6 gene as described herein. In some embodiments, the polynucleotide encoding the gap-junction β-6 polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with respect to the sequence of SEQ ID NO: 125. In some embodiments, the polynucleotide encoding the gap-junction β-6 polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 125.

[0226] In some embodiments, the polynucleotide encoding the gap-junction β-6 polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 125. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 150, at least 200, at least 250, but less than 261 consecutive amino acids of SEQ ID NO: 125.

[0227] In some embodiments, the polynucleotides of the present disclosure encode a human 3-ketodihydrosphingosine reductase polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the KDSR gene as described herein. In some embodiments, the 3-ketodihydrosphingosine reductase polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with respect to the sequence of SEQ ID NO: 126. In some embodiments, the 3-ketodihydrosphingosine reductase polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 126.

[0228] In some embodiments, the polynucleotide encoding the 3-ketodihydrosphingosine reductase polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 126. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 150, at least 200, at least 250, at least 300, but less than 332 consecutive amino acids of SEQ ID NO: 126.

[0229] In some embodiments, the polynucleotides of the present disclosure encode human keratin type II cytoskeleton 1 polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the KRT1 gene as described herein. In some embodiments, the polynucleotide encoding keratin type II cytoskeleton 1 polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with respect to the sequence of SEQ ID NO: 127. In some embodiments, the polynucleotide encoding keratin type II cytoskeleton 1 polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 127.

[0230] In some embodiments, the polynucleotide encoding the keratin type II cytoskeleton 1 polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 127. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 150, at least 200, at least 250, at least about 300, at least about 400, at least about 500, at least about 600, but less than 644 consecutive amino acids of SEQ ID NO: 127.

[0231] In some embodiments, the polynucleotides of this disclosure encode human keratin type II cytoskeleton 2 epidermal polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the KRT2 gene as described herein. In some embodiments, the polynucleotide encoding keratin type II cytoskeleton 2 epidermal polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with respect to the sequence of SEQ ID NO: 128. In some embodiments, the polynucleotide encoding keratin type II cytoskeleton 2 epidermal polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 128.

[0232] In some embodiments, the polynucleotide encoding the keratin type II cytoskeleton 2 epidermal polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 128. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 150, at least 200, at least 250, at least 300, at least 400, at least 500, at least 600, but less than 639 consecutive amino acids of SEQ ID NO: 128.

[0233] In some embodiments, the polynucleotides of this disclosure encode human keratin type I cytoskeleton 9 polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the KRT9 gene as described herein. In some embodiments, the polynucleotide encoding keratin type I cytoskeleton 9 polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with respect to the sequence of SEQ ID NO: 129. In some embodiments, the polynucleotide encoding keratin type I cytoskeleton 9 polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 129.

[0234] In some embodiments, the polynucleotide encoding the keratin type I cytoskeleton 9 polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 129. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 150, at least 200, at least 250, at least 300, at least 400, at least 500, at least 600, but less than 623 consecutive amino acids of SEQ ID NO: 129.

[0235] In some embodiments, the polynucleotides of this disclosure encode human keratin type I cytoskeleton 10 polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the KRT10 gene as described herein. In some embodiments, the polynucleotide encoding keratin type I cytoskeleton 10 polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with respect to the sequence of SEQ ID NO: 130. In some embodiments, the polynucleotide encoding keratin type I cytoskeleton 10 polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 130.

[0236] In some embodiments, the polynucleotide encoding the keratin type I cytoskeleton 10 polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 130. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 150, at least 200, at least 250, at least 300, at least 400, at least 500, but less than 584 consecutive amino acids of SEQ ID NO: 130.

[0237] In some embodiments, the polynucleotides of the present disclosure encode a human lipase member N polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the LIPN gene as described herein. In some embodiments, the polynucleotide encoding the lipase member N polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with respect to the sequence of SEQ ID NO: 131. In some embodiments, the polynucleotide encoding the lipase member N polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 131.

[0238] In some embodiments, the polynucleotide encoding the lipase member N polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 131. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 150, at least 200, at least 250, at least 300, at least 350, but less than 398 consecutive amino acids of SEQ ID NO: 131.

[0239] In some embodiments, the polynucleotides of this disclosure encode human lolicrine polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the LOR gene as described herein. In some embodiments, the polynucleotide encoding lolicrine polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with the sequence of SEQ ID NO: 132. In some embodiments, the polynucleotide encoding lolicrine polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 132.

[0240] In some embodiments, the polynucleotide encoding the loricrin polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 132. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 150, at least 200, at least 250, at least 300, but less than 312 consecutive amino acids of SEQ ID NO: 132.

[0241] In some embodiments, the polynucleotides of this disclosure encode human membrane-bound transcription factor site-2 protease polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the MBTPS2 gene as described herein. In some embodiments, the polynucleotide encoding the membrane-bound transcription factor site-2 protease polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with respect to the sequence of SEQ ID NO: 133. In some embodiments, the polynucleotide encoding the membrane-bound transcription factor site-2 protease polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 133.

[0242] In some embodiments, the polynucleotide encoding the membrane-bound transcription factor site-2 protease polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 133. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or 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, but less than 519 consecutive amino acids of SEQ ID NO: 133.

[0243] In some embodiments, the polynucleotides of the present disclosure encode the human magnesium transporter NIPA4 polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the NIPAL4 gene as described herein. In some embodiments, the polynucleotide encoding the magnesium transporter NIPA4 polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with the sequence of SEQ ID NO: 134 or SEQ ID NO: 135. In some embodiments, the polynucleotide encoding the magnesium transporter NIPA4 polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 134 or SEQ ID NO: 135.

[0244] In some embodiments, the polynucleotide encoding the magnesium transporter NIPA4 polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 134. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 150, at least 200, at least 250, at least 300, at least 350, at least 400, at least 450, but less than 466 consecutive amino acids of SEQ ID NO: 134.

[0245] In some embodiments, the polynucleotide encoding the magnesium transporter NIPA4 polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 135. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 150, at least 200, at least 250, at least 300, at least 350, at least 400, but less than 447 consecutive amino acids of SEQ ID NO: 135.

[0246] In some embodiments, the polynucleotides of the present disclosure encode human sterol-4-α-carboxylate 3-dehydrogenase, a decarboxylated polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the NSDHL gene as described herein. In some embodiments, the polynucleotide encoding sterol-4-α-carboxylate 3-dehydrogenase, a decarboxylated polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with respect to the sequence of SEQ ID NO: 136. In some embodiments, the polynucleotide encoding sterol-4-α-carboxylate 3-dehydrogenase, a decarboxylated polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 136.

[0247] In some embodiments, the polynucleotide encoding sterol-4-α-carboxylate 3-dehydrogenase, a decarboxylated polypeptide, is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 136. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 150, at least 200, at least 250, at least 300, at least 350, but less than 373 consecutive amino acids of SEQ ID NO: 136.

[0248] In some embodiments, the polynucleotides of this disclosure encode human peroxisome-targeted signal 2 receptor polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the PEX7 gene as described herein. In some embodiments, the polynucleotide encoding the peroxisome-targeted signal 2 receptor polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with respect to the sequence of SEQ ID NO: 137. In some embodiments, the polynucleotide encoding the peroxisome-targeted signal 2 receptor polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 137.

[0249] In some embodiments, the polynucleotide encoding the peroxisome-targeted signal 2 receptor polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 137. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 150, at least 200, at least 250, at least 300, but less than 323 consecutive amino acids of SEQ ID NO: 137.

[0250] In some embodiments, the polynucleotides of the present disclosure encode human D-3-phosphoglycerate dehydrogenase polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the PHGDH gene as described herein. In some embodiments, the polynucleotide encoding the D-3-phosphoglycerate dehydrogenase polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with respect to the sequence of SEQ ID NO: 138. In some embodiments, the polynucleotide encoding the D-3-phosphoglycerate dehydrogenase polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 138.

[0251] In some embodiments, the polynucleotide encoding the D-3-phosphoglycerate dehydrogenase polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 138. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or 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, but less than 533 consecutive amino acids of SEQ ID NO: 138.

[0252] In some embodiments, the polynucleotides of the present disclosure encode human phytanoyl-CoA dioxygenase, peroxysomal polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the PHYH gene as described herein. In some embodiments, the polynucleotide encoding phytanoyl-CoA dioxygenase, peroxysomal polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with respect to the sequence of SEQ ID NO: 139. In some embodiments, the polynucleotide encoding phytanoyl-CoA dioxygenase, peroxysomal polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 139.

[0253] In some embodiments, the polynucleotide encoding phytanoyl-CoA dioxygenase, peroxisomal polypeptide is a polynucleotide encoding an N-terminal truncation, C-terminal truncation or fragment of the amino acid sequence of SEQ ID NO: 139. The N-terminal truncation, C-terminal truncation or fragment 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, or at least 100, at least 150, at least 200, at least 250, at least 300, but less than 338 consecutive amino acids of SEQ ID NO: 139.

[0254] In some embodiments, the polynucleotide of the present disclosure encodes a human patatin-like phospholipase domain-containing protein 1 polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the PNPLA1 gene as described herein. In some embodiments, the polynucleotide encoding a patatin-like phospholipase domain-containing protein 1 polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity to a sequence selected from SEQ ID NOs: 140-142. In some embodiments, the polynucleotide encoding a patatin-like phospholipase domain-containing protein 1 polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid sequence selected from SEQ ID NOs: 140-142.

[0255] In some embodiments, the polynucleotide encoding the patatin-like phospholipase domain-containing protein 1 polypeptide is a polynucleotide encoding an N-terminal truncation, C-terminal truncation or fragment of the amino acid sequence of SEQ ID NO: 140. The N-terminal truncation, C-terminal truncation or fragment 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, or 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, but less than 532 consecutive amino acids of SEQ ID NO: 140.

[0256] In some embodiments, the polynucleotide encoding the patatin-like phospholipase domain-containing protein 1 polypeptide is a polynucleotide encoding an N-terminal truncation, C-terminal truncation or fragment of the amino acid sequence of SEQ ID NO: 141. The N-terminal truncation, C-terminal truncation or fragment 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, or at least 100, at least 150, at least 200, at least 250, at least 300, at least 350, at least 400, but less than 437 consecutive amino acids of SEQ ID NO: 141.

[0257] In some embodiments, the polynucleotide encoding the patatin-like phospholipase domain-containing protein 1 polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 142. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 150, at least 200, at least 250, at least 300, at least 350, at least 400, but less than 446 consecutive amino acids of SEQ ID NO: 142.

[0258] In some embodiments, the polynucleotides of this disclosure encode human proteasome mature protein polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the POMP gene as described herein. In some embodiments, the polynucleotide encoding the proteasome mature protein polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with respect to the sequence of SEQ ID NO: 143. In some embodiments, the polynucleotide encoding the proteasome mature protein polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 143.

[0259] In some embodiments, the polynucleotide encoding the proteasome mature protein polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 143. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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 125, but less than 141 consecutive amino acids of SEQ ID NO: 143.

[0260] In some embodiments, the polynucleotides of this disclosure encode a human phosphoserine aminotransferase polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the PSAT1 gene as described herein. In some embodiments, the polynucleotide encoding the phosphoserine aminotransferase polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with respect to the sequence of SEQ ID NO: 144. In some embodiments, the polynucleotide encoding the phosphoserine aminotransferase polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 144.

