Recombinant nucleic acids encoding cosmetic proteins for aesthetic uses

Abstract

Provided are compositions and methods of use for replenishing, strengthening, or replacing skin ECM components (e.g., human collagen) that address the structural changes underlying skin aging, specifically collagen damage or loss. [Solution] The present disclosure provides recombinant nucleic acids comprising one or more polynucleotides encoding one or more cosmetic proteins (e.g., one or more human collagen proteins), viruses comprising the recombinant nucleic acids, compositions (e.g., cosmetic formulations) comprising the recombinant nucleic acids and / or viruses, methods for their use, and products or kits thereof.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 62 / 663,476, filed April 27, 2018, which is incorporated herein by reference in its entirety.

[0002] Submitting a sequence listing as an ASCII text file The contents of the following submission in an ASCII text file are incorporated herein by reference in their entirety: Sequence Listing Computer Readable Form (CRF) (Filename: 761342000640SEQLIST.txt, Recorded: April 26, 2019, Size: 437 KB).

[0003] FIELD OF THE INVENTION The present disclosure relates, in part, to recombinant nucleic acids comprising one or more polynucleotides encoding one or more cosmetic proteins (e.g., one or more human collagen proteins), viruses comprising the recombinant nucleic acids, compositions (e.g., cosmetic formulations) comprising the recombinant nucleic acids and / or viruses, methods of use thereof, and products or kits thereof. [Background technology]

[0004] background Like all organs of the human body, skin undergoes continuous and often cumulative changes over time. Skin aging is the result of many factors, including intrinsic changes within the skin, the effects of gravity and facial muscles acting on the skin, loss or shift of soft tissue, and loss of tissue elasticity. Interestingly, the "aged" phenotype of skin can be accelerated by environmental factors, most notably long-term exposure to ultraviolet radiation (e.g., from the sun). Clinically, the aged phenotype of skin can be described as wrinkled, sagging, and / or generally less elastic and resilient than its younger counterpart, although variations within this phenotype exist between natural chronological aging and photoaging.

[0005] The dermal extracellular matrix (ECM) constitutes the majority of skin and provides both strength and elasticity. Collagen, the main component of connective tissue that provides support to the skin, decreases as people age. In aged skin, collagen fibrils show high levels of degradation and fragmentation and are replenished by dermal fibroblasts at a reduced rate. These degraded and fragmented collagen bundles become loose and lose strength (disrupting the structural organization of the dermal ECM), which is closely linked to the signs of "aging" skin.

[0006] A large number of skin care products have been developed to improve the appearance of human skin.Wrinkles and skin folds are generally treated by dermal and subcutaneous injection of aesthetic facial fillers, but these surface approaches do not address the structural changes underlying skin aging, specifically the damage or loss of collagen.Therefore, there is a clear need for alternative strategies to supplement, strengthen or replace skin ECM components (for example, human collagen) in individuals who wish to counteract or reverse the physiological effects of skin aging.

[0007] All references cited herein, including patent applications, patent publications, non-patent literature, and NCBI / UniProtKB / Swiss-Prot accession numbers, are hereby incorporated by reference in their entirety, as if each individual reference was specifically and individually indicated to be incorporated by reference. Summary of the Invention

[0008] overview To meet these and other needs, provided herein are recombinant nucleic acids (e.g., recombinant herpesvirus genomes) encoding one or more cosmetic proteins for use in viruses (e.g., herpesviruses), compositions, formulations, medicaments, and / or methods for aesthetic / cosmetic applications (e.g., wrinkle treatment). The inventors have shown that the recombinant attenuated viruses described herein (1) can effectively transduce human epidermal / dermal cells and (2) can successfully express the encoded exogenous human collagen (mRNA and protein), which can then be localized to the appropriate region in skin equivalent organotypic cultures (see, e.g., Example 2). Furthermore, the inventors have shown that the viruses described herein can be successfully administered either topically or intradermally without significant host cell toxicity, allowing the human collagen expressed from these viruses to localize to the appropriate region of the skin ECM after in vivo administration without observable damage to the skin (see, e.g., Examples 3 and 7). Additionally, the inventors have demonstrated that multiple different HSV backbones can be used to construct viruses that express human collagen (see, e.g., Example 2), that multiple strategies can be used to successfully express two or more human collagen proteins from a single recombinant genome (see, e.g., Example 5), and that candidate viruses can successfully express human collagen proteins in multiple relevant in vitro and in vivo models of chronological or UV-induced skin aging (see, e.g., Examples 6 and 7). Furthermore, the inventors have demonstrated that the viruses described herein can be successfully engineered to express other cosmetic proteins (e.g., human laminin) both in vitro and in vivo, and that these proteins localize to the appropriate regions of the skin ECM (see, e.g., Example 8).Without wishing to be bound by theory, the data described herein provide strong evidence that the recombinant nucleic acids and / or viruses of the present disclosure may constitute a novel means for delivering cosmetic proteins (e.g., human collagen proteins such as human collagen 1 and human collagen 3), specifically for supplementing or replacing native human skin ECM proteins in aesthetic applications (e.g., to reduce the appearance of age- or photo-induced wrinkles).

[0009] Therefore, certain aspects of the present disclosure relate to a recombinant herpesvirus genome comprising a first polynucleotide encoding a first polypeptide comprising a first cosmetic protein. In some embodiments, the recombinant herpesvirus genome comprises two or more copies of the first polynucleotide. In some embodiments, the recombinant herpesvirus genome is replication-competent. In some embodiments, the recombinant herpesvirus genome is replication-deficient. In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpesvirus genome is selected from a recombinant herpes simplex virus genome, a recombinant varicella-zoster virus genome, a recombinant human cytomegalovirus genome, a recombinant herpesvirus 6A genome, a recombinant herpesvirus 6B genome, a recombinant herpesvirus 7 genome, a recombinant Kaposi's sarcoma-associated herpesvirus genome, and any derivative thereof. In some embodiments that may be combined with any of the preceding 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.

[0010] In some embodiments, the recombinant herpes simplex virus genome is a recombinant herpes simplex virus type 1 (HSV-1) genome. In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation. In some embodiments that may be combined with any of the preceding embodiments, the inactivating mutation is in a herpes simplex virus gene. In some embodiments, the inactivating mutation is a deletion of the coding sequence of the herpes simplex virus gene. In some embodiments, the herpes simplex virus gene is selected from infected cell protein (ICP)0, ICP4, ICP22, ICP27, ICP47, thymidine kinase (tk), long unique region (UL)41, and UL55. In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in one or both copies of the ICP4 gene. In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP22 gene. In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the UL41 gene. In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in one or both copies of the ICP0 gene. In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP27 gene. In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the UL55 gene. In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the junction region. In some embodiments, the recombinant herpes simplex virus genome comprises a deletion of the junction region.In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpes simplex virus genome includes a first polynucleotide within one or both of the ICP4 viral loci.

[0011] In some embodiments that may be combined with any of the preceding embodiments, the first cosmetic protein is selected from a first collagen protein, a first fibronectin protein, a first elastin protein, a first lumican protein, a first vitronectin protein, a first vitronectin receptor protein, a first laminin protein, a first neuromodulatory protein, and a first fibrillin protein. In some embodiments that may be combined with any of the preceding embodiments, the first cosmetic protein 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 to an amino acid sequence selected from SEQ ID NOs: 15-21 and 53-64. In some embodiments, the first cosmetic protein is a structural extracellular matrix protein (e.g., collagen protein, elastin protein, fibronectin protein, laminin protein, fibrillin protein, etc.). In some embodiments, the first cosmetic protein is a collagen protein, elastin protein, fibronectin protein, or laminin protein (e.g., human collagen protein, human elastin protein, human fibronectin protein, or human laminin protein). In some embodiments that may be combined with any of the preceding embodiments, the first collagen protein is a human collagen protein. In some embodiments that may be combined with any of the preceding embodiments, the first collagen protein is selected from the group consisting of collagen alpha-1(I) chain polypeptide (COL1-1), collagen alpha-2(I) chain polypeptide (COL1-2), collagen alpha-1(II) chain polypeptide (COL2), collagen alpha-1(III) chain polypeptide (COL3), collagen alpha-1(IV) chain polypeptide (COL4-1), collagen alpha-2(IV) chain polypeptide (COL4-2), collagen alpha-3(IV) chain polypeptide (COL4-3),Collagen alpha-4(IV) chain polypeptide (COL4-4), collagen alpha-5(IV) chain polypeptide (COL4-5), collagen alpha-6(IV) chain polypeptide (COL4-6), collagen alpha-1(V) chain polypeptide (COL5-1), collagen alpha-2(V) chain polypeptide (COL5-2), collagen alpha-3(V) chain polypeptide (COL5-3), collagen alpha-1(VI) chain polypeptide (COL6-1), collagen alpha-2(VI) chain polypeptide (COL6-2), collagen collagen alpha-3(VI) chain polypeptide (COL6-3), collagen alpha-4(VI) chain polypeptide (COL6-4), collagen alpha-5(VI) chain polypeptide (COL6-5), collagen alpha-6(VI) chain polypeptide (COL6-6), collagen alpha-1(VIII) chain polypeptide (COL8), collagen alpha-1(IX) chain polypeptide (COL9-1), collagen alpha-2(IX) chain polypeptide (COL9-2), collagen alpha-3(IX) chain polypeptide (COL9-3), collagen Collagen alpha-1(X) chain polypeptide (COL10), collagen alpha-1(XI) chain polypeptide (COL11-1), collagen alpha-2(XI) chain polypeptide (COL11-2), collagen alpha-1(XII) chain polypeptide (COL12), collagen alpha-1(XIII) chain polypeptide (COL13), collagen alpha-1(XIV) chain polypeptide (COL14), collagen alpha-1(XV) chain polypeptide (COL15), collagen alpha-1(XVI) chain polypeptide (COL16), collagen alpha-1(XVII) chain polypeptide (COL17), collagen alpha-1(XVIII) chain polypeptide (COL18), collagen alpha-1(XIX) chain polypeptide (COL19), collagen alpha-1(XX) chain polypeptide (COL20), collagen alpha-1(XXI) chain polypeptide (COL21), collagen alpha-1(XXII) chain polypeptide (COL22), collagen alpha-1(XXIII) chain polypeptide (COL23), collagen alpha-1(XXIV) chain polypeptide (COL24),In some embodiments that may be combined with any of the preceding embodiments, the first collagen protein is selected from collagen alpha-1 (XXV) chain polypeptide (COL25), collagen alpha-1 (XXVI) chain polypeptide (COL26), collagen alpha-1 (XXVII) chain polypeptide (COL27), and collagen alpha-1 (XXVIII) chain polypeptide (COL28). In some embodiments that may be combined with any of the preceding embodiments, the first collagen protein is selected from COL1-1, COL1-2, COL3, COL4-1, COL4-2, COL6-1, and COL17. In some embodiments that may be combined with any of the preceding embodiments, the first collagen protein 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 to an amino acid sequence selected from SEQ ID NOs: 15-21. In some embodiments that may be combined with any of the preceding embodiments, the first collagen protein is COL3. In some embodiments that may be combined with any of the preceding embodiments, the first collagen protein is human COL3. In some embodiments that may be combined with any of the preceding embodiments, the first collagen protein 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 to the amino acid sequence of SEQ ID NO: 17. In some embodiments that may be combined with any of the preceding embodiments, the first cosmetic protein is not collagen alpha-1(VII) chain polypeptide (COL7).

[0012] In some embodiments, the first polypeptide consists essentially of a first cosmetic protein. In some embodiments, the first polypeptide consists of a first cosmetic protein. In some embodiments, the first polypeptide comprises (a) a first cosmetic protein, (b) an additional cosmetic protein, and (c) a linker polypeptide connecting (a) to (b). In some embodiments, the additional cosmetic protein is selected from a collagen protein, a fibronectin protein, an elastin protein, a lumican protein, a vitronectin protein, a vitronectin receptor protein, a laminin protein, a neuromodulatory protein, and a fibrillin protein. In some embodiments, the additional cosmetic protein is a structural extracellular matrix protein (e.g., a collagen protein, an elastin protein, a fibronectin protein, a laminin protein, a fibrillin protein, etc.). In some embodiments, the additional cosmetic protein is a collagen protein, an elastin protein, a fibronectin protein, or a laminin protein (e.g., a human collagen protein, a human elastin protein, a human fibronectin protein, or a human laminin protein). In some embodiments, the additional collagen protein (e.g., additional human collagen protein) is selected from COL1-1, COL1-2, COL2, COL3, COL4-1, COL4-2, COL4-3, COL4-4, COL4-5, COL4-6, COL5-1, COL5-2, COL5-3, COL6-1, COL6-2, COL6-3, COL6-4, COL6-5, COL6-6, COL7, COL8, COL9-1, COL9-2, COL9-3, COL10, COL11-1, COL11-2, COL12, COL13, COL14, COL15, COL16, COL17, COL18, COL19, COL20, COL21, COL22, COL23, COL24, COL25, COL26, COL27, and COL28.In some embodiments, the additional collagen protein (e.g., the additional human collagen protein) is selected from COL1-1, COL1-2, COL3, COL4-1, COL4-2, COL6-1, COL7, and COL17. In some embodiments, the first cosmetic protein and the additional cosmetic protein are different. In some embodiments, the first cosmetic protein is COL1-1 (e.g., human COL1-1) and the additional cosmetic protein is COL1-2 (e.g., human COL1-2). In some embodiments, the linker polypeptide is a cleavable linker polypeptide. In some embodiments, the linker 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 to an amino acid sequence selected from SEQ ID NOs: 28-31.

[0013] In some embodiments that may be combined with any of the preceding embodiments, the first polynucleotide encodes a polycistronic mRNA comprising: (a) a first open reading frame (ORF) encoding a first polypeptide; (b) a second ORF encoding an additional cosmetic protein; and (c) an internal ribosome entry site (IRES) separating (a) and (b). In some embodiments, the additional cosmetic protein is selected from a collagen protein, a fibronectin protein, an elastin protein, a lumican protein, a vitronectin protein, a vitronectin receptor protein, a laminin protein, a neuromodulatory protein, and a fibrillin protein. In some embodiments, the additional cosmetic protein is a structural extracellular matrix protein (e.g., a collagen protein, an elastin protein, a fibronectin protein, a laminin protein, a fibrillin protein, etc.). In some embodiments, the additional cosmetic protein is a collagen protein, an elastin protein, a fibronectin protein, or a laminin protein (e.g., a human collagen protein, a human elastin protein, a human fibronectin protein, or a human laminin protein). In some embodiments, the additional collagen protein (e.g., additional human collagen protein) is selected from COL1-1, COL1-2, COL2, COL3, COL4-1, COL4-2, COL4-3, COL4-4, COL4-5, COL4-6, COL5-1, COL5-2, COL5-3, COL6-1, COL6-2, COL6-3, COL6-4, COL6-5, COL6-6, COL7, COL8, COL9-1, COL9-2, COL9-3, COL10, COL11-1, COL11-2, COL12, COL13, COL14, COL15, COL16, COL17, COL18, COL19, COL20, COL21, COL22, COL23, COL24, COL25, COL26, COL27, and COL28.In some embodiments, the additional collagen protein (e.g., the additional human collagen protein) is selected from COL1-1, COL1-2, COL3, COL4-1, COL4-2, COL6-1, COL7, and COL17. In some embodiments, the first cosmetic protein and the additional cosmetic protein are different. In some embodiments, the first cosmetic protein is COL1-1 (e.g., human COL1-1) and the additional cosmetic protein is COL1-2 (e.g., human COL1-2). In some embodiments, the nucleic acid sequence encoding an IRES has at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to a nucleic acid sequence selected from SEQ ID NO:22 or SEQ ID NO:23.