[0261] In some embodiments, the polynucleotide encoding the phosphoserine aminotransferase polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 144. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 150, at least 200, at least 250, at least 300, at least 350, but less than 370 consecutive amino acids of SEQ ID NO: 144.

[0262] In some embodiments, the polynucleotides of the present disclosure encode the human short chain dehydrogenase / reductase family 9C member 7 polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the SDR9C7 gene as described herein. In some embodiments, the polynucleotide encoding the short chain dehydrogenase / reductase family 9C member 7 polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with respect to the sequence of SEQ ID NO: 145. In some embodiments, the polynucleotide encoding the short chain dehydrogenase / reductase family 9C member 7 polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 145.

[0263] In some embodiments, the polynucleotide encoding the short-chain dehydrogenase / reductase family 9C member 7 polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 145. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 150, at least 200, at least 250, at least 300, but less than 313 consecutive amino acids of SEQ ID NO: 145.

[0264] In some embodiments, the polynucleotides of the present disclosure encode human serpin B8 polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the SERPINB8 gene as described herein. In some embodiments, the polynucleotide encoding serpin B8 polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with the sequence of SEQ ID NO: 146. In some embodiments, the polynucleotide encoding serpin B8 polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 146.

[0265] In some embodiments, the polynucleotide encoding the serpine B8 polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 146. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 150, at least 200, at least 250, at least 300, at least 350, but less than 374 consecutive amino acids of SEQ ID NO: 146.

[0266] In some embodiments, the polynucleotides of the present disclosure encode human long-chain fatty acid transport protein 4 polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the SLC27A4 gene as described herein. In some embodiments, the polynucleotide encoding the long-chain fatty acid transport protein 4 polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with respect to the sequence of SEQ ID NO: 147. In some embodiments, the polynucleotide encoding the long-chain fatty acid transport protein 4 polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 147.

[0267] In some embodiments, the polynucleotide encoding the long-chain fatty acid transport protein 4 polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 147. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or 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, but less than 643 consecutive amino acids of SEQ ID NO: 147.

[0268] In some embodiments, the polynucleotides of this disclosure encode the human synaptosome-associated protein 29 polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the SNAP29 gene as described herein. In some embodiments, the polynucleotide encoding the synaptosome-associated protein 29 polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with respect to the sequence of SEQ ID NO: 148. In some embodiments, the polynucleotide encoding the synaptosome-associated protein 29 polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 148.

[0269] In some embodiments, the polynucleotide encoding the synaptosome-associated protein 29 polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 148. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 125, at least 150, at least 175, at least 200, at least 225, at least 250, but less than 258 consecutive amino acids of SEQ ID NO: 148.

[0270] In some embodiments, the polynucleotides of this disclosure encode human tumor suppressor 14 protein polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the ST14 gene as described herein. In some embodiments, the polynucleotide encoding tumor suppressor 14 protein polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with the sequence of SEQ ID NO: 149. In some embodiments, the polynucleotide encoding tumor suppressor 14 protein polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 149.

[0271] In some embodiments, the polynucleotide encoding the tumorigenesis inhibitor 14 protein polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 149. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or 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, but less than 855 consecutive amino acids of SEQ ID NO: 149.

[0272] In some embodiments, the polynucleotides of this disclosure encode human sterylsulfatase polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the STS gene as described herein. In some embodiments, the polynucleotide encoding sterylsulfatase polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with respect to the sequence of SEQ ID NO: 150. In some embodiments, the polynucleotide encoding sterylsulfatase polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 150.

[0273] In some embodiments, the polynucleotide encoding the sterylsulfatase polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 150. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or 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, but less than 583 consecutive amino acids of SEQ ID NO: 150.

[0274] In some embodiments, the polynucleotides of this disclosure encode the human sulfotransferase 2B1 polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the SULT2B1 gene as described herein. In some embodiments, the polynucleotide encoding the sulfotransferase 2B1 polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with respect to the sequence of SEQ ID NO: 155. In some embodiments, the polynucleotide encoding the sulfotransferase 2B1 polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 155.

[0275] In some embodiments, the polynucleotide encoding the sulfotransferase 2B1 polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 155. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 150, at least 200, at least 250, at least 300, at least 350, but less than 365 consecutive amino acids of SEQ ID NO: 155.

[0276] In some embodiments, the polynucleotides of the present disclosure encode the human vacuolar protein sorting-related protein 33B polypeptide. In some embodiments, the polynucleotide comprises the coding sequence of the VPS33B gene as described herein. In some embodiments, the polynucleotide encoding the vacuolar protein sorting-related protein 33B polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity with respect to the sequence of SEQ ID NO: 151. In some embodiments, the polynucleotide encoding the vacuolar protein sorting-related protein 33B polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 151.

[0277] In some embodiments, the polynucleotide encoding the vacuolar protein sorting associated protein 33B polypeptide is a polynucleotide encoding an N-terminal truncation, C-terminal truncation or fragment of the amino acid sequence of SEQ ID NO: 151. The N-terminal truncation, C-terminal truncation or fragment 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, or 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, but less than 617 contiguous amino acids of SEQ ID NO: 151.

[0278] In some embodiments, the polynucleotide of the present disclosure encodes a human CAAX prenyl protease 1 homolog polypeptide.In some embodiments, the polynucleotide comprises the coding sequence of the ZMPSTE24 gene as described herein.In some embodiments, the polynucleotide encoding the CAAX prenyl protease 1 homolog polypeptide is a polynucleotide encoding a polypeptide comprising an amino acid 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% identity to the sequence of SEQ ID NO: 152.In some embodiments, the polynucleotide encoding the CAAX prenyl protease 1 homolog polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 152.

[0279] In some embodiments, the polynucleotide encoding the CAAX prenylprotease 1 homolog polypeptide is a polynucleotide encoding an N-terminal cleavage, C-terminal cleavage, or fragment of the amino acid sequence of SEQ ID NO: 152. The N-terminal cleavage, C-terminal cleavage, or fragment may contain 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, or at least 100, at least 150, at least 200, at least 250, at least 300, at least 350, at least 400, at least 450, but less than 475 consecutive amino acids of SEQ ID NO: 152.

[0280] In some embodiments, the polynucleotides of this disclosure encoding an ichthyosis-related polypeptide (e.g., human ichthyosis-related polypeptide) express the ichthyosis-related polypeptide when the polynucleotide is delivered to one or more target cells of the subject (e.g., one or more epidermal cells). In some embodiments, the expression of the ichthyosis-related polypeptide (e.g., human ichthyosis-related polypeptide) enhances, increases, enhances and / or supplements the level, function and / or activity of the ichthyosis-related polypeptide in one or more target cells of the subject (e.g., compared to before the expression of the ichthyosis-related polypeptide). In some embodiments, the expression of the ichthyosis-related polypeptide (e.g., human ichthyosis-related polypeptide) provides prophylactic, symptomatic or therapeutic relief of the signs or symptoms of congenital ichthyosis in the subject (e.g., compared to before the expression of the ichthyosis-related polypeptide).

[0281] Recombinant nucleic acids In some embodiments, this disclosure relates to recombinant nucleic acids comprising one or more polynucleotides described herein. In some embodiments, the recombinant nucleic acid is a vector (e.g., an expression vector, a display vector, etc.). In some embodiments, the vector is a DNA vector or an RNA vector. Generally, a vector suitable for maintaining, amplifying, 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 (e.g., adenovirus vectors, adeno-associated virus vectors, vaccinia virus vectors, Sindbisvirus vectors, measles vectors, herpesvirus vectors, lentivirus vectors, retrovirus vectors, etc.). In some embodiments, the vector is a herpesvirus vector. In some embodiments, the vector can autonomously replicate in a host cell. In some embodiments, the vector cannot autonomously replicate in a host cell. In some embodiments, the vector can be incorporated into host DNA. In some embodiments, the vector cannot be incorporated into host DNA (e.g., an episome). Methods for preparing vectors containing one or more polynucleotides of interest are well known to those skilled in the art, and include, for example, chemical synthesis or methods involving the artificial manipulation of isolated segments of nucleic acids (e.g., by genetic engineering techniques).

[0282] In some embodiments, the recombinant nucleic acids of this disclosure are herpes simplex virus (HSV) amplicons. Herpes virus amplicons are generally known to those skilled in the art, including their structural features and methods for producing them (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 an HSV-1 hybrid amplicon. Examples of HSV-1 hybrid amplicons 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 an HSV / AAV hybrid amplicon. In some embodiments, the amplicon is an HSV / Sleeping Beauty hybrid amplicon.

[0283] In some embodiments, the recombinant nucleic acids of the Disclosure are recombinant herpesvirus genomes. Recombinant herpesvirus genomes may be recombinant genomes derived from any member of the DNA viruses of the Herpesviridae family known in the Art, such as recombinant herpes simplex virus genomes, recombinant varicella-zoster virus genomes, recombinant human cytomegalovirus genomes, recombinant herpesvirus 6A genomes, recombinant herpesvirus 6B genomes, recombinant herpesvirus 7 genomes, recombinant Kaposi's sarcoma-associated herpesvirus genomes, and any combination or derivative thereof. In some embodiments, the recombinant herpesvirus genomes include one or more inactivating mutations (e.g., 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.). In some embodiments, one or more inactivating mutations are present in one or more (e.g., 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.) herpesvirus genes. In some embodiments, the recombinant herpesvirus genome is attenuated (e.g., compared to the corresponding wild-type herpesvirus genome). In some embodiments, the recombinant herpesvirus genome is capable of replication. In some embodiments, the recombinant herpesvirus genome is replication-deficient.

[0284] 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 any derivative thereof. In some embodiments, the recombinant herpes simplex virus genome is a recombinant HSV-1 genome. In some embodiments, the recombinant HSV-1 genome is, for example, strain 17, Ty25, R62, S25, Ku86, S23, R11, Ty148, Ku47, H166 syn, 1319-2005, F-13, M-12, 90237, F-17, KOS, 3083-2008, F12g, L2, CD38, H193, M-15, India 2011, 0116209, F-11I, 66-207, 2762, 369-2007, 3355, McIntyre, McKrae, 7862, 7-hse, HF10, 1394, 2005, 270-2007, OD4, SC16, It may be any HSV-1 strain known in the art, including 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 Apr3;93(8)). In some embodiments, the recombinant HSV-1 genome is from the KOS strain. In some embodiments, the recombinant HSV-1 genome is from the McKrae strain. In some embodiments, the recombinant herpes simplex virus genome is attenuated. In some embodiments, the recombinant herpes simplex virus genome is capable of replication. In some embodiments, the recombinant herpes simplex virus genome is replication-deficient. In some embodiments, the recombinant herpes simplex virus genome contains one or more (e.g., 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, one or more inactivating mutations are present in one or more (e.g., 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.) herpes simplex virus genes. As used herein, “inactivating mutation” may refer to any mutation that results in a gene product or regulon product (RNA or protein) that is reduced in quantity and / or function, undetectable, or eliminated (for example, compared to a corresponding sequence lacking the inactivating mutation).Examples of inactivating mutations may include, but are not limited to, deletions, insertions, point mutations, and rearrangements in transcriptional regulatory sequences (promoters, enhancers, insulators, etc.) and / or coding sequences of a given gene or regulon. Any suitable method known in the art for measuring the amount of gene or regulon product can be used, such as qPCR, Northern blotting, RNA-seq, Western blotting, and ELISA.

[0285] In some embodiments, the recombinant herpes simplex virus genome contains inactivating mutations in at least one, at least two, at least three, at least four, at least five, at least six, at least seven or eight of the Infectious Cell Protein (or Infectious Cell Polypeptide) (ICP)0, ICP4, ICP22, ICP27, ICP47, thymidine kinase (tk), long unique region (UL)41, and / or UL55 herpes simplex virus genes. In some embodiments, the recombinant herpes simplex virus genome does not contain inactivating mutations in one or both copies of the ICP34.5 herpes simplex virus gene and / or the ICP47 herpes simplex virus gene (for example, to avoid the production of immunostimulatory virus). In some embodiments, the recombinant herpes simplex virus genome does not contain inactivating mutations in one or both copies of the ICP34.5 herpes simplex virus gene. In some embodiments, the recombinant herpes simplex virus genome does not contain inactivating mutations in the ICP47 herpes simplex virus gene. In some embodiments, the recombinant herpes simplex virus genome does not contain inactivating mutations in the ICP34.5 herpes simplex virus gene (one or both copies) and the ICP47 herpes simplex virus gene. In some embodiments, the recombinant herpes simplex virus genome is not oncolytic.

[0286] In some embodiments, the recombinant herpes simplex virus genome includes an inactivating mutation in one or both copies of the ICP0 gene. In some embodiments, the recombinant herpes simplex virus genome includes an inactivating mutation in one or both copies of the ICP0 gene, and further includes inactivating mutations in one or both copies of the ICP4 gene, the ICP22 gene, the ICP27 gene, the ICP47 gene, the UL41 gene, and / or the UL55 gene. In some embodiments, the recombinant herpes simplex virus genome includes an inactivating mutation in one or both copies of the ICP0 gene, and an inactivating mutation in one or both copies of the ICP4 gene. In some embodiments, the recombinant herpes simplex virus genome includes an inactivating mutation in one or both copies of the ICP0 gene, and an inactivating mutation in the ICP22 gene. In some embodiments, the recombinant herpes simplex virus genome includes an inactivating mutation in one or both copies of the ICP0 gene, and an inactivating mutation in the UL41 gene. In some embodiments, the recombinant herpes simplex virus genome includes inactivating mutations in one or both copies of the ICP0 gene, inactivating mutations in one or both copies of the ICP4 gene, and inactivating mutations in the ICP22 gene. In some embodiments, the recombinant herpes simplex virus genome includes inactivating mutations in one or both copies of the ICP0 gene, inactivating mutations in one or both copies of the ICP4 gene, and inactivating mutations in the UL41 gene. In some embodiments, the recombinant herpes simplex virus genome includes inactivating mutations in one or both copies of the ICP0 gene, inactivating mutations in the ICP22 gene, and inactivating mutations in the UL41 gene. In some embodiments, the recombinant herpes simplex virus genome includes inactivating mutations in one or both copies of the ICP0 gene, inactivating mutations in one or both copies of the ICP4 gene, inactivating mutations in the ICP22 gene, and inactivating mutations in the UL41 gene.In some embodiments, the inactivating mutation is a deletion of the coding sequence in the ICP0 gene (one or both copies), the ICP4 gene (one or both copies), the ICP22 gene, and / or the UL41 gene. In some embodiments, the recombinant herpes simplex virus genome further includes inactivating mutations in the ICP27 gene, the ICP47 gene, and / or the UL55 gene.

[0287] In some embodiments, the recombinant herpes simplex virus genome includes an inactivating mutation in one or both copies of the ICP4 gene. In some embodiments, the recombinant herpes simplex virus genome includes an inactivating mutation in one or both copies of the ICP4 gene, and further includes inactivating mutations in one or both copies of the ICP0 gene, the ICP22 gene, the ICP27 gene, the ICP47 gene, the UL41 gene, and / or the UL55 gene. In some embodiments, the recombinant herpes simplex virus genome includes an inactivating mutation in one or both copies of the ICP4 gene, and an inactivating mutation in the ICP22 gene. In some embodiments, the recombinant herpes simplex virus genome includes an inactivating mutation in one or both copies of the ICP4 gene, and an inactivating mutation in the UL41 gene. In some embodiments, the recombinant herpes simplex virus genome includes an inactivating mutation in one or both copies of the ICP4 gene, 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 in the ICP4 gene (one or both copies), the ICP22 gene, and / or the UL41 gene. In some embodiments, the recombinant herpes simplex virus genome further includes inactivating mutations in the ICP0 gene (one or both copies), the ICP27 gene, the ICP47 gene, and / or the UL55 gene.

[0288] In some embodiments, the recombinant herpes simplex virus genome includes an inactivating mutation in the ICP22 gene. In some embodiments, the recombinant herpes simplex virus genome includes an inactivating mutation in the ICP22 gene and further includes inactivating mutations in the ICP0 gene (one or both copies), the ICP4 gene (one or both copies), the ICP27 gene, the ICP47 gene, the UL41 gene and / or the UL55 gene. In some embodiments, the recombinant herpes simplex virus genome includes 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 in the ICP22 gene and / or the UL41 gene. In some embodiments, the recombinant herpes simplex virus genome further includes inactivating mutations in the ICP0 gene (one or both copies), the ICP4 gene (one or both copies), the ICP27 gene, the ICP47 gene and / or the UL55 gene.

[0289] In some embodiments, the recombinant herpes simplex virus genome includes an inactivating mutation in the ICP27 gene. In some embodiments, the recombinant herpes simplex virus genome includes an inactivating mutation in the ICP27 gene and further includes inactivating mutations in the ICP0 gene (one or both copies), the ICP4 gene (one or both copies), the ICP22 gene, the ICP47 gene, the UL41 gene, and / or the UL55 gene. In some embodiments, the inactivating mutation is a deletion in the coding sequence of the ICP27 gene.

[0290] In some embodiments, the recombinant herpes simplex virus genome includes an inactivating mutation in the ICP47 gene. In some embodiments, the recombinant herpes simplex virus genome includes an inactivating mutation in the ICP47 gene and further includes inactivating mutations in the ICP0 gene (one or both copies), the ICP4 gene (one or both copies), the ICP22 gene, the ICP27 gene, the UL41 gene, and / or the UL55 gene. In some embodiments, the inactivating mutation is a deletion in the coding sequence of the ICP47 gene.

[0291] In some embodiments, the recombinant herpes simplex virus genome includes an inactivating mutation in the UL41 gene. In some embodiments, the recombinant herpes simplex virus genome includes an inactivating mutation in the UL41 gene and further includes inactivating mutations in the ICP0 gene (one or both copies), ICP4 gene (one or both copies), ICP22 gene, ICP27 gene, ICP47 gene and / or UL55 gene. In some embodiments, the inactivating mutation is a deletion in the coding sequence of the UL41 gene.

[0292] In some embodiments, the recombinant herpes simplex virus genome includes an inactivating mutation in the UL55 gene. In some embodiments, the recombinant herpes simplex virus genome includes an inactivating mutation in the UL55 gene and further includes inactivating mutations in the ICP0 gene (one or both copies), ICP4 gene (one or both copies), ICP22 gene, ICP27 gene, ICP47 gene and / or UL41 gene. In some embodiments, the inactivating mutation is a deletion in the coding sequence of the UL55 gene.

[0293] In some embodiments, the recombinant herpes simplex virus genome has internal repeat longs (IR). L ) area and internal repeat short (IR SThe internal repeat (joint) region containing the ) region includes inactivating mutations (e.g., deletions thereof). In some embodiments, inactivation (e.g., deletion) of the joint region removes one copy each of the ICP4 and ICP0 genes. In some embodiments, inactivation (e.g., deletion) of the joint region further inactivates (e.g., deletes) the promoters of the ICP22 and ICP47 genes. If necessary, the expression of one or both of these genes can be restored by inserting a pre-early promoter into the recombinant herpes simplex virus genome (see, e.g., Hill et al. (1995). Nature 375(6530):411-415; Goldsmith et al. (1998). J Exp Med 187(3):341-348). While we do not wish to be bound by theory, it is thought that inactivating (e.g., deleting) joint regions may contribute to the stability of recombinant herpes simplex virus genomes and / or allow recombinant herpes simplex virus genomes to accommodate more and / or larger transgenes.

[0294] In some embodiments, the recombinant herpes simplex virus genome includes inactivating mutations in the ICP4 gene (one or both copies), the ICP22 gene, and the ICP27 gene. In some embodiments, the recombinant herpes simplex virus genome includes inactivating mutations in the ICP4 gene (one or both copies), the ICP27 gene, and the UL55 gene. In some embodiments, the recombinant herpes simplex virus genome includes inactivating mutations in the ICP4 gene (one or both copies), the ICP22 gene, the ICP27 gene, the ICP47 gene, and the UL55 gene. In some embodiments, the inactivating mutations in the ICP4 gene (one or both copies), the ICP27 gene, and / or the UL55 gene are deletions of the coding sequences in the ICP4 gene (one or both copies), the ICP27 gene, and / or the UL55 gene. In some embodiments, inactivating mutations in the ICP22 and ICP47 genes are deletions in the promoter regions of the ICP22 and ICP47 genes (for example, the coding sequences of ICP22 and ICP47 are intact but not transcriptionally active). In some embodiments, the recombinant herpes simplex virus genome includes deletions in the coding sequences of the ICP4 gene (one or both copies), the ICP27 and UL55 genes, and deletions in the promoter regions of the ICP22 and ICP47 genes. In some embodiments, the recombinant herpes simplex virus genome further includes inactivating mutations in the ICP0 gene (one or both copies) and / or the UL41 gene.

[0295] In some embodiments, the recombinant herpes simplex virus genome includes inactivating mutations in the ICP0 gene (one or both copies) and the ICP4 gene (one or both copies). In some embodiments, the recombinant herpes simplex virus genome includes inactivating mutations in the ICP0 gene (one or both copies), the ICP4 gene (one or both copies), and the ICP22 gene. In some embodiments, the recombinant herpes simplex virus genome includes inactivating mutations in the ICP0 gene (one or both copies), the ICP4 gene (one or both copies), the ICP22 gene, and the ICP27 gene. In some embodiments, the recombinant herpes simplex virus genome includes inactivating mutations in the ICP0 gene (one or both copies), the ICP4 gene (one or both copies), the ICP22 gene, the ICP27 gene, and the UL55 gene. In some embodiments, inactivating mutations in the ICP0 gene (one or both copies), ICP4 gene (one or both copies), ICP22 gene, ICP27 gene, and / or UL55 gene include deletions of the coding sequences in the ICP0 gene (one or both copies), ICP4 gene (one or both copies), ICP22 gene, ICP27 gene, and / or UL55 gene. In some embodiments, the recombinant herpes simplex virus genome further includes inactivating mutations in the ICP47 gene and / or UL41 gene.