[0014] In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpesvirus genome further comprises a second polynucleotide encoding a second cosmetic protein. In some embodiments, the second cosmetic protein is selected from collagen protein, fibronectin protein, elastin protein, lumican protein, vitronectin protein, vitronectin receptor protein, laminin protein, neuromodulatory protein, and fibrillin protein. In some embodiments, the second cosmetic protein is a structural extracellular matrix protein (e.g., collagen protein, elastin protein, fibronectin protein, laminin protein, fibrillin protein, etc.). In some embodiments, the second cosmetic protein is a collagen protein, elastin protein, fibronectin protein, or laminin protein (e.g., human collagen protein, human elastin protein, human fibronectin protein, or human laminin protein). In some embodiments, the second collagen protein (e.g., a second human collagen protein) is selected from COL1-1, COL1-2, COL2, COL3, COL4-1, COL4-2, COL4-3, COL4-4, COL4-5, COL4-6, COL5-1, COL5-2, COL5-3, COL6-1, COL6-2, COL6-3, COL6-4, COL6-5, COL6-6, COL7, COL8, COL9-1, COL9-2, COL9-3, COL10, COL11-1, COL11-2, COL12, COL13, COL14, COL15, COL16, COL17, COL18, COL19, COL20, COL21, COL22, COL23, COL24, COL25, COL26, COL27, and COL28. In some embodiments, the second collagen protein (e.g., a second human collagen protein) is selected from COL1-1, COL1-2, COL3, COL4-1, COL4-2, COL6-1, COL7, and COL17. In some embodiments, the first cosmetic protein and the second cosmetic protein are different.In some embodiments, the first cosmetic protein is COL1-1 (e.g., human COL1-1) and the second cosmetic protein is COL1-2 (e.g., human COL1-2). In some embodiments, the first cosmetic protein is COL1-1 (e.g., human COL1-1) and the second cosmetic protein is COL3 (e.g., human COL3).

[0015] In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpesvirus genome, when introduced into a target cell, has reduced cytotoxicity compared to the corresponding wild-type herpesvirus genome. In some embodiments, the target cell is an epidermal cell and / or a dermal cell. In some embodiments, the target cell is a human cell. In some embodiments, the target cell is a fibroblast.

[0016] Another aspect of the present disclosure relates to a herpesvirus comprising any of the recombinant herpesvirus genomes described herein. In some embodiments, the herpesvirus is replication-competent. In some embodiments, the herpesvirus is replication-deficient. In some embodiments, the herpesvirus is attenuated. In some embodiments that may be combined with any of the preceding embodiments, the herpesvirus has reduced cytotoxicity compared to a corresponding wild-type herpesvirus. In some embodiments that may be combined with any of the preceding 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 that may be combined with any of the preceding embodiments, the herpesvirus is a 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).

[0017] Another aspect of the present disclosure relates to a composition comprising (a) any of the recombinant herpesvirus genomes described herein and / or any of the herpesviruses described herein, and (b) an excipient. In some embodiments, the composition is sterile. In some embodiments that may be combined with any of the preceding embodiments, the composition is suitable for topical, transdermal, subcutaneous, intradermal, oral, intranasal, intratracheal, sublingual, buccal, rectal, intravaginal, inhalation, intravenous, intraarterial, intramuscular, intracardiac, intraosseous, intraperitoneal, transmucosal, intravitreal, subretinal, intraarticular, periarticular, local, or epicutaneous administration. In some embodiments that may be combined with any of the preceding embodiments, the composition is suitable for intradermal administration. In some embodiments that may be combined with any of the preceding embodiments, the composition is suitable for topical injection. In some embodiments that may be combined with any of the preceding embodiments, the composition is a cosmetic composition. In some embodiments that may be combined with any of the preceding embodiments, the composition is a skin care product.

[0018] Other aspects of the present disclosure relate to the use of any of the recombinant herpesvirus genomes described herein and / or any of the herpesviruses described herein as a medicament (e.g., for cosmetic purposes).

[0019] Other aspects of the present disclosure relate to the use of any of the recombinant herpesvirus genomes described herein and / or any of the herpesviruses described herein as a therapy (e.g., a cosmetic or cosmetic treatment).

[0020] Another aspect of the present disclosure relates to the use of any of the recombinant herpesvirus genomes described herein and / or any of the herpesviruses described herein in the manufacture of a medicament useful for treating one or more signs or symptoms of dermatological aging.

[0021] Another aspect of the present disclosure relates to a method of enhancing, increasing, potentiating, and / or replenishing the levels of one or more skin extracellular matrix proteins in a subject, the method comprising administering to the subject an effective amount of any of the herpesviruses described herein and / or any of the compositions described herein.

[0022] Another aspect of the present disclosure relates to methods of enhancing, increasing, potentiating, and / or replenishing levels of one or more collagen proteins in a subject, comprising administering to the subject an effective amount of any of the herpesviruses described herein and / or any of the compositions described herein. In some embodiments, the one or more collagen proteins is collagen 3. In some embodiments, endogenous collagen 3 levels are reduced as a result of chronological or photoaging.

[0023] Another aspect of the present disclosure relates to methods of strengthening, increasing, enhancing, and / or replenishing soft tissue in a subject, comprising administering to the subject an effective amount of any of the herpesviruses described herein and / or any of the compositions described herein, hi some embodiments, the composition is injected into the soft tissue of the subject.

[0024] Another aspect of the present disclosure relates to methods of improving the condition, quality, and / or appearance of skin in a subject in need thereof, comprising administering to the subject an effective amount of any of the herpesviruses described herein and / or any of the compositions described herein, hi some embodiments, the composition is administered to one or more sites of sun damage or other UV exposure, rough texture, sagging skin, wrinkles, or any combination thereof.

[0025] Another aspect of the present disclosure relates to a method of reducing the appearance of one or more surface depressions in the skin of a subject in need thereof, comprising administering to the subject an effective amount of any of the herpesviruses described herein and / or any of the compositions described herein, In some embodiments, the one or more surface depressions in the skin are selected from the group consisting of nasolabial folds, crow's feet, glabellar lines, forehead wrinkles, scars, glabellar lines, brow ptosis, tear troughs, nasojugal lines, bunny lines, cheek / midface ptosis, marionette lines, poppy dimplings, laugh lines, laugh lines, chin folds, neck wrinkles, platysma bands, and any combination thereof.

[0026] Another aspect of the present disclosure relates to a method of increasing and / or improving at least one of the texture, smoothness, elasticity, or firmness of the skin of a subject in need thereof, comprising administering to the subject an effective amount of any of the herpesviruses described herein and / or any of the compositions described herein.

[0027] In some embodiments that may be combined with any of the preceding embodiments, the subject's skin is aging skin. In some embodiments that may be combined with any of the preceding embodiments, the subject's skin has been damaged by exposure to ultraviolet light. In some embodiments that may be combined with any of the preceding embodiments, the subject's skin is wrinkled.

[0028] Another aspect of the present disclosure relates to a method of reducing one or more signs of dermatological aging in a subject in need thereof, comprising administering to the subject an effective amount of any of the herpesviruses described herein and / or any of the compositions described herein. In some embodiments, the reduction of one or more signs of dermatological aging includes (a) treatment, reduction, and / or prevention of fine lines and / or wrinkles, (b) reduction of pore size in skin, (c) improvement in skin thickness, plumpness, and / or firmness, (d) improvement in skin smoothness, suppleness, and / or softness, (e) improvement in skin tone, radiance, and / or clarity, (f) improvement in procollagen and / or collagen production, (g) improvement and / or retexturization of skin texture. (n) promoting the appearance of skin contours; (h) improving the appearance of skin contours; (i) restoring skin radiance and / or brightness; (j) improving the appearance of skin diminished by aging and / or menopause; (k) improving skin moisturization; (l) increasing skin elasticity and / or firmness; (m) treating, reducing, and / or preventing or slowing skin; (n) improving skin firmness; (o) reducing pigmented spots, mottled skin, and / or scarring (such as acne scarring); (p) improving the optical properties of the skin through light diffraction or reflection; or (q) any combination thereof.

[0029] In some embodiments that can be combined with any of the preceding embodiments, the subject is a human. In some embodiments that can be combined with any of the preceding embodiments, the herpes virus or composition is administered to the subject topically, transdermally, subcutaneously, epicutaneously, intradermally, orally, sublingually, bucally, rectally, vaginally, intravenously, intraarterially, intramuscularly, intraosseously, intracardially, intraperitoneally, transmucosally, intravitreally, subretinally, intraarticularly, periarticularly, locally, or via inhalation. In some embodiments that can be combined with any of the preceding embodiments, the herpes virus or composition is administered to the subject intradermally. In some embodiments that can be combined with any of the preceding embodiments, the herpes virus or composition is administered by topical injection.

[0030] Another aspect of the present disclosure relates to a composition comprising a herpes simplex virus (HSV) comprising a recombinant nucleic acid, the HSV comprising a first polynucleotide encoding a first polypeptide comprising a first human collagen protein, and an excipient. In some embodiments, the recombinant nucleic acid comprises two or more copies of the first polynucleotide. In some embodiments that may be combined with any of the preceding embodiments, the HSV is replication-deficient. In some embodiments that may be combined with any of the preceding embodiments, the HSV is replication-competent. In some embodiments that may be combined with any of the preceding embodiments, the HSV is herpes simplex virus type 1, herpes simplex virus type 2, or any derivative thereof.

[0031] In some embodiments, the recombinant nucleic acid is a herpes simplex virus amplicon. In some embodiments, the herpes simplex virus amplicon is an HSV-1 amplicon or an HSV-1 hybrid amplicon. In some embodiments, the HSV-1 hybrid amplicon is an HSV / AAV hybrid amplicon, an HSV / EBV hybrid amplicon, an HSV / EBV / RV hybrid amplicon, or an HSV / Sleeping Beauty hybrid amplicon.

[0032] 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 HSV-1 genome, a recombinant HSV-2 genome, or any derivative thereof. In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in a herpes simplex virus gene. In some embodiments, the herpes simplex virus gene is selected from the group consisting of infected cell protein (ICP)0, ICP4, ICP22, ICP27, ICP47, thymidine kinase (tk), long unique region (UL)41, and UL55. In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in one or both copies of the ICP4 gene. In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP22 gene. In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the UL41 gene. In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP0 gene. In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP27 gene. In some embodiments that may be combined with any of the preceding embodiments, the inactivating mutation is a deletion of the coding sequence of the gene(s).

[0033] In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpes simplex virus genome comprises a first polynucleotide within a viral locus. In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpes simplex virus genome comprises a first polynucleotide within one or both copies of the ICP4 viral locus. In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpes simplex virus genome comprises a first polynucleotide within the ICP22 viral locus. In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpes simplex virus genome comprises a first polynucleotide within the UL41 viral locus. In some embodiments that may be combined with any of the preceding embodiments, the HSV has reduced cytotoxicity compared to wild-type herpes simplex virus.

[0034] In some embodiments that may be combined with any of the preceding embodiments, the first human collagen protein is selected from the group consisting of collagen alpha-1(I) chain polypeptide (COL1-1), collagen alpha-2(I) chain polypeptide (COL1-2), collagen alpha-1(II) chain polypeptide (COL2), collagen alpha-1(III) chain polypeptide (COL3), collagen alpha-1(IV) chain polypeptide (COL4-1), collagen alpha-2(IV) chain polypeptide (COL4-2), collagen alpha-3(IV) chain polypeptide (COL4-3), collagen alpha-4(IV) chain polypeptide (COL4-4), collagen alpha-5(IV) chain polypeptide (COL4-5), collagen alpha-6(IV) chain polypeptide (COL4-6), collagen alpha-1(V) chain polypeptide (COL5-1), collagen alpha-2(V) chain polypeptide (COL5-2), collagen alpha-3(V) chain polypeptide (COL5-3), collagen alpha-1(VI) chain polypeptide (COL6-1), collagen alpha Collagen alpha-2(VI) chain polypeptide (COL6-2), collagen alpha-3(VI) chain polypeptide (COL6-3), collagen alpha-4(VI) chain polypeptide (COL6-4), collagen alpha-5(VI) chain polypeptide (COL6-5), collagen alpha-6(VI) chain polypeptide (COL6-6), collagen alpha-1(VII) chain polypeptide (COL7), collagen alpha-1(VIII) chain polypeptide (COL8), collagen alpha-1(IX) chain polypeptide (COL9-1), collagen alpha-2(IX) chain polypeptide (COL9-2), collagen alpha-3(IX) chain polypeptide (COL9-3), collagen alpha-1(X) chain polypeptide (COL10), collagen alpha-1(XI) chain polypeptide (COL11-1), collagen alpha-2(XI) chain polypeptide (COL11-2), collagen alpha-1(XII) chain polypeptide (COL12), collagen alpha-1(XIII) chain polypeptide (COL13), collagen alpha-1(XIV) chain polypeptide (COL14),The collagen alpha-1(XV) chain polypeptide is selected from collagen alpha-1(XVI) chain polypeptide (COL16), collagen alpha-1(XVII) chain polypeptide (COL17), collagen alpha-1(XVIII) chain polypeptide (COL18), collagen alpha-1(XIX) chain polypeptide (COL19), collagen alpha-1(XX) chain polypeptide (COL20), collagen alpha-1(XXI) chain polypeptide (COL21), collagen alpha-1(XXII) chain polypeptide (COL22), collagen alpha-1(XXIII) chain polypeptide (COL23), collagen alpha-1(XXIV) chain polypeptide (COL24), collagen alpha-1(XXV) chain polypeptide (COL25), collagen alpha-1(XXVI) chain polypeptide (COL26), collagen alpha-1(XXVII) chain polypeptide (COL27), and collagen alpha-1(XXVIII) chain polypeptide (COL28). In some embodiments that may be combined with any of the preceding embodiments, the first human collagen protein is selected from COL1-1, COL1-2, COL3, COL4-1, COL6-1, COL7, and COL17. In some embodiments that may be combined with any of the preceding embodiments, the nucleic acid sequence encoding the first human collagen protein has at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to a nucleic acid sequence selected from SEQ ID NOs: 1-14. In some embodiments that may be combined with any of the preceding embodiments, the first human collagen protein is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%, at least 107%, at least 108%, at least 109%, at least 110%, at least 111%, at least 112%, at least 113%, at least 114%, at least 115%, at least 116%, at least 117%, at least 118%, at least 119%, at least 119%, at least 120%, at least 121%, at least 122%, at least 123%, at least 124%, at least 125%, at least 126%, at least 127%, at least 128%, at least 129%, at least 129%, at least 129%, at least 129%, at least 130%, at least 131%, at least 132%, at least 133%, at least 134%, at least 135%, at least 136%, at least 137%, at least 138%, at least 139%, at least 139%, at least 140%, at least 141%, at least 142%, at least 143%, at least 144%, at least 145%, at least 146%, at least 147%, at least 148%, at least 149%, at least 149%, at least 149%, at least 149%, at least 149%, at least 149or a sequence having 100% sequence identity. In some embodiments that may be combined with any of the preceding embodiments, the first human collagen protein is not COL7.

[0035] In some embodiments that may be combined with any of the preceding embodiments, the first polypeptide comprises (a) a first human collagen protein, (b) an additional human collagen protein, and (c) a linker polypeptide connecting (a) to (b). In some embodiments, the linker polypeptide is a cleavable linker polypeptide. In some embodiments, the linker 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 to an amino acid sequence selected from SEQ ID NOs: 28-31. In some embodiments, the additional human collagen protein is selected from COL1-1, COL1-2, COL2, COL3, COL4-1, COL4-2, COL4-3, COL4-4, COL4-5, COL4-6, COL5-1, COL5-2, COL5-3, COL6-1, COL6-2, COL6-3, COL6-4, COL6-5, COL6-6, COL7, COL8, COL9-1, COL9-2, COL9-3, COL10, COL11-1, COL11-2, COL12, COL13, COL14, COL15, COL16, COL17, COL18, COL19, COL20, COL21, COL22, COL23, COL24, COL25, COL26, COL27, and COL28. In some embodiments, the additional human collagen protein is selected from COL1-1, COL1-2, COL3, COL4-1, COL6-1, COL7, and COL17. In some embodiments, the nucleic acid sequence encoding the additional human collagen protein has at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to a nucleic acid sequence selected from SEQ ID NOs: 1-14.In some embodiments, the additional human collagen protein 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 to an amino acid sequence selected from SEQ ID NOs: 15-21. In some embodiments, the first human collagen protein and the additional human collagen protein are different.