[0296] In some embodiments, the recombinant herpes simplex virus genome contains one or more polynucleotides of the Disclosure within one, two, three, four, five, six, or seven or more viral loci. Examples of preferred viral loci may include, but are not limited to, the ICP0 (one or both copies), ICP4 (one or both copies), ICP22, ICP27, ICP47, tk, UL41, and / or UL55 herpes simplex virus loci. In some embodiments, the recombinant herpes simplex virus genome contains one or more polynucleotides of the Disclosure within one or both ICP4 viral loci (e.g., a recombinant virus containing a polynucleotide encoding an ichthyosis-related polypeptide in one or both ICP4 loci). In some embodiments, the recombinant herpes simplex virus genome contains one or more polynucleotides of the Disclosure within the ICP22 viral locus (e.g., a recombinant virus possessing a polynucleotide encoding an ichthyosis-related polypeptide in the ICP22 locus). In some embodiments, the recombinant herpes simplex virus genome contains one or more polynucleotides of the Disclosure within the UL41 viral locus (e.g., a recombinant virus having a polynucleotide encoding an ichthyosis-related polypeptide at the UL41 locus). In some embodiments, the recombinant herpes simplex virus genome contains one or more polynucleotides of the Disclosure within the ICP27 viral locus (e.g., a recombinant virus having a polynucleotide encoding an ichthyosis-related polypeptide at the ICP27 locus). In some embodiments, the recombinant herpes simplex virus genome contains one or more polynucleotides of the Disclosure within the ICP47 viral locus (e.g., a recombinant virus having a polynucleotide encoding an ichthyosis-related polypeptide at the ICP47 locus).

[0297] In some embodiments, the recombinant herpes simplex virus genome contains one or more polynucleotides of the Disclosure in one or both ICP4 viral loci and one or more polynucleotides of the Disclosure in the ICP22 viral loci (for example, a recombinant virus having a polynucleotide encoding a first ichthyosis-related polypeptide in one or both ICP4 loci and a polynucleotide encoding a second ichthyosis-related polypeptide in the ICP22 loci). In some embodiments, the first and second ichthyosis-related polypeptides are the same. In some embodiments, the first and second ichthyosis-related polypeptides are different. In some embodiments, the recombinant herpes simplex virus genome contains one or more polynucleotides of the Disclosure in one or both ICP4 viral loci and one or more polynucleotides of the Disclosure in the UL41 viral loci (for example, a recombinant virus having a polynucleotide encoding a first ichthyosis-related polypeptide in one or both ICP4 loci and a polynucleotide encoding a second ichthyosis-related polypeptide in the UL41 loci). In some embodiments, the first and second ichthyosis-related polypeptides are the same. In some embodiments, the first and second ichthyosis-related polypeptides are different. In some embodiments, the recombinant herpes simplex virus genome contains one or more polynucleotides of the Disclosure in the UL41 viral locus and one or more polynucleotides of the Disclosure in the ICP22 viral locus (for example, a recombinant virus having a polynucleotide encoding the first ichthyosis-related polypeptide at the UL41 locus and a polynucleotide encoding the second ichthyosis-related polypeptide at the ICP22 locus). In some embodiments, the first and second ichthyosis-related polypeptides are the same. In some embodiments, the first and second ichthyosis-related polypeptides are different.In some embodiments, the recombinant herpes simplex virus genome contains one or more polynucleotides of the Disclosure in one or both ICP4 viral loci, one or more polynucleotides of the Disclosure in the ICP22 viral loci, and one or more polynucleotides of the Disclosure in the UL41 viral loci (for example, a recombinant virus having a polynucleotide encoding a first ichthyosis-associated polypeptide in one or both ICP4 loci and a polynucleotide encoding a second ichthyosis-associated polypeptide in the ICP22 loci, and a recombinant virus having a polynucleotide encoding a third ichthyosis-associated polypeptide in the UL41 loci). In some embodiments, the first, second, and / or third ichthyosis-associated polypeptides are the same. In some embodiments, the first, second, and / or third ichthyosis-associated polypeptides are different.

[0298] In some embodiments, a recombinant herpesvirus genome (e.g., recombinant herpes simplex virus genome) is engineered to reduce or eliminate the expression of one or more herpesvirus genes (e.g., one or more toxic herpesvirus genes (e.g., one or both copies of the HSV ICP0 gene, one or both copies of the HSV ICP4 gene, the HSV ICP22 gene, the HSV UL41 gene, the HSV ICP27 gene, etc.)). In some embodiments, a recombinant herpesvirus genome (e.g., recombinant herpes simplex virus genome) is engineered to reduce the cytotoxicity of the recombinant genome (e.g., when introduced into target cells) compared to the corresponding wild-type herpesvirus genome (e.g., wild-type herpes simplex virus genome). In some embodiments, the target cells are human cells. In some embodiments, the target cells are epidermal and / or dermal cells (e.g., human epidermal and / or dermal cells). In some embodiments, the target cells are keratinocytes or fibroblasts (e.g., human keratinocytes or human fibroblasts). In some embodiments, the target cells are mucosal cells.In some embodiments, the cytotoxicity of a recombinant herpesvirus genome (e.g., recombinant herpes simplex virus genome) (e.g., in human keratinocytes and / or fibroblasts) is 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%, at least about 65%, at least about 70%, at least about 75%, at least about Reduced by 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99% (e.g., measurement of the relative cytotoxicity of recombinant ΔICP4 (one or both copies) herpes simplex virus genome compared to wild-type herpes simplex virus genome in human keratinocytes or fibroblasts (primary cells or cell lines); measurement of the relative cytotoxicity of recombinant ΔICP4 (one or both copies) / ΔICP22 herpes simplex virus genome compared to wild-type herpes simplex virus genome in human keratinocytes or fibroblasts (primary cells or cell lines), etc.).In some embodiments, the cytotoxicity of a recombinant herpesvirus genome (e.g., recombinant herpes simplex virus genome) (e.g., in human keratinocytes and / or fibroblasts) is at least about 1.5 times, at least about 2 times, at least about 3 times, 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 about 25 times, at least about 50 times, at least about 75 times, at least about 100 times, and less than the corresponding wild-type herpesvirus genome. The cytotoxicity is reduced by at least approximately 250 times, at least approximately 500 times, at least approximately 750 times, or at least approximately 1000 times or more (e.g., measurement of the relative cytotoxicity of recombinant ΔICP4 (one or both copies) herpes simplex virus genome compared to wild-type herpes simplex virus genome in human keratinocytes or fibroblasts (primary cells or cell lines); measurement of the relative cytotoxicity of recombinant ΔICP4 (one or both copies) / ΔICP22 herpes simplex virus genome compared to wild-type herpes simplex virus genome in human keratinocytes or fibroblasts (primary cells or cell lines), etc.). Methods for measuring cytotoxicity are known to those skilled in the art and include, for example, the use of vital staining dyes (formazan dyes), protease biomarkers, MTT assays (or assays using related tetrazolium salts such as XTT, MTS, and water-soluble tetrazolium salts), and measurement of ATP content.

[0299] In some embodiments, recombinant herpesvirus genomes (e.g., recombinant herpes simplex virus genomes) are engineered to reduce the impact on host cell proliferation after exposure of target cells to the recombinant genome compared to the corresponding wild-type herpesvirus genomes (e.g., wild-type herpes simplex virus genomes). In some embodiments, the target cells are human cells. In some embodiments, the target cells are epidermal and / or dermal cells (e.g., human epidermal and / or dermal cells). In some embodiments, the target cells are keratinocytes or fibroblasts (e.g., human keratinocytes or human fibroblasts). In some embodiments, host cell proliferation (e.g., human keratinocytes and / or fibroblasts) after exposure to a 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 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%, and at least about 9% compared to host cell proliferation after exposure to the corresponding wild-type herpesvirus genome. 0%, at least about 95%, or at least about 99% faster (e.g., measurement of relative cell proliferation after exposure to recombinant ΔICP4 (one or both copies) herpes simplex virus genome compared to cell proliferation after exposure to wild-type herpes simplex virus genome in human keratinocytes or fibroblasts (primary cells or cell lines); measurement of relative cell proliferation after exposure to recombinant ΔICP4 (one or both copies) / ΔICP22 herpes simplex virus genome compared to cell proliferation after exposure to wild-type herpes simplex virus genome in human keratinocytes or fibroblasts (primary cells or cell lines), etc.).In some embodiments, host cell proliferation (e.g., human keratinocytes and / or fibroblasts) after exposure to a recombinant genome is at least about 1.5 times, at least about 2 times, at least about 3 times, 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 about 25 times, at least about 50 times, at least about 75 times, at least about 100 times, at least about 250 times, at least about 500 times, At least approximately 750 times or at least approximately 1000 times faster (e.g., measurement of relative cell proliferation after exposure to recombinant ΔICP4 (one or both copies) herpes simplex virus genome compared to cell proliferation after exposure to wild-type herpes simplex virus genome in human keratinocytes or fibroblasts (primary cells or cell lines); measurement of relative cell proliferation after exposure to recombinant ΔICP4 (one or both copies) / ΔICP22 herpes simplex virus genome compared to cell proliferation after exposure to wild-type herpes simplex virus genome in human keratinocytes or fibroblasts (primary cells or cell lines)). Methods for measuring cell proliferation are known to those skilled in the art and include, for example, the use of Ki67 cell proliferation assays, BrdU cell proliferation assays, etc.

[0300] A vector (e.g., a herpesvirus vector) may contain one or more polynucleotides of the present disclosure in a form suitable for the expression of polynucleotides in a host cell. The vector may contain one or more regulatory sequences operably ligated to the polynucleotide to be expressed (e.g., as described above).

[0301] In some embodiments, the recombinant nucleic acid of this disclosure (e.g., a recombinant herpesvirus genome such as a recombinant herpes simplex virus genome) comprises one or more polynucleotides described herein inserted into the recombinant nucleic acid in any direction. If the recombinant nucleic acid comprises two or more polynucleotides described herein (e.g., two or more, three or more, etc.), the polynucleotides may be inserted in the same direction or opposite directions to each other. While we do not wish to be bound by theory, incorporating two polynucleotides (e.g., two transgenes) into a recombinant nucleic acid (e.g., a vector) in an antisense direction may help avoid read-through and ensure that each polynucleotide is properly expressed.

[0302] In some embodiments, this disclosure relates to one or more heterologous polynucleotides (e.g., bacterial artificial chromosomes (BACs)) comprising any of the recombinant nucleic acids described herein.

[0303] IV. Viruses Certain aspects of this disclosure relate to viruses comprising any of the polynucleotides and / or recombinant nucleic acids described herein. In some embodiments, the virus can infect one or more target cells of a subject (e.g., human). In some embodiments, the virus is suitable for delivering polynucleotides and / or recombinant nucleic acids to one or more target cells of a subject (e.g., human). In some embodiments, this disclosure relates to one or more viral particles comprising any of the polynucleotides and / or recombinant nucleic acids described herein. In some embodiments, the one or more target cells are one or more human cells. In some embodiments, the one or more target cells are one or more cells of the skin (e.g., one or more cells of the epidermis, dermis and / or subcutaneous tissue). In some embodiments, the one or more target cells are cells of the epidermis and / or dermis (e.g., cells of human epidermis and / or dermis). In some embodiments, the one or more target cells are selected from keratinocytes, melanocytes, Langerhans cells, Merkel cells, mast cells, fibroblasts and / or adipocytes. In some embodiments, the one or more target cells are keratinocytes. In some embodiments, one or more target cells are located in the stratum corneum, stratum granulosum, stratum spinosum, stratum basale, and / or basement membrane. In some embodiments, one or more target cells are one or more epidermal cells. In some embodiments, one or more target cells are one or more dermal cells.