[0036] In some embodiments that may be combined with any of the preceding embodiments, the first polynucleotide encodes a polycistronic mRNA that includes (a) a first open reading frame (ORF) encoding a first polypeptide, (b) a second ORF encoding an additional human collagen protein, and (c) an internal ribosome entry site (IRES) separating (a) and (b). In some embodiments, the nucleic acid sequence encoding the IRES has at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to a nucleic acid sequence selected from SEQ ID NO:22 or SEQ ID NO:23. In some embodiments, the additional human collagen protein is selected from COL1-1, COL1-2, COL2, COL3, COL4-1, COL4-2, COL4-3, COL4-4, COL4-5, COL4-6, COL5-1, COL5-2, COL5-3, COL6-1, COL6-2, COL6-3, COL6-4, COL6-5, COL6-6, COL7, COL8, COL9-1, COL9-2, COL9-3, COL10, COL11-1, COL11-2, COL12, COL13, COL14, COL15, COL16, COL17, COL18, COL19, COL20, COL21, COL22, COL23, COL24, COL25, COL26, COL27, and COL28. In some embodiments, the additional human collagen protein is selected from COL1-1, COL1-2, COL3, COL4-1, COL6-1, COL7, and COL17. In some embodiments, the nucleic acid sequence encoding the additional human collagen protein has at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to a nucleic acid sequence selected from SEQ ID NOs: 1-14.In some embodiments, the additional human collagen protein 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 to an amino acid sequence selected from SEQ ID NOs: 15-21. In some embodiments, the first human collagen protein and the additional human collagen protein are different.

[0037] In some embodiments that may be combined with any of the preceding embodiments, the recombinant nucleic acid further comprises a second polynucleotide encoding a second human collagen protein. In some embodiments, the recombinant nucleic acid comprises two or more copies of the second polynucleotide. In some embodiments, the second human collagen protein is selected from COL1-1, COL1-2, COL2, COL3, COL4-1, COL4-2, COL4-3, COL4-4, COL4-5, COL4-6, COL5-1, COL5-2, COL5-3, COL6-1, COL6-2, COL6-3, COL6-4, COL6-5, COL6-6, COL7, COL8, COL9-1, COL9-2, COL9-3, COL10, COL11-1, COL11-2, COL12, COL13, COL14, COL15, COL16, COL17, COL18, COL19, COL20, COL21, COL22, COL23, COL24, COL25, COL26, COL27, and COL28. In some embodiments, the second human collagen protein is selected from COL1-1, COL1-2, COL3, COL4-1, COL6-1, COL7, and COL17. In some embodiments, the nucleic acid sequence encoding the second human collagen protein has at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to a nucleic acid sequence selected from SEQ ID NOs: 1-14. In some embodiments, the second human collagen protein 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 to an amino acid sequence selected from SEQ ID NOs: 15-21. In some embodiments, the first human collagen protein and the second human collagen protein are different.

[0038] In some embodiments that may be combined with any of the preceding embodiments, the recombinant nucleic acid is a recombinant herpes simplex virus genome, and the recombinant herpes simplex virus genome comprises a second polynucleotide within a viral locus. In some embodiments, the recombinant herpes simplex virus genome comprises the second polynucleotide within one or both copies of the ICP4 viral locus. In some embodiments, the recombinant herpes simplex virus genome comprises the second polynucleotide within the ICP22 viral locus. In some embodiments, the recombinant herpes simplex virus genome comprises the second polynucleotide within the UL41 viral locus. In some embodiments, the recombinant herpes simplex virus genome comprises the first polynucleotide within one or both copies of the ICP4 viral locus and the second polynucleotide within the ICP22 viral locus. In some embodiments, the recombinant herpes simplex virus genome comprises the first polynucleotide within one or both copies of the ICP4 viral locus and the second polynucleotide within the UL41 viral locus.

[0039] In some embodiments that may be combined with any of the preceding embodiments, the excipient is adapted for dermal (systemic or topical), transdermal, subcutaneous, and / or intradermal administration. In some embodiments that may be combined with any of the preceding embodiments, the excipient comprises hydroxypropyl methylcellulose gel. In some embodiments that may be combined with any of the preceding embodiments, the excipient is adapted for intradermal administration. In some embodiments that may be combined with any of the preceding embodiments, the excipient comprises a phosphate buffer. In some embodiments that may be combined with any of the preceding embodiments, the excipient comprises glycerol. In some embodiments that may be combined with any of the preceding embodiments, the excipient comprises a lipid carrier. In some embodiments that may be combined with any of the preceding embodiments, the excipient comprises a nanoparticle carrier.

[0040] In some embodiments that may be combined with any of the preceding embodiments, the composition is a cosmetic composition. In some embodiments, the cosmetic composition is a skin care product.

[0041] Another aspect of the present disclosure relates to a kit comprising any of the compositions described herein and instructions for administering the composition.

[0042] Another aspect of the present disclosure relates to a method of enhancing, increasing, potentiating, and / or replenishing levels of one or more human collagen proteins in a subject, comprising administering to the subject an effective amount of any of the compositions described herein.

[0043] Another aspect of the present disclosure relates to methods of strengthening, augmenting, enhancing, and / or replenishing soft tissue in a subject, comprising administering to the subject an effective amount of any of the compositions described herein, hi some embodiments, the composition is injected into the subject's soft tissue.

[0044] Another aspect of the present disclosure relates to a method of improving the quality, condition, and / or appearance of skin in a subject in need thereof, comprising administering to the subject an effective amount of any of the compositions described herein, in some embodiments, the condition is selected from sun damage, aging, UV exposure, coarse texture, sagging skin, wrinkles, and any combination thereof.

[0045] Another aspect of the present disclosure relates to a method for reducing the appearance of one or more surface depressions in the skin of a subject in need thereof, the method comprising administering to the subject an effective amount of any of the compositions described herein. In some embodiments, administration of the composition reduces the appearance of one or more surface depressions in the subject's skin for at least about 3 months, at least about 6 months, at least about 9 months, or at least about 12 months. In some embodiments, the appearance of one or more surface depressions in the subject's skin is reduced after administration of the composition compared to the appearance of one or more surface depressions in the subject's skin before administration of the composition.

[0046] Another aspect of the present disclosure relates to a method of increasing and / or improving at least one of the texture, smoothness, elasticity, or firmness of the skin of a subject in need thereof, the method comprising administering to the subject an effective amount of any of the compositions described herein. In some embodiments, the subject's skin maintains the increased and / or improved at least one of the texture, smoothness, elasticity, or firmness for at least about 3 months, at least about 6 months, at least about 9 months, or at least about 12 months after administration of the composition. In some embodiments, at least one of the texture, smoothness, elasticity, or firmness of the subject's skin is increased and / or improved after administration of the composition compared to the texture, smoothness, elasticity, or firmness of the subject's skin before administration of the composition.

[0047] In some embodiments that may be combined with any of the preceding embodiments, the subject's skin is aging skin. In some embodiments that may be combined with any of the preceding embodiments, the subject's skin has been damaged by exposure to ultraviolet light. In some embodiments that may be combined with any of the preceding embodiments, the subject's skin is wrinkled.

[0048] Another aspect of the present disclosure relates to a method of reducing one or more signs of dermatological aging in a subject in need thereof, comprising administering to the subject an effective amount of any of the compositions described herein. In some embodiments, the reduction of one or more signs of dermatological aging includes (a) treating, reducing, and / or preventing fine lines and / or wrinkles, (b) reducing pore size in the skin, (c) improving skin thickness, plumpness, and / or firmness, (d) improving skin smoothness, suppleness, and / or softness, (e) improving skin tone, radiance, and / or clarity, (f) improving procollagen and / or collagen production, (g) improving skin texture and / or promoting re-texturing, (h) improving the appearance of skin contours, (i) restoring skin radiance and / or brightness, (j) improving skin appearance diminished by aging and / or menopause, (k) improving skin moisturization, (l) increasing skin elasticity and / or firmness, (m) treating, reducing, and / or preventing or correcting sagging skin, (n) improving skin firmness, (o) reducing pigmented spots, mottled skin, and / or acne scars, (p) improving the optical properties of the skin through light diffraction or reflection, and (q) any combination thereof. In some embodiments, one or more dermatological signs of aging in the subject are alleviated after administration of the composition compared to one or more dermatological signs of aging in the subject before administration of the composition.

[0049] In some embodiments that may be combined with any of the preceding embodiments, the subject is a human. In some embodiments that may be combined with any of the preceding embodiments, the composition is administered to the subject dermally (systemically or topically), transdermally, subcutaneously, or intradermally. In some embodiments, the composition is administered by topical injection. In some embodiments, the composition is administered to the subject intradermally. In some embodiments, the composition is administered to the subject once. In some embodiments, the composition is administered to the subject at least twice. In some embodiments, at least about 15 days, at least about 30 days, at least about 60 days, at least about 90 days, or at least about 120 days elapse between administrations. In some embodiments that may be combined with any of the preceding embodiments, the composition is administered to one or more affected and / or unaffected areas of the subject. In some embodiments that may be combined with any of the preceding embodiments, the skin is abraded prior to administration.

[0050] Another aspect of the present disclosure relates to a recombinant nucleic acid comprising a first polynucleotide encoding a first polypeptide comprising a first human collagen protein, wherein the recombinant nucleic acid is a recombinant herpes simplex virus genome. In some embodiments, the recombinant nucleic acid comprises two or more copies of the first polynucleotide. In some embodiments, the recombinant herpes simplex virus genome is a recombinant HSV-1 genome, a recombinant HSV-2 genome, or any derivative thereof.

[0051] In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in a herpes simplex virus gene. In some embodiments, the herpes simplex virus gene is selected from the group consisting of infected cell protein (ICP)0, ICP4, ICP22, ICP27, ICP47, thymidine kinase (tk), long unique region (UL)41, and UL55. In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in one or both copies of the ICP4 gene. In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP22 gene. In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the UL41 gene. In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP0 gene. In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP27 gene. In some embodiments that may be combined with any of the preceding embodiments, the inactivating mutation is a deletion of the coding sequence of the gene(s).

[0052] In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpes simplex virus genome comprises a first polynucleotide within a viral locus. In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpes simplex virus genome comprises a first polynucleotide within one or both copies of the ICP4 viral locus. In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpes simplex virus genome comprises a first polynucleotide within the ICP22 viral locus. In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpes simplex virus genome comprises a first polynucleotide within the UL41 viral locus. In some embodiments that may be combined with any of the preceding embodiments, the HSV has reduced cytotoxicity compared to wild-type herpes simplex virus.

[0053] In some embodiments that may be combined with any of the preceding embodiments, the first human collagen protein is selected from COL1-1, COL1-2, COL2, COL3, COL4-1, COL4-2, COL4-3, COL4-4, COL4-5, COL4-6, COL5-1, COL5-2, COL5-3, COL6-1, COL6-2, COL6-3, COL6-4, COL6-5, COL6-6, COL7, COL8, COL9-1, COL9-2, COL9-3, COL10, COL11-1, COL11-2, COL12, COL13, COL14, COL15, COL16, COL17, COL18, COL19, COL20, COL21, COL22, COL23, COL24, COL25, COL26, COL27, and COL2. In some embodiments that may be combined with any of the preceding embodiments, the first human collagen protein is selected from COL1-1, COL1-2, COL3, COL4-1, COL6-1, COL7, and COL17. In some embodiments that may be combined with any of the preceding embodiments, the nucleic acid sequence encoding the first human collagen protein has at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to a nucleic acid sequence selected from SEQ ID NOs: 1-14. In some embodiments that may be combined with any of the preceding embodiments, the first human collagen protein 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 to an amino acid sequence selected from SEQ ID NOs: 15-21. In some embodiments that may be combined with any of the preceding embodiments, the first human collagen protein is not COL7.

[0054] In some embodiments that may be combined with any of the preceding embodiments, the first polypeptide comprises (a) a first human collagen protein, (b) an additional human collagen protein, and (c) a linker polypeptide connecting (a) to (b). In some embodiments, the linker polypeptide is a cleavable linker polypeptide. In some embodiments, the linker 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 to an amino acid sequence selected from SEQ ID NOs: 28-31. In some embodiments, the additional human collagen protein is selected from COL1-1, COL1-2, COL2, COL3, COL4-1, COL4-2, COL4-3, COL4-4, COL4-5, COL4-6, COL5-1, COL5-2, COL5-3, COL6-1, COL6-2, COL6-3, COL6-4, COL6-5, COL6-6, COL7, COL8, COL9-1, COL9-2, COL9-3, COL10, COL11-1, COL11-2, COL12, COL13, COL14, COL15, COL16, COL17, COL18, COL19, COL20, COL21, COL22, COL23, COL24, COL25, COL26, COL27, and COL28. In some embodiments, the additional human collagen protein is selected from COL1-1, COL1-2, COL3, COL4-1, COL6-1, COL7, and COL17. In some embodiments, the nucleic acid sequence encoding the additional human collagen protein has at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to a nucleic acid sequence selected from SEQ ID NOs: 1-14.In some embodiments, the additional human collagen protein 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 to an amino acid sequence selected from SEQ ID NOs: 15-21. In some embodiments, the first human collagen protein and the additional human collagen protein are different.

[0055] In some embodiments that may be combined with any of the preceding embodiments, the first polynucleotide encodes a polycistronic mRNA that includes (a) a first open reading frame (ORF) encoding a first polypeptide, (b) a second ORF encoding an additional human collagen protein, and (c) an internal ribosome entry site (IRES) separating (a) and (b). In some embodiments, the nucleic acid sequence encoding the IRES has at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to a nucleic acid sequence selected from SEQ ID NO:22 or SEQ ID NO:23. In some embodiments, the additional human collagen protein is selected from COL1-1, COL1-2, COL2, COL3, COL4-1, COL4-2, COL4-3, COL4-4, COL4-5, COL4-6, COL5-1, COL5-2, COL5-3, COL6-1, COL6-2, COL6-3, COL6-4, COL6-5, COL6-6, COL7, COL8, COL9-1, COL9-2, COL9-3, COL10, COL11-1, COL11-2, COL12, COL13, COL14, COL15, COL16, COL17, COL18, COL19, COL20, COL21, COL22, COL23, COL24, COL25, COL26, COL27, and COL28. In some embodiments, the additional human collagen protein is selected from COL1-1, COL1-2, COL3, COL4-1, COL6-1, COL7, and COL17. In some embodiments, the nucleic acid sequence encoding the additional human collagen protein has at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to a nucleic acid sequence selected from SEQ ID NOs: 1-14.In some embodiments, the additional human collagen protein 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 to an amino acid sequence selected from SEQ ID NOs: 15-21. In some embodiments, the first human collagen protein and the additional human collagen protein are different.

[0056] In some embodiments that may be combined with any of the preceding embodiments, the recombinant nucleic acid further comprises a second polynucleotide encoding a second human collagen protein. In some embodiments, the recombinant nucleic acid comprises two or more copies of the second polynucleotide. In some embodiments, the second human collagen protein is selected from COL1-1, COL1-2, COL2, COL3, COL4-1, COL4-2, COL4-3, COL4-4, COL4-5, COL4-6, COL5-1, COL5-2, COL5-3, COL6-1, COL6-2, COL6-3, COL6-4, COL6-5, COL6-6, COL7, COL8, COL9-1, COL9-2, COL9-3, COL10, COL11-1, COL11-2, COL12, COL13, COL14, COL15, COL16, COL17, COL18, COL19, COL20, COL21, COL22, COL23, COL24, COL25, COL26, COL27, and COL28. In some embodiments, the second human collagen protein is selected from COL1-1, COL1-2, COL3, COL4-1, COL6-1, COL7, and COL17. In some embodiments, the nucleic acid sequence encoding the second human collagen protein has at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to a nucleic acid sequence selected from SEQ ID NOs: 1-14. In some embodiments, the second human collagen protein 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 to an amino acid sequence selected from SEQ ID NOs: 15-21. In some embodiments, the first human collagen protein and the second human collagen protein are different.

[0057] In some embodiments that may be combined with any of the preceding embodiments, the recombinant herpes simplex virus genome comprises a second polynucleotide within a viral locus. In some embodiments, the recombinant herpes simplex virus genome comprises a second polynucleotide within one or both copies of the ICP4 viral locus. In some embodiments, the recombinant herpes simplex virus genome comprises a second polynucleotide within the ICP22 viral locus. In some embodiments, the recombinant herpes simplex virus genome comprises a second polynucleotide within the UL41 viral locus. In some embodiments, the recombinant herpes simplex virus genome comprises a first polynucleotide within one or both copies of the ICP4 viral locus and a second polynucleotide within the ICP22 viral locus. In some embodiments, the recombinant herpes simplex virus genome comprises a first polynucleotide within one or both copies of the ICP4 viral locus and a second polynucleotide within the UL41 viral locus.

[0058] Another aspect of the present disclosure relates to a host cell comprising any of the recombinant nucleic acids described herein. In some embodiments, the host cell is a eukaryotic cell. In some embodiments, the host cell is a mammalian cell. In some embodiments, the host cell is a human cell or a non-human primate cell. In some embodiments, the host cell is a Vero cell. In some embodiments, the host cell is a complementing host cell.

[0059] Another aspect of the present disclosure relates to a method of harvesting a herpes simplex virus, the method comprising: (a) contacting a complementing host cell with any of the recombinant nucleic acids described herein; and (b) harvesting the herpes simplex virus produced by the complementing host cell.

[0060] Another aspect of the present disclosure relates to a method for harvesting a herpes simplex virus, the method comprising: (a) culturing a host cell containing any of the recombinant nucleic acids described herein; and (b) harvesting the herpes simplex virus produced by the host cell. [The present invention 1001] A recombinant herpesvirus genome comprising a first polynucleotide encoding a first polypeptide comprising a first cosmetic protein. [The present invention 1002] 1001. A recombinant herpesvirus genome of the present invention, comprising two or more copies of said first polynucleotide. [The present invention 1003] A replication-competent recombinant herpesvirus genome of the present invention 1001 or 1002. [The present invention 1004] The recombinant herpesvirus genome of invention 1001 or invention 1002, which is replication-deficient. [The present invention 1005] A recombinant herpesvirus genome according to any one of claims 1001 to 1004 of the present invention, selected from the group consisting of a recombinant herpes simplex virus genome, a recombinant varicella-zoster virus genome, a recombinant human cytomegalovirus genome, a recombinant herpesvirus 6A genome, a recombinant herpesvirus 6B genome, a recombinant herpesvirus 7 genome, a recombinant Kaposi's sarcoma-associated herpesvirus genome, and any derivative thereof. [The present invention 1006] The recombinant herpesvirus genome of any one of 1001 to 1005 of the present invention, which is a recombinant herpes simplex virus genome. [The present invention 1007] 1006. The recombinant herpesvirus genome of the present invention, wherein said 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. [The present invention 1008] The recombinant herpesvirus genome of invention 1006 or invention 1007, wherein the recombinant herpes simplex virus genome is a recombinant herpes simplex virus type 1 (HSV-1) genome. [The present invention 1009] The recombinant herpesvirus genome of any one of 1006 to 1008, wherein the recombinant herpes simplex virus genome comprises an inactivating mutation. [The present invention 1010] 1009. The recombinant herpesvirus genome of the present invention, wherein the inactivating mutation is present in a herpes simplex virus gene. [The present invention 1011] 10. The recombinant herpesvirus genome of the present invention, wherein the inactivating mutation is a deletion in the coding sequence of the herpes simplex virus gene. [The present invention 1012] The recombinant herpesvirus genome of the present invention 1010 or 1011, wherein the herpes simplex virus gene is selected from the group consisting of infected cell protein (ICP) 0, ICP4, ICP22, ICP27, ICP47, thymidine kinase (tk), long unique region (UL) 41, and UL55. [The present invention 1013] 1012. The recombinant herpes simplex virus genome of the present invention, wherein said recombinant herpes simplex virus genome comprises an inactivating mutation in one or both copies of the ICP4 gene. [The present invention 1014] The recombinant herpesvirus genome of invention 1012 or 1013, wherein the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP22 gene. [The present invention 1015] The recombinant herpesvirus genome of any one of 1012 to 1014 of the present invention, wherein the recombinant herpes simplex virus genome comprises an inactivating mutation in the UL41 gene. [The present invention 1016] 10. The recombinant herpes simplex virus genome of any one of claims 1012 to 1015, wherein the recombinant herpes simplex virus genome comprises an inactivating mutation in one or both copies of the ICP0 gene. [The present invention 1017] The recombinant herpesvirus genome of any one of 1012 to 1016 of the present invention, wherein the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP27 gene. [The present invention 1018] 10. The recombinant herpes simplex virus genome of any one of claims 1006 to 1017, wherein the recombinant herpes simplex virus genome comprises the first polynucleotide within one or both of the ICP4 viral loci. [The present invention 1019] A recombinant herpesvirus genome of any of claims 1001 to 1018, wherein the first cosmetic protein is selected from the group consisting of a first collagen protein, a first fibronectin protein, a first elastin protein, a first lumican protein, a first vitronectin protein, a first vitronectin receptor protein, a first laminin protein, a first neuromodulatory protein, and a first fibrillin protein. [The present invention 1020] A recombinant herpesvirus genome of any of the present inventions 1001 to 1019, wherein the first cosmetic protein 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 to an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 to 21 and 53 to 64. [The present invention 1021] The recombinant herpesvirus genome of any one of claims 1001 to 1020, wherein the first cosmetic protein is a structural extracellular matrix protein. [The present invention 1022] The recombinant herpesvirus genome of any one of claims 1019 to 1021, wherein the first collagen protein is a human collagen protein. [The present invention 1023] The first collagen protein is selected from the group consisting of collagen alpha-1(I) chain polypeptide (COL1-1), collagen alpha-2(I) chain polypeptide (COL1-2), collagen alpha-1(II) chain polypeptide (COL2), collagen alpha-1(III) chain polypeptide (COL3), collagen alpha-1(IV) chain polypeptide (COL4-1), collagen alpha-2(IV) chain polypeptide (COL4-2), collagen alpha-3(IV) chain polypeptide (COL4-3), collagen alpha-4(I) Collagen alpha-V) chain polypeptide (COL4-4), collagen alpha-5(IV) chain polypeptide (COL4-5), collagen alpha-6(IV) chain polypeptide (COL4-6), collagen alpha-1(V) chain polypeptide (COL5-1), collagen alpha-2(V) chain polypeptide (COL5-2), collagen alpha-3(V) chain polypeptide (COL5-3), collagen alpha-1(VI) chain polypeptide (COL6-1), collagen alpha-2(VI) chain polypeptide (COL6-2), collagen alpha-3 (VI) chain polypeptide (COL6-3), collagen alpha-4 (VI) chain polypeptide (COL6-4), collagen alpha-5 (VI) chain polypeptide (COL6-5), collagen alpha-6 (VI) chain polypeptide (COL6-6), collagen alpha-1 (VIII) chain polypeptide (COL8), collagen alpha-1 (IX) chain polypeptide (COL9-1), collagen alpha-2 (IX) chain polypeptide (COL9-2), collagen alpha-3 (IX) chain polypeptide (COL9-3), collagen Alpha-1(X) chain polypeptide (COL10), collagen alpha-1(XI) chain polypeptide (COL11-1), collagen alpha-2(XI) chain polypeptide (COL11-2), collagen alpha-1(XII) chain polypeptide (COL12), collagen alpha-1(XIII) chain polypeptide (COL13), collagen alpha-1(XIV) chain polypeptide (COL14), collagen alpha-1(XV) chain polypeptide (COL15), collagen alpha-1(XVI) chain polypeptide (COL16),The recombinant herpesvirus genome of any one of claims 1019 to 1022, wherein the recombinant herpesvirus genome is selected from the group consisting of collagen alpha-1(XVII) chain polypeptide (COL17), collagen alpha-1(XVIII) chain polypeptide (COL18), collagen alpha-1(XIX) chain polypeptide (COL19), collagen alpha-1(XX) chain polypeptide (COL20), collagen alpha-1(XXI) chain polypeptide (COL21), collagen alpha-1(XXII) chain polypeptide (COL22), collagen alpha-1(XXIII) chain polypeptide (COL23), collagen alpha-1(XXIV) chain polypeptide (COL24), collagen alpha-1(XXV) chain polypeptide (COL25), collagen alpha-1(XXVI) chain polypeptide (COL26), collagen alpha-1(XXVII) chain polypeptide (COL27), and collagen alpha-1(XXVIII) chain polypeptide (COL28). [The present invention 1024] The recombinant herpesvirus genome of any one of claims 1019 to 1023, wherein the first collagen protein is selected from the group consisting of COL1-1, COL1-2, COL3, COL4-1, COL4-2, COL6-1, and COL17. [The present invention 1025] The recombinant herpesvirus genome of any of claims 1019 to 1024, wherein the first human collagen protein 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 to the amino acid sequence of SEQ ID NO: 17. [The present invention 1026] The recombinant herpesvirus genome of any one of claims 1001 to 1025, wherein the first cosmetic protein is not collagen alpha-1(VII) chain polypeptide (COL7). [The present invention 1027] The recombinant herpesvirus genome of any one of claims 1001 to 1026, wherein said first polypeptide consists essentially of said first cosmetic protein or consists of said first cosmetic protein. [The present invention 1028] the first polypeptide is (a) the first cosmetic protein; (b) further cosmetic proteins, and (c) a linker polypeptide connecting (a) to (b). A recombinant herpesvirus genome according to any one of claims 1001 to 1026 of the present invention, comprising: [The present invention 1029] 1028. The recombinant herpesvirus genome of the present invention, wherein the linker polypeptide is a cleavable linker polypeptide. [The present invention 1030] The recombinant herpesvirus genome of the present invention 1028 or 1029, wherein the linker 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 to an amino acid sequence selected from the group consisting of SEQ ID NOs: 28 to 31. [The present invention 1031] The recombinant herpesvirus genome of any one of claims 1028 to 1030, wherein the first cosmetic protein and the further cosmetic protein are different. [The present invention 1032] the first polynucleotide is (a) a first open reading frame (ORF) encoding said first polypeptide; (b) a second ORF encoding an additional cosmetic protein; and (c) Internal ribosome entry site (IRES) separating (a) and (b). A recombinant herpesvirus genome according to any one of claims 1001 to 1031, which encodes a polycistronic mRNA comprising the above. [The present invention 1033] The recombinant herpesvirus genome of the present invention 1032, wherein the nucleic acid sequence encoding the IRES has at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to a nucleic acid sequence selected from SEQ ID NO:22 or SEQ ID NO:23. [The present invention 1034] The recombinant herpesvirus genome of invention 1032 or invention 1033, wherein the first cosmetic protein and the additional cosmetic protein are different. [This invention 1035] The recombinant herpesvirus genome of any one of claims 1001 to 1034, further comprising a second polynucleotide encoding a second cosmetic protein. [The present invention 1036] 1035. The recombinant herpesvirus genome of the present invention, wherein the first cosmetic protein and the second cosmetic protein are different. [This invention 1037] A recombinant herpesvirus genome according to any one of claims 1001 to 1036, which, when introduced into a target cell, has reduced cytotoxicity compared to the corresponding wild-type herpesvirus genome. [The present invention 1038] The recombinant herpesvirus genome of the present invention 1037, wherein the target cells are epidermal cells and / or dermal cells. [This invention 1039] The recombinant herpesvirus genome of the present invention 1037 or 1038, wherein the target cell is a human cell. [The present invention 1040] The recombinant herpesvirus genome of any one of claims 1037 to 1039, wherein the target cell is a fibroblast. [The present invention 1041] A herpesvirus comprising the recombinant herpesvirus genome of any one of 1001 to 1040 of the present invention. [The present invention 1042] 1041. A herpesvirus of the present invention having replication ability. [This invention 1043] 1041. A herpesvirus of the present invention that is replication-deficient. [This invention 1044] The herpesvirus of any of the present inventions 1041 to 1043, which has reduced cytotoxicity compared to the corresponding wild-type herpesvirus. [This invention 1045] Any of the herpesviruses of the present invention 1041 to 1044, which is 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. [The present invention 1046] The herpesvirus of any one of claims 1041 to 1045 of the present invention, which is a herpes simplex virus. [This invention 1047] The herpesvirus of the present invention 1046, wherein the herpes simplex virus is herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), or any derivative thereof. [This invention 1048] (a) a recombinant herpesvirus genome of any one of the present inventions 1001 to 1040 or a herpesvirus of any one of the present inventions 1041 to 1047, (b) excipients and A composition comprising: [This invention 1049] The composition of the present invention 1048, which is sterile. [The present invention 1050] A composition of invention 1048 or invention 1049 suitable for topical, transdermal, subcutaneous, intradermal, oral, intranasal, intratracheal, sublingual, buccal, rectal, intravaginal, urethral, ​​inhalation, intravenous, intraarterial, intramuscular, intracardiac, intraosseous, intraperitoneal, transmucosal, intravitreal, subretinal, intraarticular, periarticular, local, or epicutaneous administration. [This invention 1051] Any of the compositions of 1048 to 1050 of the present invention, which is suitable for intradermal administration. [This invention 1052] 1048-1051. Any of the compositions of inventions 1048-1051, which is suitable for topical injection. [This invention 1053] Any one of the compositions of inventions 1048 to 1052, which is a cosmetic composition. [This invention 1054] The composition of any one of claims 1048 to 1053, which is a skin care product. [This invention 1055] A herpesvirus according to any one of claims 1041 to 1047 or a composition according to any one of claims 1048 to 1054 for use as a medicament. [This invention 1056] A herpesvirus according to any one of claims 1041 to 1047 or a composition according to any one of claims 1048 to 1054 for use in therapy. [This invention 1057] Use of any of the herpesviruses of inventions 1041 to 1047 or any of the compositions of inventions 1048 to 1054 in the manufacture of a medicament for treating one or more signs or symptoms of dermatological aging. [This invention 1058] A method for enhancing, increasing, potentiating, and / or replenishing the levels of one or more skin extracellular matrix proteins in a subject, the method comprising administering to the subject an effective amount of any of the herpesviruses of inventions 1041 to 1047 or any of the compositions of inventions 1048 to 1054. [This invention 1059] A method for strengthening, increasing, enhancing, and / or replenishing the level of one or more collagen proteins in a subject, the method comprising administering to the subject an effective amount of any of the herpesviruses of inventions 1041 to 1047 or any of the compositions of inventions 1048 to 1054. [The present invention 1060] A method for strengthening, increasing, enhancing, and / or replenishing soft tissue in a subject, the method comprising administering to the subject an effective amount of any of the herpesviruses of the present inventions 1041 to 1047 or any of the compositions of the present inventions 1048 to 1054. [This invention 1061] The method of claim 1060, wherein said composition is injected into the soft tissue of said subject. [This invention 1062] A method for improving the condition, quality, and / or appearance of skin in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the herpesviruses of the present inventions 1041 to 1047 or any of the compositions of the present inventions 1048 to 1054. [This invention 1063] The method of claim 1062, wherein said composition is administered to one or more sites of sun damage or other UV exposure, rough texture, sagging skin, wrinkles, or any combination thereof. [This invention 1064] A method for reducing the appearance of one or more surface depressions in the skin of a subject in need thereof, said method comprising administering to said subject an effective amount of any of the herpesviruses of inventions 1041 to 1047 or any of the compositions of inventions 1048 to 1054. [This invention 1065] 1064. The method of claim 1064, wherein said one or more surface depressions in said skin are selected from the group consisting of nasolabial folds, crow's feet, glabellar lines, forehead wrinkles, scars, glabellar lines, brow ptosis, tear troughs, nasojugal lines, bunny lines, cheek / midface ptosis, marionette lines, poppy dimplings, laugh lines, laugh lines, chin folds, neck wrinkles, platysma bands, and any combination thereof. [The present invention 1066] A method for increasing and / or improving at least one of the texture, smoothness, elasticity, or firmness of the skin of a subject in need of such an increase and / or improvement, the method comprising administering to the subject an effective amount of any of the herpesviruses of inventions 1041 to 1047 or any of the compositions of inventions 1048 to 1054. [This invention 1067] Any of the methods of claims 1062 to 1066, wherein the skin of the subject is aging skin. [The present invention 1068] 8. The method of any one of claims 1062 to 1067, wherein the subject's skin is damaged by exposure to ultraviolet light. [The present invention 1069] 1068. The method of any one of claims 1062 to 1068, wherein the subject's skin is wrinkled. [The present invention 1070] A method for reducing one or more signs of dermatological aging in a subject in need thereof, comprising administering to the subject an effective amount of any of the herpesviruses of inventions 1041 to 1047 or any of the compositions of inventions 1048 to 1054. [This invention 1071] (c) improving skin thickness, plumpness, and / or firmness; (d) improving skin smoothness, suppleness, and / or softness; (e) improving skin tone, radiance, and / or clarity; (f) improving procollagen and / or collagen production; (g) improving skin texture and / or promoting retexturization; (h) improving the appearance of dermatological aging; (i) improving the appearance of dermatological aging; (j) improving the appearance of dermatological aging; (k ... (h) improving the appearance of skin contours, (i) restoring skin radiance and / or brightness, (j) improving skin appearance diminished by aging and / or menopause, (k) improving skin moisturization, (l) increasing skin elasticity and / or firmness, (m) treating, reducing, and / or preventing or reducing skin laxity, (n) improving skin firmness, (o) reducing pigmented spots, mottled skin, and / or scarring, (p) improving the optical properties of the skin due to light diffraction or reflection, or (q) any combination thereof. [This invention 1072] The method of any one of claims 1058 to 1071, wherein the subject is a human. [This invention 1073] 1073. The method of any of claims 1058 to 1072, wherein the herpesvirus or composition is administered to the subject topically, transdermally, subcutaneously, epicutaneously, intradermally, orally, sublingually, bucally, rectally, vaginally, intraurethrally, intravenously, intraarterially, intramuscularly, intraosseously, intracardially, intraperitoneally, transmucosally, intravitreally, subretinaly, intraarticularly, periarticularly, locally, or via inhalation. [This invention 1074] The method of any of claims 1058 to 1073, wherein the herpesvirus or the composition is administered intradermally to the subject. [This invention 1075] 1075. The method of any one of claims 1058 to 1074, wherein said herpesvirus or said composition is administered by topical injection. [Brief explanation of the drawings]