[0304] Any suitable virus known in the art may be used, including, for example, adenoviruses, adeno-associated viruses, retroviruses, lentiviruses, Sendai viruses, papillomaviruses, herpesviruses (e.g., herpes simplex virus), vaccinia viruses and / or any hybrid or derived viruses thereof. In some embodiments, the virus is attenuated. In some embodiments, the virus is replication-deficient. In some embodiments, the virus is replication-capable. In some embodiments, the virus is modified to alter its tissue tropism compared to the tissue tropism of the corresponding unmodified wild-type virus. In some embodiments, the virus is less cytotoxic compared to the corresponding wild-type virus. Methods for producing viruses containing recombinant nucleic acids are well known to those skilled in the art.

[0305] In some embodiments, the virus is a member of the Herpesviridae family of DNA viruses, including, for example, herpes simplex virus, varicella-zoster virus, human cytomegalovirus, herpesvirus 6A, herpesvirus 6B, herpesvirus 7, and Kaposi's sarcoma-associated herpesvirus. In some embodiments, the herpesvirus is attenuated. In some embodiments, the herpesvirus is replication-deficient. In some embodiments, the herpesvirus is replication-capable. In some embodiments, the herpesvirus is replication-capable. In some embodiments, the herpesvirus is less cytotoxic compared to the corresponding wild-type herpesvirus. In some embodiments, the herpesvirus is not oncolytic.

[0306] In some embodiments, the herpesvirus is herpes simplex virus. Herpes simplex virus containing recombinant nucleic acid can be produced, for example, by the processes disclosed in International Patent No. WO2015 / 009952 and / or WO2017 / 176336. In some embodiments, the herpes simplex virus is attenuated. In some embodiments, the herpes simplex virus is capable of replication. In some embodiments, the herpes simplex virus is replication-deficient. In some embodiments, the herpes simplex virus is herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), or any derivative thereof. In some embodiments, the herpes simplex virus is herpes simplex virus type 1 (HSV-1). In some embodiments, HSV-1 is replication-deficient. In some embodiments, HSV-1 is capable of replication. In some embodiments, HSV-1 is attenuated. In some embodiments, herpes simplex virus (e.g., HSV-1) exhibits reduced cytotoxicity compared to the corresponding wild-type herpes simplex virus (e.g., wild-type HSV-1). In some embodiments, herpes simplex virus (e.g., HSV-1) is not oncolytic.

[0307] In some embodiments, the herpes simplex virus is modified to alter its tissue tropism compared to that of unmodified wild-type herpes simplex virus. In some embodiments, the herpes simplex virus includes a modified envelope. In some embodiments, the modified envelope includes one or more (e.g., one or more, two or more, three or more, four or more, etc.) mutated herpes simplex virus glycoproteins. Examples of herpes simplex virus glycoproteins may include, but are not limited to, glycoproteins gB, gC, gD, gH, and gL. In some embodiments, the modified envelope alters the tissue tropism of the herpes simplex virus compared to that of wild-type herpes simplex virus.

[0308] In some embodiments, the transduction efficiency (in vitro and / or in vivo) of the virus of the Disclosure (e.g., a herpesvirus such as herpes simplex virus) to one or more target cells (e.g., one or more human keratinocytes and / or fibroblasts) is at least about 25%. For example, the transduction efficiency of the virus to 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%, or at least about 99.5% or more. In some embodiments, the virus is herpes simplex virus, and the transduction efficiency of the virus to one or more target cells (e.g., one or more human keratinocytes and / or fibroblasts) is about 85% to about 100%. In some embodiments, the virus is a herpes simplex virus, and the transduction efficiency of the virus to one or more target cells (e.g., one or more human keratinocytes and / or fibroblasts) is at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 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 transduction efficiency of the virus in vitro or in vivo are well known to those skilled in the art and include, for example, qPCR analysis, deep sequencing, Western blotting, fluorescence analysis (e.g., fluorescence in situ hybridization (FISH), fluorescence reporter gene expression, immunofluorescence, FACS), etc.

[0309] V. Pharmaceutical Compositions and Formulations Certain aspects of the present disclosure relate to pharmaceutical compositions and / or formulations comprising any one or more of the recombinant nucleic acids (e.g., recombinant herpesvirus genomes) and / or viruses (e.g., herpesviruses comprising recombinant genomes) described herein (such as herpes simplex virus comprising a recombinant herpes simplex virus genome), and a pharmaceutically acceptable excipient or carrier.

[0310] In some embodiments, the pharmaceutical composition or formulation comprises any one or more of the viruses (e.g., herpesvirus) described herein. In some embodiments, the pharmaceutical composition or formulation comprises from about 10 4 to about 10 12 plaque forming units (PFU) / mL of virus. For example, the pharmaceutical composition or formulation comprises from about 10 4 to about 10 12 , from about 10 5 to about 10 12 , from about 10 6 to about 10 12 , from about 10 7 to about 10 12 , from about 10 8 to about 10 12 , from about 10 9 to about 10 12 , from about 10 10 to about 10 12 ... , from about 10 11 to about 10 12 , from about 10 4 to about 10 11 , from about 10 5 to about 10 11 , from about 10 6 to about 10 11 , from about 10 ... 7 to about 10 11 , from about 10 8 to about 10 11 , from about 10 9 )]]to about 10 11 , from about 10 10 to about 10 11 [[ID=<<68]]from about 10 4 to about 10 10 , from about 10 5 to about 10 10 , from about 10 6 to about 10 10 , from about 10 7 to about 10 10, about 10 8 ~about 10 10 , about 10 9 ~about 10 10 , about 10 4 ~about 10 9 , about 10 5 ~about 10 9 , about 10 6 ~about 10 9 , about 10 7 ~about 10 9 , about 10 8 ~about 10 9 , about 10 4 ~about 10 8 , about 10 5 ~about 10 8 , about 10 6 ~approximately 108, approximately 10 7 ~about 10 8 , about 10 4 ~about 10 7 , about 10 5 ~about 10 7 , about 10 6 ~about 10 7 , about 10 4 ~about 10 6 , about 10 5 ~about 10 6 or about 10 4 ~about 10 5 It may contain virus at PFU / mL. In some embodiments, the pharmaceutical composition or formulation contains about 10 4 , about 10 5 , about 10 6 , about 10 7 , about 10 8 , about 10 9 , about 10 10 , about 10 11 or about 10 12 Contains virus at PFU / mL.

[0311] Pharmaceutical compositions and formulations can be prepared by mixing one or more active ingredients (such as recombinant nucleic acids and / or viruses) of a desired purity with one or more pharmaceutically acceptable carriers or excipients. Pharmaceutically acceptable carriers or excipients are generally non-toxic to the recipient at the doses and concentrations used and are not limited to: buffers (e.g., phosphates, citrates, acetates and other organic acids); antioxidants (e.g., ascorbic acid and methionine); preservatives (e.g., octadecyldimethylbenzylammonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl alcohol or benzyl alcohol, alkylparabens, catechol, resorcinol, cyclohexanol, 3-pentanol and m-cresol); amino acids (e.g., glycine, glutamine, asparagine, histidine, arginine or lysine); low molecular weight (less than about 10 residues) polypeptides; and proteins. (e.g., serum albumin, gelatin, or immunoglobulin); polyols (e.g., glycerol formulations containing glycerol in concentrations such as 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%)); hydrophilic polymers (e.g., polyvinylpyrrolidone); monosaccharides, disaccharides, and other carbohydrates (including glucose, mannose, or dextrin); chelating agents (e.g., EDTA); sugars (e.g., sucrose, mannitol, trehalose, or sorbitol); salt-forming counterions (e.g., sodium); metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants (e.g., polyethylene glycol (PEG)). A complete discussion of pharmaceutically acceptable carriers is available in REMINGTON'S PHARMACEUTICAL SCIENCES (Mack Pub. Co., NJ 1991).

[0312] In some embodiments, the pharmaceutical composition or formulation comprises one or more lipid (e.g., cationic lipid) carriers. In some embodiments, the pharmaceutical composition or formulation comprises one or more nanoparticle carriers. Nanoparticles are submicron (less than about 1000 nm) sized drug delivery vehicles that can deliver encapsulated drugs (such as synthetic small molecules, proteins, peptides, cells, viruses, and nucleic acid-based biological preparations) for rapid or controlled release. Various molecules (e.g., proteins, peptides, recombinant nucleic acids, etc.) can be efficiently encapsulated in nanoparticles using processes well known in the art. In some embodiments, a molecule "encapsulated" in a nanoparticle may 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 thereof. Nanoparticles for use in the compositions or formulations described herein may be any type of biocompatible nanoparticle known in the art, including, for example, nanoparticles containing poly(lactic acid), poly(glycolic acid), PLGA, PLA, PGA, and any combination thereof (see, for example, Vauthier et al. Adv Drug Del Rev. (2003) 55:519-48, U.S. Patents 2007 / 0148074, 2007 / 0092575, 2006 / 0246139, 5753234, 7081483, and International Patent No. WO2006 / 052285).

[0313] In some embodiments, the pharmaceutically acceptable carrier or excipient is suitable for any route of administration known in the art, including, for example, intravenous, intramuscular, subcutaneous, cutaneous, oral, nasal, intratracheal, sublingual, buccal, topical, transdermal, intradermal, intraperitoneal, intraorbital, subretinal, intravitreous, transmucosal, intra-articular, transplantation, inhalation, intrathecal, intraventricular, and / or intranasal administration. In some embodiments, the pharmaceutical composition or formulation is compatible with or may be compatible with any route of administration known in the art, including, for example, intravenous, intramuscular, subcutaneous, cutaneous, oral, nasal, intratracheal, sublingual, buccal, topical, transdermal, intradermal, intraperitoneal, intraorbital, intravitreous, subretinal, transmucosal, intra-articular, transplantation, inhalation, intrathecal, intraventricular, and / or intranasal administration. In some embodiments, a pharmaceutically acceptable carrier or excipient is compatible with or suitable for topical, transdermal, subcutaneous, intradermal, and / or transmucosal administration. In some embodiments, the pharmaceutical composition or formulation is compatible with or suitable for topical, transdermal, subcutaneous, intradermal, and / or transmucosal administration. In some embodiments, a pharmaceutically acceptable carrier or excipient is compatible with or suitable for topical, transdermal, subcutaneous, and / or transmucosal administration. In some embodiments, the pharmaceutical composition or formulation is suitable for or conforms to topical, transdermal, subcutaneous, and / or intradermal administration. In some embodiments, the pharmaceutically acceptable carrier or excipient is suitable for or conforms to topical, transdermal, and / or intradermal administration. In some embodiments, the pharmaceutical composition or formulation is suitable for or conforms to topical, transdermal, and / or intradermal administration. In some embodiments, the pharmaceutically acceptable carrier or excipient is suitable for or conforms to topical administration. In some embodiments, the pharmaceutical composition or formulation is suitable for or conforms to topical administration.

[0314] Examples of carriers or excipients suitable for use in the pharmaceutical compositions or formulations of this disclosure include, but are not limited to, ointments, oils, pastes, creams, aerosols, suspensions, emulsions, fatty ointments, gels (e.g., methylcellulose gels such as carboxymethylcellulose and hydroxypropylmethylcellulose), powders, liquids, lotions, solutions, sprays, patches (e.g., transdermal patches or microneedle patches), adhesive strips, microneedles or microneedle arrays, and inhalants. In some embodiments, the carrier or excipient (e.g., pharmaceutically acceptable carrier or excipient) includes one or more (e.g., one or more, two or more, three or more, four or more, five or more, etc.) ointments, oils, pastes, creams, aerosols, suspensions, emulsions, fatty ointments, gels, powders, liquids, lotions, solutions, sprays, patches, adhesive strips, and inhalants. In some embodiments, the carrier includes patches (e.g., patches that adhere to the skin), such as transdermal patches or microneedle patches. In some embodiments, the carrier comprises microneedles or a microneedle array. Methods for preparing and using microneedle arrays suitable for composition delivery are generally known in the art (see Kim Y. et al. “Microneedles for drug and vaccine delivery”. Advanced Drug Delivery Reviews 2012, 64(14):1547-68).