[0061] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0062] [Figure 1-1] 1A-N show schematic diagrams of wild-type and modified herpes simplex virus genomes: Figure 1A shows the wild-type herpes simplex virus genome. [Figure 1-2] Figures 1A-N show schematic diagrams of wild-type and modified herpes simplex virus genomes. Figure 1B shows a modified herpes simplex virus genome containing deletions of the coding sequences for ICP4 (both copies) and ICP22, where a polynucleotide comprising the coding sequence for a first human collagen polypeptide operably linked to a heterologous promoter has been integrated into each of the ICP4 loci. Figure 1C shows a modified herpes simplex virus genome containing deletions of the coding sequence for ICP4 (both copies), where a polynucleotide comprising the coding sequence for a first human collagen polypeptide operably linked to a heterologous promoter has been integrated into each of the ICP4 loci. [Figure 1-3]Figures 1A-N show schematic diagrams of wild-type and modified herpes simplex virus genomes. Figure 1D shows a modified herpes simplex virus genome containing deletions of the coding sequences for ICP4 (both copies) and ICP22, where each ICP4 locus contains a polynucleotide comprising (1) a coding sequence for a first human collagen polypeptide operably linked to a first heterologous promoter and (2) a coding sequence for a second human collagen polypeptide operably linked to a second heterologous promoter. Both the first and second human collagen polypeptides are encoded on the same strand of DNA. Figure 1E shows a modified herpes simplex virus genome containing deletions of the coding sequence for ICP4 (both copies), where each ICP4 locus contains a polynucleotide comprising (1) a coding sequence for a first human collagen polypeptide operably linked to a first heterologous promoter and (2) a coding sequence for a second human collagen polypeptide operably linked to a second heterologous promoter. Both the first and second human collagen polypeptides are encoded on the same strand of DNA. [Figure 1-4]Figures 1A-N show schematic diagrams of wild-type and modified herpes simplex virus genomes. Figure 1F shows a modified herpes simplex virus genome containing deletions of the coding sequences for ICP4 (both copies) and ICP22, where each ICP4 locus contains a polynucleotide comprising (1) a coding sequence for a first human collagen polypeptide operably linked to a first heterologous promoter and (2) a coding sequence for a second human collagen polypeptide operably linked to a second heterologous promoter. The first and second human collagen polypeptides are encoded on opposite strands of DNA. Figure 1G shows a modified herpes simplex virus genome containing deletions of the coding sequence for ICP4 (both copies), where each ICP4 locus contains a polynucleotide comprising (1) a coding sequence for a first human collagen polypeptide operably linked to a first heterologous promoter and (2) a coding sequence for a second human collagen polypeptide operably linked to a second heterologous promoter. The first human collagen polypeptide and the second human collagen polypeptide are encoded on opposite strands of DNA. [Figure 1-5] Figures 1A-N show schematic diagrams of wild-type and modified herpes simplex virus genomes. Figure 1H shows a modified herpes simplex virus genome containing deletions of the coding sequences for ICP4 (both copies) and ICP22, where a polynucleotide encoding a polycistronic mRNA operably linked to a heterologous promoter has been integrated into each of the ICP4 loci. The polycistronic mRNA contains coding sequences for a first human collagen polypeptide and a second human collagen polypeptide separated by an internal ribosome entry site (IRES). Figure 1I shows a modified herpes simplex virus genome containing deletions of the coding sequence for ICP4 (both copies), where a polynucleotide encoding a polycistronic mRNA operably linked to a heterologous promoter has been integrated into each of the ICP4 loci. The polycistronic mRNA contains coding sequences for a first human collagen polypeptide and a second human collagen polypeptide separated by an internal ribosome entry site (IRES). [Figure 1-6] Figures 1A-N show schematic diagrams of wild-type and modified herpes simplex virus genomes. Figure 1J shows a modified herpes simplex virus genome containing deletions of the coding sequences for ICP4 (both copies) and ICP22, where a polynucleotide comprising the coding sequence for a chimeric polypeptide operably linked to a heterologous promoter has been integrated into each of the ICP4 loci. The chimeric polypeptides comprise the amino acid sequences of a first human collagen polypeptide and a second human collagen polypeptide, separated by a cleavable linker. Figure 1K shows a modified herpes simplex virus genome containing deletions of the coding sequence for ICP4 (both copies), where a polynucleotide comprising the coding sequence for a chimeric polypeptide operably linked to a heterologous promoter has been integrated into each of the ICP4 loci. The chimeric polypeptides comprise the amino acid sequences of a first human collagen polypeptide and a second human collagen polypeptide, separated by a cleavable linker. [Figure 1-7] Figures 1A-N show schematic diagrams of wild-type and modified herpes simplex virus genomes. Figure 1L shows a modified herpes simplex virus genome containing deletions of the coding sequences for ICP4 (both copies) and ICP22, in which a first polynucleotide comprising the coding sequence for a first human collagen polypeptide operably linked to a heterologous promoter is integrated into each of the ICP4 loci, and a second polynucleotide comprising the coding sequence for a second human collagen polypeptide operably linked to a heterologous promoter is integrated into the ICP22 locus. [Figure 1-8]Figures 1A-N show schematic diagrams of wild-type and modified herpes simplex virus genomes. Figure 1M shows a modified herpes simplex virus genome containing deletions of the coding sequences for ICP4 (both copies), ICP22, and UL41, in which a first polynucleotide comprising a coding sequence for a first human collagen polypeptide operably linked to a heterologous promoter is integrated into each of the ICP4 loci and a second polynucleotide comprising a coding sequence for a second human collagen polypeptide operably linked to a heterologous promoter is integrated into the UL41 locus. Figure 1N shows a modified herpes simplex virus genome containing deletions of the coding sequences for ICP4 (both copies) and UL41, in which a first polynucleotide comprising a coding sequence for a first human collagen polypeptide operably linked to a heterologous promoter is integrated into each of the ICP4 loci and a second polynucleotide comprising a coding sequence for a second human collagen polypeptide operably linked to a heterologous promoter is integrated into the UL41 locus. [Figure 2] Figures 2A-B show schematic diagrams of replication-deficient herpes simplex virus type 1 carrying a human collagen 7 (COL7) expression cassette. Figure 2A shows a schematic diagram of the virus "KCA211." Figure 2B shows a schematic diagram of the virus "SAR-COL7." [Figure 3] Figures 3A-B show human COL7 expression in HaCaT cells infected with KCA211 or SAR-COL7 at the indicated MOIs. Figure 3A shows human COL7 expression in HaCaT cells infected with KCA211 or SAR-COL7 at the indicated MOIs, as assessed by qPCR. Data are shown as fold change relative to SAR-COL7 after normalization to GAPDH. Figure 3B shows human COL7 expression in uninfected HaCaT cells or in HaCaT cells infected with KCA211 or SAR-COL7 at the indicated MOIs, as assessed by Western blot analysis. [Figure 4]Figures 4A-B show immunofluorescence images of human COL7 expression in mock-infected primary human cells isolated from healthy patients (normal) and in mock- or SAR-COL7-infected primary human cells isolated from patients with recessive dystrophic epidermolysis bullosa (RDEB). Figure 4A shows human COL7 expression in mock-infected wild-type and RDEB primary human keratinocytes or in RDEB primary human keratinocytes infected with SAR-COL7 at the indicated multiplicity of infection (MOI). Figure 4B shows human COL7 expression in mock-infected wild-type and RDEB primary human fibroblasts or in RDEB primary human fibroblasts infected with SAR-COL7 at the indicated MOI. [Figure 5] Figures 5A-B show quantitative PCR analysis of human COL7 expression in mock-infected primary human cells isolated from healthy patients and in mock- or SAR-COL7-infected primary human cells isolated from patients with recessive dystrophic epidermolysis bullosa (EB). Figure 5A shows human COL7 expression in mock-infected wild-type (N-HDK) and RDEB (EB-HDK) primary human keratinocytes, or in RDEB primary human keratinocytes infected with SAR-COL7 at the indicated MOI. COL7 expression is shown as the relative fold change compared to mock-infected wild-type primary human keratinocytes. Figure 5B shows human COL7 expression in mock-infected wild-type (N-HDF) and RDEB (EB-HDF) primary human fibroblasts, or in RDEB primary human fibroblasts infected with SAR-COL7 at the indicated MOI. COL7 expression is shown as fold change relative to mock-infected wild-type primary human fibroblasts. [Figure 6] Figures 6A-B show cell adhesion of uninfected (control) or SAR-COL7-infected RDEB primary human keratinocytes to untreated (plastic) or treated wells of a microwell plate. Figure 6A shows cell adhesion to untreated wells (plastic) or wells treated with increasing concentrations of rat tail collagen 1. Figure 6B shows cell adhesion to untreated wells (plastic) or wells treated with increasing concentrations of human plasma fibronectin. [Figure 7] Representative immunofluorescence images of human COL7 expression and deposition in the basement membrane zone (BMZ) in organotypic cultures established with SAR-COL7-infected RDEB primary human keratinocytes and fibroblasts on day 5 are shown. After culture establishment, both keratinocytes and fibroblasts were infected in situ at the indicated MOI. [Figure 8] Figures 8A-D show the transcript and genomic levels of human COL7A1 observed in uninfected mouse skin (control) or mouse skin after topical or intradermal delivery of SAR-COL7, as assessed by qPCR. Error bars represent SEM. Figure 8A shows the human COL7A1 transcript levels / 100 ng of total RNA in mouse skin at day 3 post-infection. Figure 8B shows the human COL7A1 DNA copy number / 100 ng of total DNA in mouse skin at day 3 post-infection. Figure 8C shows the human COL7A1 transcript levels / 100 ng of total RNA in mouse skin at day 6 post-infection. Figure 8D shows the human COL7A1 DNA copy number / 100 ng of total DNA in mouse skin at day 6 post-infection. [Figure 9] Figures 9A-B show representative immunofluorescence images of human COL7 expression in mouse skin after intradermal delivery of SAR-COL7. Figure 9A shows a representative immunofluorescence image of human COL7 expression in mouse skin after intradermal delivery of SAR-COL7. Figure 9B shows a representative immunofluorescence image of human COL7 expression in mouse skin after topical delivery of SAR-COL7. [Figure 10] Figures 10A-B show transcript and genomic levels of human COL7A1 observed in BALB / c mouse skin after intradermal delivery of vehicle, SAR-COL7, or KCA211, as assessed by qPCR. Figure 10A shows human COL7A1 transcript levels / 100 ng of total RNA in BALB / c mouse skin. Figure 10B shows human COL7A1 DNA copy numbers / 100 ng of total DNA in BALB / c mouse skin. [Figure 11]Figures 11A-B show the transcript and genome levels of human COL7A1 observed at each injection site in hypomorphic mouse skin after high-dose intradermal delivery of HSV-GFP (GFP control) or SAR-COL7, as assessed by qPCR. Each bar represents a single sample at the indicated time point. Figure 11A shows the human COL7A1 transcript level / 100 ng of total RNA in hypomorphic mouse skin. Figure 11B shows the copy number of human COL7A1 DNA / 100 ng of total DNA in hypomorphic mouse skin. [Figure 12] Figures 12A-B show representative immunofluorescence images of human COL7 expression in hypomorph mouse skin after high-dose intradermal delivery of HSV-GFP (GFP control) or SAR-COL7. Figure 12A shows control (GFP) and SAR-COL7 immunofluorescence images from hypomorph mouse 1 (collected on day 3) at 10x and 20x magnification. Figure 12B shows SAR-COL7 immunofluorescence images from hypomorph mouse 2 and hypomorph mouse 3 (collected on day 7). This figure represents tiled images of 16 fields acquired with a 10x lens, capturing the entire skin section. [Figure 13] H&E stained samples from hypomorph mice 1, 2, and 3 (collected on days 3 and 3) are shown. These samples were taken from untreated hypomorph mouse skin and from hypomorph mouse skin after intradermal delivery of HSV-GFP or SAR-COL7. [Figure 14] Figures 14A-B show representative electron micrographs of human COL7 expression in hypomorphic mouse skin after intradermal delivery of SAR-COL7. The stratum densa is the dark band shown through the center of the image. The black dots are the stained NC domains of human COL7l, and the blue arrows indicate the formation of anchoring fibrils. Figure 14A shows an electron micrograph of infected hypomorphic mouse skin stained with an antibody specific for the NC2 domain of human COL7 (LH24). Figure 14B shows an electron micrograph of infected hypomorphic mouse skin stained with an antibody specific for the NC1 domain of human COL7 (NP185). [Figure 15]Figures 15A-B show the transcript and genomic levels of human COL7A1 observed at each injection site in hypomorphic mouse skin after low-dose intradermal delivery of SAR-COL7, as assessed by qPCR. Each bar represents a single sample at the indicated time point. Figure 15A shows the human COL7A1 transcript level / 100 ng of total RNA in hypomorphic mouse skin. Figure 15B shows the copy number of human COL7A1 DNA / 100 ng of total DNA in hypomorphic mouse skin. [Figure 16] Representative immunofluorescence images of human COL7 expression in hypomorphic mouse skin (derived from mouse 1) after low-dose intradermal delivery of SAR-COL7 are shown. [Figure 17] Figures 17A-C show human COL1A1 and COL1A2 nucleic acid and protein analyses in Vero cells infected with the indicated clones of HSV encoding either COL1A1 alone (inserted at the ICP4 locus) or COL1A1 and COL1A2 (inserted at the ICP4 and ICP22 loci, respectively). Figure 17A shows the levels of human COL1A1 transcripts present in Vero cells 5 days after infection with the indicated HSV clones, as determined by qRT-PCR analysis. Data are presented for two replicates ± SEM. Figure 17B shows the levels of human COL1A2 transcripts present in Vero cells 5 days after infection with the indicated HSV clones, as determined by qRT-PCR analysis. Data are presented for two replicates ± SEM. Figure 17C shows Western blot analysis of human COL1A1 and COL1A2 protein expression in Vero cells 5 days after infection with the indicated COL1A1 / COL1A2-positive clones, as determined by qRT-PCR. Uninfected (mock) Vero cells were used as a negative control, and GAPDH was used as a loading control. [Figure 18]Western blot analysis of human COL1A1 and COL1A2 protein expression in Vero cells 5 days after infection with an HSV isolate encoding a COL1A1-IRES-COL1A2 sequence inserted into the ICP4 locus (IRES-isolate 6). Infection with an isolate without an IRES construct (no insert) was used as a negative control, and GAPDH was used as a loading control. [Figure 19] Figures 19A-B show human COL3 nucleic acid and protein analysis in immortalized human keratinocytes (HaCaT) infected with C3vec01. Figure 19A shows the levels of human COL3A1 transcripts present in immortalized human keratinocytes (HK) after infection with C3vec01 at the indicated MOI. Uninfected (mock) and HSV-mCherry-infected (mCherry) cells were used as negative controls. Data are presented for two replicates ± SEM. Figure 19B shows representative immunofluorescence images of human COL3 protein expression in immortalized human keratinocytes 48 hours after infection with C3vec01 at the indicated MOI. Uninfected (mock) cells were used as a negative control. [Figure 20] Figures 20A-B show human COL3 nucleic acid and protein analysis in immortalized human dermal fibroblasts (HDFs) infected with C3vec01. Figure 20A shows the human COL3A1 transcript levels present in immortalized human dermal fibroblasts (HDFs) after infection with C3vec01 at the indicated MOI. Uninfected (mock) and HSV-mCherry-infected (mCherry) cells were used as negative controls. Data are presented for two replicates ± SEM. Figure 20B shows representative immunofluorescence images of human COL3 protein expression in immortalized human dermal fibroblasts 48 hours after infection with C3vec01 at the indicated MOI. Uninfected (mock) cells were used as a negative control. [Figure 21]Figures 21A-D show human COL3 nucleic acid and protein analysis in senescent primary human fibroblasts (HDFs) sourced from two different vendors and infected with C3vec01 at the indicated MOI. Figure 21A shows the levels of human COL3A1 transcripts present in primary HDFs (Vendor 1) collected from either a 65-year-old female patient or a 73-year-old male patient after infection with C3vec01 at the indicated MOI. Uninfected (mock) cells were used as a negative control. Data are presented for two replicates ± SEM. Figure 21B shows Western blot analysis of human COL3A1 protein expression in primary HDFs (Vendor 1) collected from a 73-year-old male patient after infection with C3vec01 at the indicated MOI. Uninfected (mock) cells were used as a negative control, recombinant human COL3A1 (rCOL3A1) was used as a positive control, and GAPDH was used as a loading control. Figure 21C shows the levels of human COL3A1 transcripts present in primary HDFs (Vendor 2) collected from either a 75-year-old female patient or a 73-year-old male patient after infection with C3vec01 at the indicated MOI. Uninfected (mock) cells were used as a negative control. Data are presented for two replicates ± SEM. Figure 21D shows Western blot analysis of human COL3A1 protein expression in primary HDFs (Vendor 2) collected from a 75-year-old female patient after infection with C3vec01 at the indicated MOI. Uninfected (mock) cells were used as a negative control, recombinant human COL3A1 (rCOL3A1) was used as a positive control, and GAPDH was used as a loading control. [Figure 22]Figures 22A-B show human COL3 nucleic acid and protein analysis in immortalized human dermal fibroblasts (HDFs) upon UV exposure. Figure 22A shows the concentration of COL3 secreted into the supernatant of cultured HDFs 24 hours after exposure to various doses and times of UV light, as assessed by ELISA. Supernatant collected from non-UV-exposed (-UV) HDFs cultured in parallel was used as a control. Figure 22B shows the levels of human COL3A1 transcripts present in UV-exposed immortalized human dermal fibroblasts (HDFs) after infection with C3vec01 at the indicated MOI. Uninfected (mock) cells and HSV-mCherry-infected (mCherry) cells were used as negative controls. Data are presented for two replicates ± SEM. [Figure 23A] Figures 23A-C show COL3 nucleic acid and protein analysis of skin biopsies taken from young (6-8 weeks old) and old (approximately 13 months old) C57BL / 6 mice treated with control or C3vec01 48 hours after intradermal application. Figure 23A shows the levels of human COL3A1 DNA present in skin biopsies taken from young and old mice 48 hours after intradermal administration of either C3vec01 or vehicle control, as assessed by qPCR analysis. [Figure 23B] Figures 23A-C show COL3 nucleic acid and protein analysis of skin biopsies taken from young (6-8 weeks old) and old (approximately 13 months old) C57BL / 6 mice treated with control or C3vec01 48 hours after intradermal application. Figure 23B shows the levels of human COL3A1 transcript present in skin biopsies taken from young and old mice 48 hours after intradermal administration of either C3vec01 or vehicle control, as assessed by qRT-PCR analysis. For each condition in the qPCR and qRT-PCR analyses, data are presented as the mean ± SEM of four tissue samples (two replicates per tissue sample). [Figure 23C]Figures 23A-C show COL3 nucleic acid and protein analysis of skin biopsies taken from young (6-8 weeks old) and old (approximately 13 months old) C57BL / 6 mice treated with control or C3vec01 48 hours after intradermal application. Figure 23C shows representative immunofluorescence images of human COL3 expression in skin biopsies taken from young and old mice 48 hours after intradermal administration of C3vec01. Young mice administered vehicle alone intradermally were used as negative controls. Nuclei were visualized using DAPI staining. [Figure 24] Figures 24A-B show wild-type (WT) human LamB3 expression in Vero cells infected with the indicated virus isolates. Figure 24A shows wild-type human LAMB3 expression in infected Vero cells as assessed by qPCR analysis. Figure 24B shows wild-type human LamB3 protein expression in infected Vero cells as assessed by Western blot. [Figure 25] Figure 1 shows the expression of wild-type (WT) or codon-optimized (CO) human LamB3 protein in Vero cells infected with the indicated virus isolates, as assessed by Western blot. Uninfected Vero cells were used as a negative control. [Figure 26] Figure 1 shows the expression of wild-type (WT) or codon-optimized (CO) human LamB3 protein in primary human keratinocytes infected with the indicated virus isolates, as assessed by Western blot. Uninfected primary keratinocytes were used as a negative control. [Figure 27]Figures 27A-C show the expression of wild-type (WT) and codon-optimized (CO) human LamC2 in Vero cells infected with the indicated viral isolates. Figure 27A shows the expression of wild-type human LAMC2 in infected Vero cells as assessed by qPCR analysis. Figure 27B shows the expression of codon-optimized human LAMC2 in infected Vero cells as assessed by qPCR analysis. Figure 27C shows the expression of wild-type and codon-optimized human LamC2 proteins in infected Vero cells as assessed by Western blot. The enclosed viral isolate "LGA," expressing codon-optimized LamC2, was selected for further experiments. [Figure 28A] Figure 1 shows human LAMC2 expressed from viral isolate "LGA" in immortalized primary human keratinocytes infected at the indicated multiplicity of infection (MOI). Figure 2 shows viral genome copy numbers in primary immortalized human keratinocytes after infection with viral isolate "LGA" at the indicated MOI. [Figure 28B] Figure 1 shows human LAMC2 expressed from viral isolate "LGA" in immortalized primary human keratinocytes infected at the indicated multiplicity of infection (MOI). Figure 2 shows transcript levels of codon-optimized LAMC2 expressed in primary immortalized human keratinocytes after infection with viral isolate "LGA" at the indicated MOI. [Figure 28C] Figure 1 shows human LAMC2 expressed from viral isolate "LGA" in immortalized primary human keratinocytes infected at the indicated multiplicity of infection (MOI). Figure 2 shows human LamC2 protein expression in primary immortalized human keratinocytes after infection with viral isolate "LGA" at the indicated MOI, as assessed by Western blot. [Figure 29A] Figures 29A-D show LAMC2 nucleic acid and protein analysis of skin biopsies taken from control (vehicle) mice or mice treated with HSV isolate "LGA" 72 hours after intradermal application. Figure 29A shows a schematic diagram of the intradermal injection site on a treated animal. [Figure 29B]Figures 29A-D show LAMC2 nucleic acid and protein analysis of skin biopsies taken from control (vehicle) mice or mice treated with HSV isolate "LGA" 72 hours after intradermal application. Figure 29B shows the levels of human LAMC2 DNA present in skin biopsies taken from mice 72 hours after intradermal administration of either HSV isolate LGA or vehicle control, as assessed by qPCR analysis. [Figure 29C] Figures 29A-D show LAMC2 nucleic acid and protein analysis of skin biopsies taken from control (vehicle) mice or mice treated with HSV isolate "LGA" 72 hours after intradermal application. Figure 29C shows human LAMC2 transcript levels present in skin biopsies taken from mice 72 hours after intradermal administration of either HSV isolate LGA or vehicle control, as assessed by qRT-PCR analysis. For each condition in the qPCR and qRT-PCR analyses, data are presented as the mean ± SEM of two replicates. [Figure 29D] Figures 29A-D show LAMC2 nucleic acid and protein analysis of skin biopsies taken from control (vehicle) mice or mice treated with HSV isolate "LGA" 72 hours after intradermal application. Figure 29D shows representative immunofluorescence images of human LAMC2 expression in skin biopsies taken from mice 72 hours after intradermal administration of HSV isolate LGA. A site administered vehicle alone was used as a negative control. Nuclei were visualized using DAPI staining, and mouse laminin-332 was visualized using pKal staining. DETAILED DESCRIPTION OF THE INVENTION

[0063] Detailed Description In some embodiments, the present disclosure relates to recombinant nucleic acids (e.g., recombinant herpesvirus genomes) encoding one or more cosmetic proteins and the use of these recombinant nucleic acids in viruses (e.g., in herpesviruses), compositions, formulations, medicaments, and / or methods for delivering one or more cosmetic proteins to, e.g., on, into, and / or through the skin (e.g., to the skin ECM). In some embodiments, the present disclosure relates to recombinant nucleic acids (e.g., recombinant herpesvirus genomes) encoding one or more cosmetic proteins and the use of these recombinant nucleic acids in viruses (e.g., in herpesviruses), compositions, formulations, medicaments, and / or methods for increasing, enhancing, and / or replenishing one or more skin ECM proteins (e.g., one or more collagen proteins). In some embodiments, the present disclosure relates to recombinant nucleic acids (e.g., recombinant herpesvirus genomes) encoding one or more cosmetic proteins and the use of these recombinant nucleic acids in viruses (e.g., in herpesviruses), compositions, formulations, medicaments, and / or methods in aesthetic settings (e.g., to reduce one or more signs of dermatological aging). In some embodiments, the present disclosure relates to compositions comprising recombinant herpesvirus vectors and methods comprising delivering the recombinant herpesvirus vector onto, into, and / or through mammalian skin, wherein the recombinant herpesvirus vector comprises a promoter operable in mammalian cells and a heterologous nucleic acid expressed to achieve a cosmetic effect in the mammalian skin. The heterologous nucleic acid can be delivered to target mammalian skin cells in a mammal by contacting the epidermis, dermis, or subcutaneous tissue of the mammal with a composition comprising the recombinant herpesvirus vector under conditions such that the recombinant herpesvirus vector is transported onto, into, and / or through the epidermis, dermis, or subcutaneous tissue and introduced into the target skin cells where it is expressed. Without wishing to be bound by theory, it is believed that administering one or more of the recombinant nucleic acids, viruses, and / or formulations described herein to an individual allows for increased production of functional skin ECM proteins (e.g., human collagen) in the individual.Furthermore, without wishing to be bound by theory, it is believed that increasing, enhancing, and / or replenishing levels of cosmetic proteins in an individual by administering one or more of the recombinant nucleic acids, viruses, and / or formulations described herein results in at least one of the following: (1) strengthening, augmenting, and / or replenishing soft tissue; (2) improving skin quality, condition, and / or appearance; (3) reducing one or more surface depressions in the skin (e.g., wrinkles); (4) improving skin texture, smoothness, elasticity, and / or firmness; and / or (5) reducing one or more dermatological signs of aging. Finally, without wishing to be bound by theory, it is believed that the recombinant nucleic acids, viruses, compositions, and methods described herein provide novel strategies for delivering functional cosmetic proteins in aesthetic environments.

[0064] The following description sets forth example methods, parameters, etc. However, it should be recognized that such description is not intended to limit the scope of the present disclosure, but is instead provided as a description of example embodiments.

[0065] I. General Techniques Details of the specific methods used in the manufacturing process are described in 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)). eds.(1995)),Harlow and Lane,eds.(1988)、Oligonucleotide Synthesis(MJGait,ed.,1984)、Methods in Molecular Biology,Humana Press、Cell Biology:A Laboratory Notebook(JECellis,ed.,1998)Academic Press、Animal Cell Culture(RIFreshney),ed.,1987)、Introduction to Cell and Tissue Culture(JPMather and PERoberts,1998)Plenum Press、Cell and Tissue Culture:Laboratory Procedures(A.Doyle,JBGriffiths,and DGNewell,eds.,1993-8)J.Wiley and Sons Transfer Vectors for Mammalian Cells(JMMiller and MPCalos,eds.,1987)、PCR:The Polymerase Chain Reaction,(Mullis et al.,eds.These methods are well understood and commonly used by those skilled in the art, using conventional methodologies such as those widely used in "Short Protocols in Molecular Biology" (Wiley and Sons, 1999) and "Biochemistry and Biology: A Brief History of Molecular Biology" (Wiley and Sons, 1999).

[0066] II. Definition Before describing the present disclosure in detail, it is to be understood that this disclosure is not limited to particular compositions or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0067] As used herein, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to "a molecule" includes any combination of two or more such molecules, and so on.

[0068] As used herein, the term "and / or" may include any and all combinations of one or more of the associated listed 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."

[0069] As used herein, the term "about" refers to a normal error range for the respective value, which is readily known to one of ordinary skill in the art. Reference herein to "about" a value or parameter includes (and describes) embodiments that are directed to the value or parameter itself.

[0070] It is to be understood that aspects and embodiments of the present disclosure include "comprising," "consisting of," and "consisting essentially of" aspects and embodiments.

[0071] As used herein, the terms "polynucleotide," "nucleic acid sequence," "nucleic acid," and variations thereof are inclusive of 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, provided that the polymer contains nucleobases in a configuration that allows for base pairing and base stacking, as found in DNA and RNA. Thus, these terms include known types of nucleic acid sequence modifications, such as substitution of one or more analogs of naturally occurring nucleotides and internucleotide modifications.

[0072] As used herein, a nucleic acid is "operably linked" or "operably linked" when it is placed into a functional relationship with another nucleic acid sequence. For example, a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the coding sequence, and a ribosome binding site is operably linked to a coding sequence if it is positioned so as to facilitate translation. Generally, "operably linked" or "operably linked" means that the DNA sequences being linked are contiguous.

[0073] As used herein, the term "vector" refers to a discrete element used to introduce heterologous nucleic acid into cells for either expression or replication of the heterologous nucleic acid. Expression vectors include vectors capable of expressing nucleic acids operably linked to regulatory sequences, such as promoter regions, that are capable of effecting expression of such nucleic acids. Thus, an expression vector can refer to a DNA or RNA construct, such as a plasmid, phage, recombinant virus, or other vector, that, when introduced into an appropriate host cell, results in expression of a nucleic acid. Suitable expression vectors are well known to those of skill in the art and include those that are replicable in eukaryotic cells and those that remain episomal or that integrate into the host cell genome.

[0074] As used herein, "open reading frame" or "ORF" refers to a contiguous stretch of nucleic acid, either DNA or RNA, that encodes a protein or polypeptide. Typically, the nucleic acid includes a translation initiation signal or start codon, such as ATG or AUG, and a stop codon.

[0075] As used herein, "untranslated region" or "UTR" refers to untranslated nucleic acid at the 5' and / or 3' end of an open reading frame. Inclusion of one or more UTRs in a polynucleotide can affect post-transcriptional regulation, mRNA stability, and / or translation of the polynucleotide.

[0076] As used herein, the term "transgene" refers to a polynucleotide that, after being introduced into a cell, can be transcribed into RNA and translated and / or expressed under appropriate conditions, in some aspects conferring a desired characteristic on the cell into which it is introduced, or otherwise producing a desired cosmetic, therapeutic, or diagnostic result.

[0077] As used herein, the terms "polypeptide," "protein," and "peptide" are used interchangeably and may refer to a polymer of two or more amino acids.

[0078] As used herein, "subject," "host," or "individual" refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sport, or pet animals such as dogs, horses, cats, cows, and animals used in research, such as mice, rats, hamsters, rabbits, and non-human primates. In some embodiments, the mammal is a human.

[0079] As used herein, the term "pharmaceutical formulation" or "pharmaceutical composition" refers to a preparation that is in a form that allows the biological activity of the active ingredient(s) to be effective and that does not contain additional components that are unacceptably toxic to the subject to which the composition or formulation is administered. A "pharmaceutically acceptable" excipient (e.g., vehicle, additive) is one that can be reasonably administered to a subject to provide an effective dose of the active ingredient(s) employed.

[0080] As used herein, "dermal administration" or "administering dermal" refers to delivering a composition to a subject by directly or otherwise contacting a formulation containing the composition with all ("systemic") or a portion ("topical") of the subject's skin. The term encompasses several routes of administration, including, but not limited to, topical and transdermal. Topical administration can be used as a means to deliver a composition to a subject's epidermis or dermis, or to specific layers thereof.

[0081] As used herein, "treatment" refers to a clinical intervention designed to alter the natural course of the individual or cell being treated during clinical pathology. Desirable effects of treatment include a reduction in the rate of progression of a disease / disorder / deficiency, an improvement or alleviation of the disease / disorder / deficiency condition, and remission or improved prognosis. For example, an individual is successfully "treated" if one or more symptoms associated with dermatological aging, including the reduction or elimination of wrinkles, are reduced, alleviated, or eliminated.

[0082] As used herein, the term "delaying the progression" of a disease / disorder / defect refers to withholding, preventing, delaying, retarding, stabilizing, and / or postponing the onset of the disease / disorder / defect (e.g., skin wrinkling). This delay can be of varying length or time, depending on the disease / disorder / defect and / or the medical history of the individual being treated. As will be apparent to one of skill in the art, a sufficient or significant delay can actually encompass prevention, in that the individual does not develop the disease / disorder / defect.