[0315] In some embodiments, the pharmaceutical composition or formulation further comprises one or more additional components. Examples of additional components include binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose), fillers (e.g., lactose and other sugars, crystalline cellulose, pectin, gelatin, calcium sulfate, ethylcellulose, polyacrylate or calcium hydrogen phosphate), lubricants (e.g., magnesium stearate, talc, silica, colloidal silicon dioxide, stearic acid, metal stearate, hydrogenated vegetable oil, corn starch, polyethylene glycol, sodium benzoate, sodium acetate, etc.), disintegrants (e.g., This may include, but is not limited to, starch (such as starch and sodium starch glycolate), humectants (e.g., sodium lauryl sulfate), salt solutions, alcohols, polyethylene glycol, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, methylcellulose (e.g., carboxymethylcellulose, hydroxypropylmethylcellulose), polyvinylpyrrolidone, sweeteners, flavoring agents, fragrances, colorants, humectants, sunscreens, antibacterial agents, and agents that can stabilize polynucleotides or prevent their degradation. In some embodiments, the pharmaceutical composition or formulation comprises a methylcellulose gel (e.g., hydroxypropyl methylcellulose, carboxymethylcellulose, etc.) (e.g., in about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, about 10%, about 10.5%, about 11%, about 11.5%, about 12%, etc.). In some embodiments, the pharmaceutical composition or formulation comprises a phosphate buffer. In some embodiments, the pharmaceutical composition or formulation contains glycerol (for example, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, etc.).In some embodiments, the pharmaceutical composition or formulation comprises a methylcellulose gel (e.g., hydroxypropylmethylcellulose, carboxymethylcellulose, etc.), a phosphate buffer, and / or glycerol.

[0316] Compositions and formulations used for in vivo administration (e.g., pharmaceutical compositions and formulations) are generally sterile. Sterility can be easily achieved, for example, by filtration through a sterile filtration membrane.

[0317] In some embodiments, one or more polynucleotides encoding an ichthyosis-related polypeptide (e.g., human steryl sulfatase polypeptide) can be delivered into one or more target cells (e.g., one or more steryl sulfatase-deficient cells, one or more cells having an STS gene mutation) using any of the recombinant nucleic acids, viruses, and / or pharmaceutical compositions or formulations described herein. In some embodiments, any of the recombinant nucleic acids, viruses, and / or pharmaceutical compositions or formulations described herein can be used for therapeutic purposes. In some embodiments, any of the recombinant nucleic acids, viruses, and / or pharmaceutical compositions or formulations described herein can be used to treat diseases, disorders, defects, or conditions that benefit from the expression of ichthyosis-related polypeptides (e.g., one or more forms of congenital ichthyosis; diseases, disorders, defects, or conditions associated with ichthyosis-related polypeptide deficiency (e.g., X-linked ichthyosis); diseases, disorders, defects, or conditions associated with ichthyosis-related gene mutations, etc.).In some embodiments, any of the recombinant nucleic acids, viruses and / or pharmaceutical compositions or formulations described herein may be used to treat one or more forms of congenital ichthyosis (e.g., harlequin ichthyosis (HI), autosomal recessive congenital ichthyosis (ARCI), phyllodes ichthyosis (LI), congenital ichthyotic erythroderma (CIE), Shanarin-Dorfmann syndrome (CDS), Sjögren-Larsson syndrome (SLS), intellectual disability, intestinal disease, hearing loss, peripheral neuropathy, ichthyosis, and keratosis (MEDNIK) syndromes, chondrodysplasia punctata 1 (CDPX1), chondrodysplasia punctata 2 (CDPX2), peeling skin syndrome (PSS), neonatal ichthyosis sclerosing cholangitis (NISCH) syndrome, ichthyosis vulgaris, keratitis-ichthyosis-hearing loss (KID) syndrome, palmoplantar keratosis (PPK), palmoplantar keratosis with sensorineural hearing loss ( PPK / SNHL), epidermolytic palmoplantar keratosis (EPPK), erythematous keratosis variable (EKV), Crowston syndrome, progressive symmetric erythematous keratoderma, epidermolytic ichthyosis (EI), superficial epidermolytic ichthyosis Scale syndrome (SEI), loricrin keratoderma, follicular ichthyosis, alopecia, and photophobia (IFAP) syndrome, Olmstead syndrome, ichthyosiform erythroderma, and ...

Claims

1. A recombinant herpesvirus genome containing one or more polynucleotides encoding an ichthyosis-related polypeptide.

2. A recombinant herpesvirus genome according to claim 1, having replication ability.

3. The recombinant herpesvirus genome according to claim 1, which is a replication defect.

4. A recombinant herpesvirus genome according to any one of claims 1 to 3, comprising one or more polynucleotides encoding the ichthyosis-related polypeptide within one or more viral loci.

5. A recombinant herpesvirus genome according to any one of claims 1 to 4, selected from the group consisting of recombinant herpes simplex virus genome, recombinant varicella-zoster virus genome, recombinant human cytomegalovirus genome, recombinant herpesvirus 6A genome, recombinant herpesvirus 6B genome, recombinant herpesvirus 7 genome, recombinant Kaposi's sarcoma-associated herpesvirus genome, and any derivative thereof.

6. A recombinant herpes simplex virus genome according to any one of claims 1 to 5.

7. The recombinant herpesvirus genome according to claim 6, wherein the recombinant herpesvirus genome is a recombinant herpesvirus type 1 (HSV-1) genome, a recombinant herpesvirus type 2 (HSV-2) genome, or any derivative thereof.

8. The recombinant herpesvirus genome according to claim 6 or claim 7, wherein the recombinant herpesvirus genome is a recombinant herpesvirus type 1 (HSV-1) genome.

9. The recombinant herpesvirus genome according to any one of claims 5 to 8, wherein the recombinant herpesvirus genome is manipulated to reduce or eliminate the expression of one or more toxic herpesvirus genes.

10. The recombinant herpes simplex virus genome according to any one of claims 5 to 9, wherein the recombinant herpes simplex virus genome includes an inactivating mutation.

11. The recombinant herpesvirus genome according to claim 10, wherein the inactivating mutation is present in the herpes simplex virus gene.

12. The recombinant herpesvirus genome according to claim 11, wherein the inactivating mutation is a deletion of the coding sequence of the herpes simplex virus gene.

13. The recombinant herpesvirus genome according to claim 11 or claim 12, wherein the herpes simplex virus gene is selected from the group consisting of infecting cell protein (ICP) 0, ICP4, ICP22, ICP27, ICP47, thymidine kinase (tk), long unique region (UL) 41, and UL55.

14. The recombinant herpes simplex virus genome according to claim 13, wherein the recombinant herpes simplex virus genome comprises an inactivating mutation in one or both copies of the ICP4 gene.

15. The recombinant herpes simplex virus genome according to claim 13 or claim 14, wherein the recombinant herpes simplex virus genome includes an inactivating mutation in the ICP22 gene.

16. The recombinant herpes simplex virus genome according to any one of claims 13 to 15, wherein the recombinant herpes simplex virus genome includes an inactivating mutation in the UL41 gene.

17. The recombinant herpes simplex virus genome according to any one of claims 13 to 16, wherein the recombinant herpes simplex virus genome comprises an inactivating mutation in one or both copies of the ICP0 gene.

18. The recombinant herpes simplex virus genome according to any one of claims 13 to 17, wherein the recombinant herpes simplex virus genome includes an inactivating mutation in the ICP27 gene.

19. The recombinant herpes simplex virus genome according to any one of claims 13 to 18, wherein the recombinant herpes simplex virus genome includes an inactivating mutation in the ICP47 gene.

20. The recombinant herpes simplex virus genome according to any one of claims 13 to 19, wherein the recombinant herpes simplex virus genome includes an inactivating mutation in the UL55 gene.

21. The recombinant herpes simplex virus genome according to any one of claims 6 to 20, wherein the recombinant herpes simplex virus genome comprises one or more polynucleotides encoding the ichthyosis-associated polypeptide within one or both ICP4 virus loci.

22. The recombinant herpes simplex virus genome according to any one of claims 6 to 21, wherein the recombinant herpes simplex virus genome contains one or more polynucleotides encoding the ichthyosis-related polypeptide within the ICP22 viral locus.

23. The recombinant herpes simplex virus genome according to any one of claims 6 to 22, wherein the recombinant herpes simplex virus genome contains one or more polynucleotides encoding the ichthyosis-related polypeptide within the UL41 virus locus.

24. The recombinant herpes simplex virus genome according to any one of claims 6 to 23, wherein the recombinant herpes simplex virus genome comprises one or more polynucleotides encoding the ichthyosis-associated polypeptide within one or both ICP0 virus loci.

25. The recombinant herpes simplex virus genome according to any one of claims 6 to 24, wherein the recombinant herpes simplex virus genome contains one or more polynucleotides encoding the ichthyosis-related polypeptide within the ICP27 viral locus.

26. The recombinant herpes simplex virus genome according to any one of claims 6 to 25, wherein the recombinant herpes simplex virus genome contains one or more polynucleotides encoding the ichthyosis-related polypeptide within the ICP47 virus locus.

27. The recombinant herpes simplex virus genome according to any one of claims 6 to 26, wherein the recombinant herpes simplex virus genome contains one or more polynucleotides encoding the ichthyosis-related polypeptide within the UL55 virus locus.

28. The recombinant herpesvirus genome according to any one of claims 1 to 27, wherein the ichthyosis-related polypeptide is not a transglutaminase (TGM) polypeptide.

29. The recombinant herpesvirus genome according to any one of claims 1 to 28, wherein the ichthyosis-related polypeptide is neither a transglutaminase 1 (TGM1) polypeptide nor a transglutaminase 5 (TGM5) polypeptide.