[0083] III. Recombinant Nucleic Acids Certain aspects of the present 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 cosmetic proteins. Any suitable cosmetic protein described herein or known in the art can be encoded by a polynucleotide of the present disclosure, including, for example, collagen proteins, fibronectin, elastin, lumican, vitronectin / vitronectin receptor, laminin, neuromodulators, fibrillin, additional skin ECM proteins, etc. In some embodiments, the cosmetic protein is a structural extracellular matrix protein (e.g., collagen, elastin, fibronectin, laminin, fibrillin, etc.). In some embodiments, the cosmetic protein is a collagen, elastin, fibronectin, or laminin protein (e.g., human collagen, elastin, fibronectin, or laminin protein).

[0084] In some embodiments, the 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 a collagen protein. In some embodiments, the collagen protein is a human collagen protein. In some embodiments, the disclosure relates to recombinant nucleic acids comprising one or more polynucleotides encoding a homotrimeric collagen (e.g., a homotrimeric human collagen, e.g., human collagen 3 (e.g., comprising three COL3A1 (COL3) polypeptides) or human collagen 7 (e.g., comprising three COL7A1 (COL7) polypeptides). In some embodiments, the disclosure relates to recombinant nucleic acids comprising one or more polynucleotides encoding a heterotrimeric collagen (e.g., a heterotrimeric human collagen, e.g., human collagen 1 (e.g., comprising two COL1A1 (COL1-1) polypeptides and one COL1A2 (COL1-2) polypeptide) or human collagen 4 (e.g., comprising two COL4A1 (COL4 In some embodiments, the disclosure relates to recombinant nucleic acids comprising one or more polynucleotides encoding human collagen 1 and human collagen 3. In some embodiments, the disclosure relates to recombinant nucleic acids comprising one or more polynucleotides encoding human collagen 1. In some embodiments, the disclosure relates to recombinant nucleic acids comprising one or more polynucleotides encoding human collagen 3.

[0085] In some embodiments, the present disclosure relates to a recombinant nucleic acid comprising a first polynucleotide encoding a first polypeptide comprising a first cosmetic protein (e.g., a first human collagen protein). In some embodiments, the first polypeptide consists essentially of or consists of the first cosmetic protein (e.g., consists essentially of or consists of the first human collagen protein). In some embodiments, the present disclosure relates to a recombinant nucleic acid comprising a first polynucleotide encoding a first polypeptide comprising the first cosmetic protein (e.g., the first human collagen protein), a linker polypeptide, and an additional cosmetic protein (e.g., an additional human collagen protein). In some embodiments, the first cosmetic protein and the additional cosmetic protein (e.g., the first human collagen protein and the additional human collagen protein) are the same. In some embodiments, the first cosmetic protein and the additional cosmetic protein (e.g., the first human collagen protein and the additional human collagen protein) are different. In some embodiments, the linker polypeptide is a cleavable linker polypeptide.

[0086] In some embodiments, the present disclosure relates to a recombinant nucleic acid comprising a first polynucleotide encoding a first polypeptide comprising a first cosmetic protein (e.g., a first human collagen protein), wherein the first polynucleotide encodes a polycistronic mRNA comprising a first open reading frame (ORF) encoding the first polypeptide, an internal ribosome entry site (IRES), and a second ORF encoding an additional cosmetic protein (e.g., an additional human collagen protein). In some embodiments, the first cosmetic protein and the additional cosmetic protein (e.g., the first human collagen protein and the additional human collagen protein) are the same. In some embodiments, the first cosmetic protein and the additional cosmetic protein (e.g., the first human collagen protein and the additional human collagen protein) are different.

[0087] In some embodiments, the present disclosure relates to a recombinant nucleic acid comprising a first polynucleotide encoding a first polypeptide comprising a first cosmetic protein (e.g., a first human collagen protein) and a second polynucleotide encoding a second cosmetic protein (e.g., a second human collagen protein). In some embodiments, the first cosmetic protein and the second cosmetic protein (e.g., the first human collagen protein and the second human collagen protein) are the same. In some embodiments, the first cosmetic protein and the second cosmetic protein (e.g., the first human collagen protein and the second human collagen protein) are different.

[0088] In some embodiments, the recombinant nucleic acid is a vector. In some embodiments, the recombinant nucleic acid is a viral vector. In some embodiments, the recombinant nucleic acid is a herpes virus vector. In some embodiments, the recombinant nucleic acid is a herpes simplex virus amplicon. In some embodiments, the recombinant nucleic acid is a recombinant herpes virus 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.

[0089] Polynucleotides encoding cosmetic proteins Polynucleotides encoding collagen proteins In some embodiments, the present disclosure relates to recombinant nucleic acids comprising one or more polynucleotides comprising a coding sequence of a collagen gene, such as a human collagen gene (see, e.g., NCBI Gene IDs: 1277, 1278, 1281, 1282, 1284, 1291, 1294, 1308, etc.), a mouse collagen gene (see, e.g., NCBI Gene IDs: 12842, 12843, 12825, 12826, 12827, 12833, 12836, 12821, etc.), a chimpanzee collagen gene (see, e.g., NCBI Gene IDs: 104001053, 455117, 459815, 452689, 452661, 450204, 101056895, 101058306, etc.), a rat collagen gene ( The coding sequence of any collagen gene (including any isoforms thereof) from any suitable species known in the art can be encoded by the polynucleotides of the present disclosure, including, for example, NCBI Gene IDs: 29393, 84352, 84032, 290905, 306628, 294337, 301012, 294027, etc.), rabbit collagen genes (see, for example, NCBI Gene IDs: 100347598, 100008997, 100009177, 100358256, 100358522, 100343947, 100356561, 100339335, etc.), etc. Methods for identifying collagen gene homologs / orthologs from additional species are known to those of skill in the art, including, for example, the use of nucleic acid sequence alignment programs such as the BLAST® blastn suite. In some embodiments, polynucleotides of the present disclosure comprise 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 to the sequence of any of the collagen genes (and / or their coding sequences) described herein or known in the art.

[0090] In some embodiments, polynucleotides of the present disclosure comprise codon-optimized variants of the coding sequence of any of the collagen genes described herein or known in the art. In some embodiments, use of codon-optimized variants of the coding sequence of a collagen gene increases the stability and / or yield of heterologous expression (RNA and / or protein) of the encoded collagen protein in target cells (such as epidermal and / or dermal cells) compared to the stability and / or yield of heterologous expression of the corresponding non-codon-optimized wild-type sequence. Any suitable method known in the art for codon-optimizing sequences for expression in one or more target cells (e.g., one or more human cells) can be used, including, for example, the method described by Fath et al. (PLoS One. 2011 Mar 3;6(3):e17596).

[0091] In some embodiments, the present disclosure relates to one or more polynucleotides (i.e., one or more first polynucleotides and / or one or more second polynucleotides) comprising a coding sequence of a human collagen gene, such as the COL1A1 gene (see, e.g., NCBI Gene ID: 1277, SEQ ID NO: 1), the COL1A2 gene (see, e.g., NCBI Gene ID: 1278, SEQ ID NO: 3), the COL2A1 gene (see, e.g., NCBI Gene ID: 1280), the COL3A1 gene (see, e.g., NCBI Gene ID: 1281, SEQ ID NO: 5), the COL4A1 gene (see, e.g., NCBI Gene ID: 1282, SEQ ID NO: 7), the COL4A2 gene (see, e.g., NCBI Gene ID: 1283, SEQ ID NO: 7), the COL5A1 gene (see, e.g., NCBI Gene ID: 1284, SEQ ID NO: 7), the COL6A1 gene (see, e.g., NCBI Gene ID: 1285, SEQ ID NO: 7), the COL7A2 gene (see, e.g., NCBI Gene ID: 1286, SEQ ID NO: 7), the COL8A1 gene (see, e.g., NCBI Gene ID: 1287, SEQ ID NO: 7), the COL9A1 gene (see, e.g., NCBI Gene ID: 1288, SEQ ID NO: 8), the COL10A1 gene (see, e.g., NCBI Gene ID: 1289, SEQ ID NO: 9), the COL11A1 gene (see, e.g., NCBI Gene ID: 1290, SEQ ID NO: 9), the COL12A1 gene (see, NCBI Gene ID: 1284), COL4A3 gene (see, e.g., NCBI Gene ID: 1285), COL4A4 gene (see, e.g., NCBI Gene ID: 1286), COL4A5 gene (see, e.g., NCBI Gene ID: 1287), COL4A6 gene (see, e.g., NCBI Gene ID: 1288), COL5A1 gene (see, e.g., NCBI Gene ID: 1289), COL5A2 gene (see, e.g., NCBI Gene ID: 1281), COL5A3 gene (see, e.g., NCBI Gene ID: 1282), COL4A4 gene (see, e.g., NCBI Gene ID: 1283), COL4A5 gene (see, e.g., NCBI Gene ID: 1284), COL4A6 gene (see, e.g., NCBI Gene ID: 1285), COL4A7 gene (see, e.g., NCBI Gene ID: 1286), COL4A8 gene (see, e.g., NCBI Gene ID: 1287), COL4A9 gene (see, e.g., NCBI Gene ID: 1288), COL5A1 gene (see, e.g., NCBI Gene ID: 1289), COL5A2 gene (see, e.g., NCBI Gene ID: 1281), COL5A3 gene (see, e.g., NCBI Gene ID: 1282), COL5A4 gene (see, e.g., NCBI Gene ID: 1283), COL5A5 gene (see, e.g., NCBI Gene ID: 1284), COL4A6 gene (see, e.g., NCBI Gene ID: 1284), COL4A7 ID: 1290), COL5A3 gene (see, e.g., NCBI Gene ID: 50509), COL6A1 gene (see, e.g., NCBI Gene ID: 1291, SEQ ID NO: 9), COL6A2 gene (see, e.g., NCBI Gene ID: 1292), COL6A3 gene (see, e.g., NCBI Gene ID: 1293), COL6A4 gene (see, e.g., NCBI Gene ID: 344875), COL6A5 gene (see, e.g., NCBI Gene ID: 256076), COL6A6 gene (see, e.g., NCBI Gene ID: 131873), COL7A1 gene (see, e.g., NCBI Gene ID: 1294, SEQ ID NO: 10), COL8A1 gene (see, e.g., NCBI Gene ID: 1295), COL9A1 gene (see, e.g., NCBI Gene ID: 1297), COL9A2 gene (see, e.g., NCBI Gene ID: 1298), COL9A3 gene (see, e.g., NCBI Gene ID: 1299), COL9A4 gene (see, e.g., NCBI Gene ID: 1299), COL9A5 gene (see, e.g., NCBI Gene ID: 1299), COL9A6 gene (see, e.g., NCBI Gene ID: 131873), COL7A1 gene (see, e.g., NCBI Gene ID: 1294, SEQ ID NO: 10), COL8A1 gene (see, e.g., NCBI Gene ID: 1295), COL9A1 gene (see, e.g., NCBI Gene ID: 1297), COL9A2 gene (see, e.g., NCBI Gene ID: 1298), COL9A3 gene (see, e.g.,See NCBI Gene ID: 1299), COL10A1 gene (see, e.g., NCBI Gene ID: 1300), COL11A1 gene (see, e.g., NCBI Gene ID: 1301), COL11A2 gene (see, e.g., NCBI Gene ID: 1302), COL12A1 gene (see, e.g., NCBI Gene ID: 1303), COL13A1 gene (see, e.g., NCBI Gene ID: 1305), COL14 A1 gene (see, e.g., NCBI Gene ID: 7373), COL15A1 gene (see, e.g., NCBI Gene ID: 1306), COL16A1 gene (see, e.g., NCBI Gene ID: 1307), COL17A1 gene (see, e.g., NCBI Gene ID: 1308, SEQ ID NO: 12), COL18A1 gene (see, e.g., NCBI Gene ID: 80781), COL19A1 gene (see, e.g., NCBI Gene ID: 1310), the COL20A1 gene (see, e.g., NCBI Gene ID: 57642), the COL21A1 gene (see, e.g., NCBI Gene ID: 81578), the COL22A1 gene (see, e.g., NCBI Gene ID: 169044), the COL23A1 gene (see, e.g., NCBI Gene ID: 91522), the COL24A1 gene (see, e.g., NCBI Gene ID: 255631), the COL25A1 gene Any suitable human collagen gene (including any isoforms thereof) known in the art can be encoded by the nucleic acids of the present disclosure, including the COL26A1 gene (see, e.g., NCBI Gene ID: 84570), the COL26A1 gene (see, e.g., NCBI Gene ID: 136227), the COL27A1 gene (see, e.g., NCBI Gene ID: 85301), the COL28A1 gene (see, e.g., NCBI Gene ID: 340267), etc. In some embodiments, the polynucleotides (i.e., one or more first polynucleotides and / or one or more second polynucleotides) of the present disclosure share at least 75%, at least 80%, or at least 90% similarity to the sequence of any of the human collagen genes (and / or their coding sequences) described herein or known in the art.The sequences include those having 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.

[0092] In some embodiments, the polynucleotides of the present disclosure (i.e., one or more first polynucleotides and / or one or more second polynucleotides) comprise a codon-optimized variant of any of the human collagen genes described herein. In some embodiments, the use of a codon-optimized variant of a human collagen gene increases the stability and / or yield of heterologous expression (RNA and / or protein) of human collagen in target cells (such as human keratinocytes or fibroblasts) compared to the stability and / or yield of heterologous expression of the corresponding non-codon-optimized wild-type sequence.

[0093] In some embodiments, a polynucleotide of the present disclosure comprises a coding sequence of the human COL1A1 gene (or a codon-optimized variant thereof). In some embodiments, a polynucleotide of the present disclosure comprises a sequence having at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of SEQ ID NO:1 or SEQ ID NO:2. In some embodiments, a polynucleotide of the present disclosure comprises the sequence of SEQ ID NO:1 or SEQ ID NO:2.

[0094] In some embodiments, polynucleotides of the disclosure comprise a 5' truncation, a 3' truncation, or a fragment of the sequence of SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, a 5' truncation, a 3' truncation, or a fragment of the sequence of SEQ ID NO: 1 or SEQ ID NO: 2 is a polynucleotide having at least 25, at least 50, at least 75, at least 100, at least 125, at least 150, at least 175, at least 200, at least 250, at least 300, or at least 350, at least 400, at least 450, at least 500, at least 750, at least 1000, at least 1250, at least 1500, at least 1750, at least 2000, at least 2500, at least 3000, at least 3500, at least 4000, but fewer than 4395 contiguous nucleotides of SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, a polynucleotide of the disclosure comprises a sequence having at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of nucleic acids 1-4392 of SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, a polynucleotide of the disclosure comprises the sequence of nucleic acids 1-4392 of SEQ ID NO: 1 or SEQ ID NO: 2.

[0095] In some embodiments, a polynucleotide of the present disclosure comprises a coding sequence of the human COL1A2 gene (or a codon-optimized variant thereof). In some embodiments, a polynucleotide of the present disclosure comprises a sequence having at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of SEQ ID NO:3 or SEQ ID NO:4. In some embodiments, a polynucleotide of the present disclosure comprises the sequence of SEQ ID NO:3 or SEQ ID NO:4.

[0096] In some embodiments, polynucleotides of the disclosure comprise a 5' truncation, a 3' truncation, or a fragment of the sequence of SEQ ID NO: 3 or SEQ ID NO: 4. In some embodiments, a 5' truncation, a 3' truncation, or a fragment of the sequence of SEQ ID NO: 3 or SEQ ID NO: 4 is a polynucleotide having at least 25, at least 50, at least 75, at least 100, at least 125, at least 150, at least 175, at least 200, at least 250, at least 300, or at least 350, at least 400, at least 450, at least 500, at least 750, at least 1000, at least 1250, at least 1500, at least 1750, at least 2000, at least 2500, at least 3000, at least 3500, at least 4000, but fewer than 4101 contiguous nucleotides of SEQ ID NO: 3 or SEQ ID NO: 4. In some embodiments, a polynucleotide of the disclosure comprises a sequence having at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of nucleic acids 1-4098 of SEQ ID NO: 3 or SEQ ID NO: 4. In some embodiments, a polynucleotide of the disclosure comprises the sequence of nucleic acids 1-4098 of SEQ ID NO: 3 or SEQ ID NO: 4.