30. The aforementioned ichthyosis-related polypeptides include ATP-binding cassette subfamily A member 12 polypeptide (ABCA12), 1-acylglycerol-3-phosphate O-acyltransferase ABHD5 polypeptide (ABHD5), aldehyde dehydrogenase family 3 member A2 polypeptide (ALDH3A2), arachidonate 12-lipoxygenase 12R type polypeptide (ALOX12B), and hydroperoxide isomerase ALOXE3 polypeptide (A LOXE3), AP-1 complex subunit sigma-1A polypeptide (AP1S1), arylsulfatase E polypeptide (ARSE), caspase-14 polypeptide (CASP14), corneodesmosine polypeptide (CDSN), ceramide synthase 3 polypeptide (CERS3), carbohydrate sulfotransferase 8 polypeptide (CHST8), claudin-1 polypeptide (CLDN1), cystatin A polypeptide (CSTA), cytochrome P450 4F22 polypeptide (CYP4F22), 3-β-hydroxysteroid delta(8), delta(7)-isomerase polypeptide (EBP), Elongation of very long chain fatty acid protein 4 polypeptide (ELOVL4), filaggrin polypeptide (FLG), filaggrin 2 polypeptide (FLG2), gap junction β-2 polypeptide (GJB2), gap junction β-3 polypeptide (GJB3), gap junction β-4 polypeptide (GJB4), gap junction β-6 polypeptide (GJB6), 3-ketodihydrosphingosine reductase polypeptide (KDSR), keratin type II cytoskeleton 1 polypeptide (KRT1), keratin type II cytoskeleton 2 (Keratin type II cytoskeletal 2) Epidermal polypeptide (KRT2), Keratin type I cytoskeleton 9 (Keratin, type I cytoskeleton 9) polypeptide (KRT9), Keratin type I cytoskeleton 10 (Keratin,Type I cytoskeletal 10) polypeptide (KRT10), lipase member N polypeptide (LIPN), loricrin polypeptide (LOR), membrane-bound transcription factor site-2 protease polypeptide (MBTPS2), magnesium transporter NIPA4 polypeptide (NIPAL4), sterol-4-α-carboxylate 3-dehydrogenase, decarboxylated polypeptide (NSDHL), peroxisome-targeted signal 2 receptor polypeptide (PEX7), D-3-phosphoglycerate dehydrogenase polypeptide (PHGDH), phytanoyl-CoA dioxygenase, peroxysomal polypeptide (PHYH), patatin-like phospholipase A recombinant herpesvirus genome according to any one of claims 1 to 29, selected from the group consisting of main-containing protein 1 polypeptide (PNPLA1), proteasome maturation protein polypeptide (POMP), phosphoserine aminotransferase polypeptide (PSAT1), short-chain dehydrogenase / reductase family 9C member 7 polypeptide (SDR9C7), serpin B8 polypeptide (SERPINB8), long-chain fatty acid transport protein 4 polypeptide (SLC27A4), synaptosome-related protein 29 polypeptide (SNAP29), tumorigenesis inhibitor 14 protein polypeptide (ST14), steryl sulfatase polypeptide (STS), sulfotransferase 2B1 polypeptide (SULT2B1), vacuolar protein sorting-related protein 33B polypeptide (VPS33B), and CAAX prenylprotease 1 homolog polypeptide (ZMPSTE24).

31. The recombinant herpesvirus genome according to any one of claims 1 to 30, wherein the ichthyosis-related polypeptide is a human ichthyosis-related polypeptide.

32. The recombinant herpesvirus genome according to any one of claims 1 to 31, wherein the ichthyosis-related 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 an amino acid sequence selected from the group consisting of SEQ ID NOs: 102 to 152 or SEQ ID NO:

155.

33. The recombinant herpesvirus genome according to any one of claims 1 to 32, wherein the ichthyosis-related polypeptide is selected from the group consisting of ABCA12, ABHD5, ALDH3A2, ALOX12B, ALOXE3, AP1S1, ARSE, CASP14, CDSN, CERS3, CHST8, CLDN1, CSTA, CYP4F22, ELOVL4, KDSR, LIPN, MBTPS2, NIPAL4, PEX7, PHGDH, PHYH, PNPLA1, POMP, PSAT1, SDR9C7, SERPINB8, SLC27A4, SNAP29, ST14, STS, SULT2B1, VPS33B, and ZMPSTE24.

34. The recombinant herpesvirus genome according to any one of claims 1 to 33, wherein the ichthyosis-related polypeptide is selected from the group consisting of ABCA12, ABHD5, ALDH3A2, ALOX12B, ALOXE3, AP1S1, CASP14, CDSN, CERS3, CHST8, CLDN1, CSTA, CYP4F22, ELOVL4, KDSR, LIPN, NIPAL4, PEX7, PHGDH, PHYH, PNPLA1, POMP, PSAT1, SDR9C7, SERPINB8, SLC27A4, SNAP29, ST14, SULT2B1, VPS33B, and ZMPSTE24.

35. The recombinant herpesvirus genome according to any one of claims 1 to 33, wherein the ichthyosis-related polypeptide is selected from the group consisting of ARSE, MBTPS2, and STS.

36. A recombinant herpesvirus genome according to any one of claims 1 to 35, wherein cytotoxicity is reduced when introduced into target cells compared to the corresponding wild-type herpesvirus genome.

37. The recombinant herpesvirus genome according to claim 36, wherein the target cells are epidermal and / or dermal cells.

38. The recombinant herpesvirus genome according to claim 36 or claim 37, wherein the target cell is a human cell.

39. A herpesvirus comprising the recombinant herpesvirus genome described in any one of claims 1 to 38.

40. The herpes virus according to claim 39, having the ability to replicate.

41. The herpesvirus according to claim 39, which is replication-deficient.

42. The herpesvirus according to any one of claims 39 to 41, wherein the cytotoxicity is reduced compared to the corresponding wild-type herpesvirus.

43. A herpesvirus according to any one of claims 39 to 42, selected from the group consisting of herpes simplex virus, varicella-zoster virus, human cytomegalovirus, herpesvirus 6A, herpesvirus 6B, herpesvirus 7, and Kaposi's sarcoma-associated herpesvirus.

44. A herpes simplex virus, as described in any one of claims 39 to 43.

45. The herpesvirus according to claim 43 or claim 44, wherein the herpes simplex virus is herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), or any derivative thereof.

46. The herpes virus according to any one of claims 43 to 45, wherein the herpes simplex virus is herpes simplex virus type 1 (HSV-1).

47. A pharmaceutical composition comprising a recombinant herpesvirus genome according to any one of claims 1 to 38 or a herpesvirus according to any one of claims 39 to 46, and a pharmaceutically acceptable excipient.

48. The pharmaceutical composition according to claim 47, which is suitable for topical administration, transdermal administration, subcutaneous administration, intradermal administration, oral administration, intranasal administration, intratracheal administration, sublingual administration, buccal administration, rectal administration, vaginal administration, inhalation administration, intravenous administration, intra-arterial administration, intramuscular administration, intracardiac administration, intraosseous administration, intraperitoneal administration, transmucosal administration, intravitreous administration, subretinal administration, intra-articular administration, peri-articular administration, local administration, or administration on the skin.

49. The pharmaceutical composition according to claim 47 or claim 48, which is suitable for local administration, transdermal administration, subcutaneous administration, intradermal administration, or transmucosal administration.

50. A pharmaceutical composition according to any one of claims 47 to 49, suitable for local administration, transdermal administration, or intradermal administration.

51. A pharmaceutical composition according to any one of claims 47 to 50, suitable for local administration.

52. A herpes virus according to any one of claims 39 to 46 or a pharmaceutical composition according to any one of claims 47 to 51, for use as a drug.

53. A herpes virus according to any one of claims 39 to 46 or a pharmaceutical composition according to any one of claims 47 to 51, for use in therapy.

54. Use of a herpesvirus according to any one of claims 39 to 46 or a pharmaceutical composition according to any one of claims 47 to 51 in the manufacture of a drug for treating one or more forms of congenital ichthyosis.

55. A method for providing preventive, symptomatic, or therapeutic relief of one or more signs or symptoms of congenital ichthyosis in a subject in need thereof, comprising administering to the subject an effective amount of the herpesvirus described in any one of claims 39 to 46 or the pharmaceutical composition described in any one of claims 47 to 51.

56. The aforementioned congenital ichthyosis includes harlequin ichthyosis (HI), autosomal recessive congenital ichthyosis (ARCI), lobed ichthyosis (LI), congenital ichthyoid erythroderma (CIE), Shanarin-Dorfman syndrome (CDS), Sjögren-Larsson syndrome (SLS), intellectual disability, intestinal disorders, hearing loss, peripheral neuropathy, ichthyosis and keratosis (MEDNIK) syndrome, and chondrodysplasia punctata. Ichthyosis 1 (CDPX1), Chondrodysplasia punctata 2 (CDPX2), Peeling Skin Syndrome (PSS), Neonatal Ichthyosicle Sclerosing Cholangitis (NISCH) Syndrome, Ichthyosis Vulgaris, Keratitis-Ichthyosis-Hearing Loss (KID) Syndrome, Palmoplantar Keratosis (PPK), Palmoplantar Keratosis with Sensorineural Hearing Loss (PPK / SNHL), Epidermal-Liquid Palmoplantar Keratosis (EPPK), Variable Erythema-Keratosis The method according to claim 55, selected from the group consisting of (EKV), Crowston syndrome, progressive symmetrical erythema keratoderma, epidermolytic ichthyosis (EI), superficial epidermolytic ichthyosis (SEI), loricrin keratoderma, follicular ichthyosis, alopecia, and photophobia (IFAP) syndrome, Olmsted syndrome, ichthyoid erythroderma and congenital hemiplegia (CHILD) syndrome with limb defects, Refsum disease, Neu-Laksoa syndrome, linear keratosis (KLICK) syndrome with congenital ichthyosis and sclerosing keratosis, ichthyosis prematurity syndrome (IPS), cerebral malformation, neurological disorders, ichthyosis, and palmoplantar keratosis (CEDNIK) syndrome, X-linked ichthyosis, joint contracture-renal dysfunction-cholestasis (ARC) syndrome, and restrictive skin disorders.

57. A method for providing preventive, symptomatic, or therapeutic relief of one or more signs or symptoms of harlequin ichthyosis (HI) in a subject in need thereof, comprising administering to the subject an effective amount of the herpesvirus described in any one of claims 39 to 46 or the pharmaceutical composition described in any one of claims 47 to 51.

58. The method according to claim 57, wherein the recombinant herpesvirus genome comprises one or more polynucleotides encoding the ABCA12 polypeptide.

59. A method for providing preventive, symptomatic, or therapeutic relief of one or more signs or symptoms of Shanalin-Dorfmann syndrome (CDS) in a subject in need thereof, comprising administering to the subject an effective amount of the herpesvirus described in any one of claims 39 to 46 or the pharmaceutical composition described in any one of claims 47 to 51.

60. The method according to claim 59, wherein the recombinant herpesvirus genome comprises one or more polynucleotides encoding the ABHD5 polypeptide.

61. A method for providing preventive, symptomatic, or therapeutic relief of one or more signs or symptoms of Sjögren-Larsson syndrome in a subject in need thereof, comprising administering to the subject an effective amount of the herpesvirus described in any one of claims 39 to 46 or the pharmaceutical composition described in any one of claims 47 to 51.

62. The method according to claim 61, wherein the recombinant herpesvirus genome comprises one or more polynucleotides encoding the ALDH3A2 polypeptide.

63. A method for providing prophylactic, symptomatic, or therapeutic relief of one or more signs or symptoms of autosomal recessive congenital ichthyosis (ARCI) in a subject in need thereof, comprising administering to the subject an effective amount of the herpesvirus described in any one of claims 39 to 46 or the pharmaceutical composition described in any one of claims 47 to 51.

64. The method according to claim 63, wherein the recombinant herpesvirus genome comprises one or more polynucleotides encoding a polypeptide selected from the group consisting of ALOX12B, ALOXE3, CASP14, CERS3, CYP4F22, LIPN, NIPAL4, PNPLA1, SDR9C7, SLC27A4, ST14, and SULT2B1.

65. A method for providing preventive, symptomatic, or therapeutic relief of one or more signs or symptoms of intellectual disability, intestinal disease, hearing loss, peripheral neuropathy, ichthyosis, and keratosis (MEDNIK) syndrome in a subject in need thereof, comprising administering to the subject an effective amount of the herpes virus according to any one of claims 39 to 46 or the pharmaceutical composition according to any one of claims 47 to 51.

66. The method according to claim 65, wherein the recombinant herpesvirus genome comprises one or more polynucleotides encoding the AP1S1 polypeptide.

67. A method for providing preventive, symptomatic, or therapeutic relief of one or more signs or symptoms of chondrodysplasia punctate 1 (CDPX1) in a subject in need thereof, comprising administering to the subject an effective amount of the herpes virus according to any one of claims 39 to 46 or the pharmaceutical composition according to any one of claims 47 to 51.

68. The method according to claim 67, wherein the recombinant herpesvirus genome comprises one or more polynucleotides encoding an ARSE polypeptide.

69. A method for providing preventive, symptomatic, or therapeutic relief of one or more signs or symptoms of chondrodysplasia punctate 2 (CDPX2) in a subject in need thereof, comprising administering to the subject an effective amount of the herpes virus according to any one of claims 39 to 46 or the pharmaceutical composition according to any one of claims 47 to 51.

70. The method according to claim 69, wherein the recombinant herpesvirus genome comprises one or more polynucleotides encoding an EBP polypeptide.

71. A method for providing preventive, symptomatic, or therapeutic relief of one or more signs or symptoms of peeling skin syndrome (PSS) in a subject in need thereof, comprising administering to the subject an effective amount of the herpes virus according to any one of claims 39 to 46 or the pharmaceutical composition according to any one of claims 47 to 51.

72. The method according to claim 71, wherein the recombinant herpesvirus genome comprises one or more polynucleotides encoding a polypeptide selected from the group consisting of CDSN, CHST8, CSTA, FLG2, and SERPINB8.

73. A method for providing prophylactic, symptomatic, or therapeutic relief of one or more signs or symptoms of neonatal ichthyosis sclerosing cholangitis (NISCH) syndrome in a subject in need thereof, comprising administering to the subject an effective amount of the herpesvirus described in any one of claims 39 to 46 or the pharmaceutical composition described in any one of claims 47 to 51.

74. The method according to claim 73, wherein the recombinant herpesvirus genome comprises one or more polynucleotides encoding a CLDN1 polypeptide.

75. A method for providing preventive, symptomatic, or therapeutic relief of one or more signs or symptoms of ichthyosis vulgaris in a subject in need thereof, comprising administering to the subject an effective amount of the herpesvirus described in any one of claims 39 to 46 or the pharmaceutical composition described in any one of claims 47 to 51.

76. The method according to claim 75, wherein the recombinant herpesvirus genome comprises one or more polynucleotides encoding an FLG polypeptide.

77. A method for providing preventive, symptomatic, or therapeutic relief of one or more signs or symptoms of keratitis-ichthyosis-hearing loss (KID) syndrome, Crowston syndrome, and / or palmoplantar keratoderma with sensorineural hearing loss (PPK / SNHL) in a subject in need thereof, comprising administering to the subject an effective amount of the herpes virus according to any one of claims 39 to 46 or the pharmaceutical composition according to any one of claims 47 to 51.

78. The method according to claim 77, wherein the recombinant herpesvirus genome comprises one or more polynucleotides encoding a GJB2 or GJB6 polypeptide.

79. A method for providing prophylactic, symptomatic, or therapeutic relief of one or more signs or symptoms of variable erythema keratoderma (EKV) in a subject in need thereof, comprising administering to the subject an effective amount of the herpesvirus described in any one of claims 39 to 46 or the pharmaceutical composition described in any one of claims 47 to 51.

80. The method according to claim 79, wherein the recombinant herpesvirus genome comprises one or more polynucleotides encoding a GJB3 or GJB4 polypeptide.

81. A method for providing prophylactic, symptomatic, or therapeutic relief of one or more signs or symptoms of progressive symmetric erythematous keratoderma in a subject in need thereof, comprising administering to the subject an effective amount of the herpesvirus described in any one of claims 39 to 46 or the pharmaceutical composition described in any one of claims 47 to 51.

82. The method according to claim 81, wherein the recombinant herpesvirus genome comprises one or more polynucleotides encoding a KDSR polypeptide.

83. A method for providing preventive, symptomatic, or therapeutic relief of one or more signs or symptoms of epidermolytic ichthyosis (EI) and / or superficial epidermolytic ichthyosis (SEI) in a subject in need thereof, comprising administering to the subject an effective amount of the herpes virus according to any one of claims 39 to 46 or the pharmaceutical composition according to any one of claims 47 to 51.

84. The method according to claim 83, wherein the recombinant herpesvirus genome comprises one or more polynucleotides encoding a polypeptide selected from the group consisting of KRT1, KRT2, and KRT10.

85. A method for providing prophylactic, symptomatic, or therapeutic relief of one or more signs or symptoms of epidermal keratoderma (EPPK) in a subject in need thereof, comprising administering to the subject an effective amount of the herpes virus according to any one of claims 39 to 46 or the pharmaceutical composition according to any one of claims 47 to 51.

86. The method according to claim 85, wherein the recombinant herpesvirus genome comprises one or more polynucleotides encoding a KRT9 polypeptide.

87. A method for providing prophylactic, symptomatic, or therapeutic relief of one or more signs or symptoms of loricrin keratoderma in a subject in need thereof, comprising administering to the subject an effective amount of the herpes virus according to any one of claims 39 to 46 or the pharmaceutical composition according to any one of claims 47 to 51.

88. The method according to claim 87, wherein the recombinant herpesvirus genome comprises one or more polynucleotides encoding an LOR polypeptide.

89. A method for providing preventive, symptomatic, or therapeutic relief of one or more signs or symptoms of follicular ichthyosis, alopecia, photophobia (IFAP) syndrome, and / or Olmsted syndrome in a subject in need thereof, comprising administering to the subject an effective amount of the herpes virus according to any one of claims 39 to 46 or the pharmaceutical composition according to any one of claims 47 to 51.

90. The method according to claim 89, wherein the recombinant herpesvirus genome comprises one or more polynucleotides encoding the MBTPS2 polypeptide.

91. A method for providing prophylactic, symptomatic, or therapeutic relief of one or more signs or symptoms of ichthyosis-like erythroderma and unilateral dysplasia (CHILD) syndrome with limb defects in a subject in need thereof, comprising administering to the subject an effective amount of the herpes virus according to any one of claims 39 to 46 or the pharmaceutical composition according to any one of claims 47 to 51.

92. The method according to claim 91, wherein the recombinant herpesvirus genome comprises one or more polynucleotides encoding an NSDHL polypeptide.

93. A method for providing preventive, symptomatic, or therapeutic relief of one or more signs or symptoms of Refsum disease in a subject in need thereof, comprising administering to the subject an effective amount of the herpes virus according to any one of claims 39 to 46 or the pharmaceutical composition according to any one of claims 47 to 51.

94. The method according to claim 93, wherein the recombinant herpesvirus genome comprises one or more polynucleotides encoding PEX7 or a PHYH polypeptide.

95. A method for providing preventive, symptomatic, or therapeutic relief of one or more signs or symptoms of Neu-Laksowa syndrome in a subject in need thereof, comprising administering to the subject an effective amount of the herpes virus according to any one of claims 39 to 46 or the pharmaceutical composition according to any one of claims 47 to 51.

96. The method according to claim 95, wherein the recombinant herpesvirus genome comprises one or more polynucleotides encoding PHGDH or PSAT1 polypeptide.

97. A method for providing prophylactic, symptomatic, or therapeutic relief of one or more signs or symptoms of congenital ichthyosis and linear keratosis syndrome with sclerosing keratosis (KLICK) in a subject in need thereof, comprising administering to the subject an effective amount of the herpes virus according to any one of claims 39 to 46 or the pharmaceutical composition according to any one of claims 47 to 51.

98. The method according to claim 97, wherein the recombinant herpesvirus genome comprises one or more polynucleotides encoding a POMP polypeptide.

99. A method for providing preventive, symptomatic, or therapeutic relief of one or more signs or symptoms of ichthyosis prematurity syndrome (IPS) in a subject in need thereof, comprising administering to the subject an effective amount of the herpesvirus described in any one of claims 39 to 46 or the pharmaceutical composition described in any one of claims 47 to 51.

100. The method according to claim 99, wherein the recombinant herpesvirus genome comprises one or more polynucleotides encoding the SLC27A4 polypeptide.

101. A method for providing preventive, symptomatic, or therapeutic relief of one or more signs or symptoms of cerebral malformation, neurological disorders, ichthyosis, and palmoplantar keratoderma (CEDNIK) syndrome in a subject in need thereof, comprising administering to the subject an effective amount of the herpes virus according to any one of claims 39 to 46 or the pharmaceutical composition according to any one of claims 47 to 51.

102. The method according to claim 101, wherein the recombinant herpesvirus genome comprises one or more polynucleotides encoding a SNAP29 polypeptide.

103. A method for providing prophylactic, symptomatic, or therapeutic relief of one or more signs or symptoms of X-linked ichthyosis in a subject in need thereof, comprising administering to the subject an effective amount of the herpesvirus described in any one of claims 39 to 46 or the pharmaceutical composition described in any one of claims 47 to 51.

104. The method according to claim 103, wherein the recombinant herpesvirus genome comprises one or more polynucleotides encoding an STS polypeptide.

105. A method for providing preventive, symptomatic, or therapeutic relief of one or more signs or symptoms of joint contracture-renal dysfunction-cholestasis (ARC) syndrome in a subject in need thereof, comprising administering to the subject an effective amount of the herpes virus according to any one of claims 39 to 46 or the pharmaceutical composition according to any one of claims 47 to 51.

106. The method according to claim 105, wherein the recombinant herpesvirus genome comprises one or more polynucleotides encoding the VPS33B polypeptide.

107. A method for providing preventive, symptomatic, or therapeutic relief of one or more signs or symptoms of restrictive skin disorder in a subject in need thereof, comprising administering to the subject an effective amount of the herpes virus according to any one of claims 39 to 46 or the pharmaceutical composition according to any one of claims 47 to 51.

108. The method according to claim 107, wherein the recombinant herpesvirus genome comprises one or more polynucleotides encoding the ZMPSTE24 polypeptide.

109. The method according to any one of claims 55 to 108, wherein the subject is a human.

110. The method according to any one of claims 55 to 109, wherein the target genome includes a pathogenic variant of an ichthyosis-related gene.

111. The method according to any one of claims 55 to 110, wherein the target genome includes loss-of-function mutations in ichthyosis-related genes.

112. The method according to any one of claims 55 to 111, wherein the herpes virus or the pharmaceutical composition is administered to the target topically, percutaneously, subcutaneously, on the skin, intradermally, orally, sublingually, buccally, rectally, vaginally, intravenously, intraarterially, intramuscularly, intrabonely, intracardiacly, intraperitoneally, transmucosally, intravitreously, subretinally, intraarticularly, periarticularly, locally, or by inhalation.

113. The method according to any one of claims 55 to 112, wherein the herpes virus or the pharmaceutical composition is administered to the subject locally, percutaneously, subcutaneously, intradermally, or transmucosally.

114. The method according to any one of claims 55 to 113, wherein the herpes virus or the pharmaceutical composition is administered to the subject topically, transdermally, or intradermally.

115. The method according to any one of claims 55 to 114, wherein the herpes virus or the pharmaceutical composition is administered topically to the subject.

116. The method according to any one of claims 55 to 115, wherein the target skin is rubbed before administration.

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