[0097] In some embodiments, a polynucleotide of the present disclosure comprises a coding sequence of the human COL3A1 gene (or a codon-optimized variant thereof). In some embodiments, a polynucleotide of the present disclosure comprises a sequence having at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of SEQ ID NO:5 or SEQ ID NO:6. In some embodiments, a polynucleotide of the present disclosure comprises the sequence of SEQ ID NO:5 or SEQ ID NO:6.

[0098] In some embodiments, polynucleotides of the disclosure comprise a 5' truncation, a 3' truncation, or a fragment of the sequence of SEQ ID NO: 5 or SEQ ID NO: 6. In some embodiments, a 5' truncation, a 3' truncation, or a fragment of the sequence of SEQ ID NO: 5 or SEQ ID NO: 6 is a polynucleotide having at least 25, at least 50, at least 75, at least 100, at least 125, at least 150, at least 175, at least 200, at least 250, at least 300, or at least 350, at least 400, at least 450, at least 500, at least 750, at least 1000, at least 1250, at least 1500, at least 1750, at least 2000, at least 2500, at least 3000, at least 3500, at least 4000, but fewer than 4401 contiguous nucleotides of SEQ ID NO: 5 or SEQ ID NO: 6. In some embodiments, a polynucleotide of the disclosure comprises a sequence having at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of nucleic acids 1-4398 of SEQ ID NO: 5 or SEQ ID NO: 6. In some embodiments, a polynucleotide of the disclosure comprises the sequence of nucleic acids 1-4398 of SEQ ID NO: 5 or SEQ ID NO: 6.

[0099] In some embodiments, a polynucleotide of the present disclosure comprises a coding sequence of the human COL4A1 gene (or a codon-optimized variant thereof). In some embodiments, a polynucleotide of the present disclosure comprises a sequence having at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of SEQ ID NO:7 or SEQ ID NO:8. In some embodiments, a polynucleotide of the present disclosure comprises the sequence of SEQ ID NO:7 or SEQ ID NO:8.

[0100] In some embodiments, polynucleotides of the disclosure comprise a 5' truncation, a 3' truncation, or a fragment of the sequence of SEQ ID NO: 7 or SEQ ID NO: 8. In some embodiments, a 5' truncation, a 3' truncation, or a fragment of the sequence of SEQ ID NO: 7 or SEQ ID NO: 8 is a polynucleotide having at least 25, at least 50, at least 75, at least 100, at least 125, at least 150, at least 175, at least 200, at least 250, at least 300, or at least 350, at least 400, at least 450, at least 500, at least 750, at least 1000, at least 1250, at least 1500, at least 1750, at least 2000, at least 2500, at least 3000, at least 3500, at least 4000, at least 4500, at least 5000, but fewer than 5010 contiguous nucleotides of SEQ ID NO: 7 or SEQ ID NO: 8. In some embodiments, a polynucleotide of the disclosure comprises a sequence having at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of nucleic acids 1-5007 of SEQ ID NO: 7 or SEQ ID NO: 8. In some embodiments, a polynucleotide of the disclosure comprises the sequence of nucleic acids 1-5007 of SEQ ID NO: 7 or SEQ ID NO: 8.

[0101] In some embodiments, a polynucleotide of the present disclosure comprises a coding sequence of the human COL6A1 gene (or a codon-optimized variant thereof). In some embodiments, a polynucleotide of the present disclosure comprises a sequence having at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of SEQ ID NO:9 or SEQ ID NO:10. In some embodiments, a polynucleotide of the present disclosure comprises the sequence of SEQ ID NO:9 or SEQ ID NO:10.

[0102] In some embodiments, polynucleotides of the disclosure comprise a 5' truncation, a 3' truncation, or a fragment of the sequence of SEQ ID NO:9 or SEQ ID NO:10. In some embodiments, a 5' truncation, a 3' truncation, or a fragment of the sequence of SEQ ID NO:9 or SEQ ID NO:10 is a polynucleotide having at least 25, at least 50, at least 75, at least 100, at least 125, at least 150, at least 175, at least 200, at least 250, at least 300, or at least 350, at least 400, at least 450, at least 500, at least 750, at least 1000, at least 1250, at least 1500, at least 1750, at least 2000, at least 2500, at least 3000, but fewer than 3087 contiguous nucleotides of SEQ ID NO:9 or SEQ ID NO:10. In some embodiments, a polynucleotide of the disclosure comprises a sequence having at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of nucleic acids 1-3084 of SEQ ID NO:9 or SEQ ID NO:10. In some embodiments, a polynucleotide of the disclosure comprises the sequence of nucleic acids 1-3084 of SEQ ID NO:9 or SEQ ID NO:10.

[0103] In some embodiments, a polynucleotide of the present disclosure comprises a coding sequence of the human COL7A1 gene (or a codon-optimized variant thereof). In some embodiments, a polynucleotide of the present disclosure comprises a sequence having at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of SEQ ID NO:11 or SEQ ID NO:12. In some embodiments, a polynucleotide of the present disclosure comprises the sequence of SEQ ID NO:11 or SEQ ID NO:12.

[0104] In some embodiments, polynucleotides of the disclosure comprise a 5' truncation, a 3' truncation, or a fragment of the sequence of SEQ ID NO:11 or SEQ ID NO:12. In some embodiments, a 5' truncation, 3' truncation, or fragment of the sequence of SEQ ID NO:11 or SEQ ID NO:12 is a polynucleotide having at least 25, at least 50, at least 75, at least 100, at least 125, at least 150, at least 175, at least 200, at least 250, at least 300, or at least 350, at least 400, at least 450, at least 500, at least 750, at least 1000, at least 1250, at least 1500, at least 1750, at least 2000, at least 2500, at least 3000, at least 3500, at least 4000, at least 4500, at least 5000, at least 5500, at least 6000, at least 6500, at least 7000, at least 7500, at least 8000, at least 8500, but fewer than 8835 contiguous nucleotides of SEQ ID NO:11 or SEQ ID NO:12. In some embodiments, a polynucleotide of the disclosure comprises a sequence having at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of nucleic acids 1-8832 of SEQ ID NO: 11 or SEQ ID NO: 12. In some embodiments, a polynucleotide of the disclosure comprises the sequence of nucleic acids 1-8832 of SEQ ID NO: 11 or SEQ ID NO: 12.

[0105] In some embodiments, a polynucleotide of the present disclosure comprises a coding sequence of the human COL17A1 gene (or a codon-optimized variant thereof). In some embodiments, a polynucleotide of the present disclosure comprises a sequence having at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of SEQ ID NO: 13 or SEQ ID NO: 14. In some embodiments, a polynucleotide of the present disclosure comprises the sequence of SEQ ID NO: 13 or SEQ ID NO: 14.

[0106] In some embodiments, polynucleotides of the disclosure comprise a 5' truncation, a 3' truncation, or a fragment of the sequence of SEQ ID NO: 13 or SEQ ID NO: 14. In some embodiments, a 5' truncation, a 3' truncation, or a fragment of the sequence of SEQ ID NO: 13 or SEQ ID NO: 14 is a polynucleotide having at least 25, at least 50, at least 75, at least 100, at least 125, at least 150, at least 175, at least 200, at least 250, at least 300, or at least 350, at least 400, at least 450, at least 500, at least 750, at least 1000, at least 1250, at least 1500, at least 1750, at least 2000, at least 2500, at least 3000, at least 3500, at least 4000, but fewer than 4494 contiguous nucleotides of SEQ ID NO: 13 or SEQ ID NO: 14. In some embodiments, a polynucleotide of the disclosure comprises a sequence having at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of nucleic acids 1-4491 of SEQ ID NO: 13 or SEQ ID NO: 14. In some embodiments, a polynucleotide of the disclosure comprises the sequence of nucleic acids 1-4491 of SEQ ID NO: 13 or SEQ ID NO: 14.

[0107] In some embodiments, polynucleotides of the present disclosure encoding one or more human collagen proteins (e.g., a first human collagen protein, a further human collagen protein, an additional human collagen protein, and / or a second human collagen protein) 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 to a nucleic acid sequence selected from SEQ ID NOs: 1-14. In some embodiments, polynucleotides of the present disclosure encoding one or more human collagen proteins (e.g., a first human collagen protein, a further human collagen protein, an additional human collagen protein, and / or a second human collagen protein) comprise a sequence selected from SEQ ID NOs: 1-14.

[0108] Polynucleotides encoding fibronectin proteins In some embodiments, the present disclosure relates to recombinant nucleic acids comprising one or more polynucleotides comprising the coding sequence of a fibronectin gene. For example, the coding sequence of any fibronectin gene (including any isoform thereof) from any suitable species known in the art, including the human fibronectin gene (see, for example, NCBI gene ID: 2335), mouse fibronectin gene (see, for example, NCBI gene ID: 14268), chimpanzee fibronectin gene (see, for example, NCBI gene ID: 459926), rat fibronectin gene (see, for example, NCBI gene ID: 25661), and rabbit fibronectin gene (see, for example, NCBI gene ID: 100328589), can be encoded by the polynucleotides of the present disclosure. Methods for identifying fibronectin gene homologs / orthologs from additional species are known to those skilled in the art. In some embodiments, polynucleotides of the present disclosure comprise 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 to the sequence of any of the fibronectin genes (and / or their coding sequences) described herein or known in the art. In some embodiments, polynucleotides of the present disclosure comprise a codon-optimized variant of any of the fibronectin genes (and / or their coding sequences) described herein or known in the art.

[0109] In some embodiments, the present disclosure relates to one or more polynucleotides (i.e., one or more first polynucleotides and / or one or more second polynucleotides) comprising a coding sequence of a human fibronectin gene. In some embodiments, the polynucleotides of the present disclosure comprise the coding sequence of the human FN1 gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the present disclosure comprise 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 to the sequence of SEQ ID NO:35 or SEQ ID NO:36. In some embodiments, the polynucleotides of the present disclosure comprise the sequence of SEQ ID NO:35 or SEQ ID NO:36.

[0110] In some embodiments, polynucleotides of the disclosure comprise a 5' truncation, a 3' truncation, or a fragment of the sequence of SEQ ID NO:35 or SEQ ID NO:36. In some embodiments, a 5' truncation, 3' truncation, or fragment of the sequence of SEQ ID NO:35 or SEQ ID NO:36 is a polynucleotide having at least 25, at least 50, at least 75, at least 100, at least 125, at least 150, at least 175, at least 200, at least 250, at least 300, or at least 350, at least 400, at least 450, at least 500, at least 750, at least 1000, at least 1250, at least 1500, at least 1750, at least 2000, at least 2500, at least 3000, at least 3500, at least 4000, at least about 4500, at least about 5000, at least about 5500, at least about 6000, at least about 6500, at least about 7000, but fewer than 7434 contiguous nucleotides of SEQ ID NO:35 or SEQ ID NO:36. In some embodiments, a polynucleotide of the disclosure comprises a sequence having at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of nucleic acids 1-7431 of SEQ ID NO: 35 or SEQ ID NO: 36. In some embodiments, a polynucleotide of the disclosure comprises the sequence of nucleic acids 1-7431 of SEQ ID NO: 35 or SEQ ID NO: 36.

[0111] Polynucleotides encoding elastin proteins In some embodiments, the present disclosure relates to recombinant nucleic acids comprising one or more polynucleotides comprising the coding sequence of an elastin gene. For example, the coding sequence of any elastin gene (including any isoforms thereof) from any suitable species known in the art can be encoded by the polynucleotides of the present disclosure, including the human elastin gene (see, e.g., NCBI Gene ID: 2006), mouse elastin gene (see, e.g., NCBI Gene ID: 13717), chimpanzee elastin gene (see, e.g., NCBI Gene ID: 463943), rat elastin gene (see, e.g., NCBI Gene ID: 25043), rabbit elastin gene (see, e.g., NCBI Gene ID: 100344271), etc. Methods for identifying elastin gene homologs / orthologs from additional species are known to those of skill in the art. In some embodiments, polynucleotides of the present disclosure comprise 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 to the sequence of any of the elastin genes (and / or their coding sequences) described herein or known in the art. In some embodiments, polynucleotides of the present disclosure comprise a codon-optimized variant of any of the elastin genes (and / or their coding sequences) described herein or known in the art.

[0112] In some embodiments, the present disclosure relates to one or more polynucleotides (i.e., one or more first polynucleotides and / or one or more second polynucleotides) comprising a coding sequence of a human elastin gene. In some embodiments, the polynucleotides of the present disclosure comprise a coding sequence of a human ELN gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the present disclosure comprise 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 to the sequence of SEQ ID NO:37 or SEQ ID NO:38. In some embodiments, the polynucleotides of the present disclosure comprise the sequence of SEQ ID NO:37 or SEQ ID NO:38.

[0113] In some embodiments, polynucleotides of the disclosure comprise a 5' truncation, a 3' truncation, or a fragment of the sequence of SEQ ID NO: 37 or SEQ ID NO: 38. In some embodiments, a 5' truncation, a 3' truncation, or a fragment of the sequence of SEQ ID NO: 37 or SEQ ID NO: 38 is a polynucleotide having at least 25, at least 50, at least 75, at least 100, at least 125, at least 150, at least 175, at least 200, at least 250, at least 300, or at least 350, at least 400, at least 450, at least 500, at least 750, at least 1000, at least 1250, at least 1500, at least 1750, at least 2000, at least 2250, but fewer than 2361 contiguous nucleotides of SEQ ID NO: 37 or SEQ ID NO: 38. In some embodiments, a polynucleotide of the disclosure comprises a sequence having at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of nucleic acids 1-2358 of SEQ ID NO: 37 or SEQ ID NO: 38. In some embodiments, a polynucleotide of the disclosure comprises the sequence of nucleic acids 1-2358 of SEQ ID NO: 37 or SEQ ID NO: 38.

[0114] Polynucleotide encoding lumican protein In some embodiments, the present disclosure relates to recombinant nucleic acids comprising one or more polynucleotides comprising a coding sequence of a lumican gene. For example, the coding sequence of any lumican gene (including any isoforms thereof) from any suitable species known in the art can be encoded by the polynucleotides of the present disclosure, including the human lumican gene (see, e.g., NCBI Gene ID: 4060), mouse lumican gene (see, e.g., NCBI Gene ID: 17022), chimpanzee lumican gene (see, e.g., NCBI Gene ID: 452119), rat lumican gene (see, e.g., NCBI Gene ID: 81682), rabbit lumican gene (see, e.g., NCBI Gene ID: 100008665), etc. Methods for identifying lumican gene homologs / orthologs from additional species are known to those of skill in the art. In some embodiments, polynucleotides of the present disclosure comprise 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 to the sequence of any of the lumican genes (and / or their coding sequences) described herein or known in the art. In some embodiments, polynucleotides of the present disclosure comprise a codon-optimized variant of any of the lumican genes (and / or their coding sequences) described herein or known in the art.

[0115] In some embodiments, the present disclosure relates to one or more polynucleotides (i.e., one or more first polynucleotides and / or one or more second polynucleotides) comprising a coding sequence of the human lumican gene. In some embodiments, the polynucleotides of the present disclosure comprise a coding sequence of the human LUM gene (or a codon-optimized variant thereof). In some embodiments, the polynucleotides of the present disclosure comprise 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 to the sequence of SEQ ID NO:39 or SEQ ID NO:40. In some embodiments, the polynucleotides of the present disclosure comprise the sequence of SEQ ID NO:39 or SEQ ID NO:40.

[0116] In some embodiments, polynucleotides of the disclosure comprise a 5' truncation, a 3' truncation, or a fragment of the sequence of SEQ ID NO: 39 or SEQ ID NO: 40. In some embodiments, a 5' truncation, a 3' truncation, or a fragment of the sequence of SEQ ID NO: 39 or SEQ ID NO: 40 is a polynucleotide having at least 25, at least 50, at least 75, at least 100, at least 125, at least 150, at least 175, at least 200, at least 250, at least 300, or at least 350, at least 400, at least 450, at least 500, at least 750, at least 1000, but fewer than 10 contiguous nucleotides of SEQ ID NO: 39 or SEQ ID NO: 40. In some embodiments, a polynucleotide of the disclosure comprises a sequence having at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of nucleic acids 1-1014 of SEQ ID NO: 39 or SEQ ID NO: 40. In some embodiments, a polynucleotide of the disclosure comprises the sequence of nucleic acids 1-1014 of SEQ ID NO: 39 or SEQ ID NO: 40.

[0117] Polynucleotides encoding vitronectin and vitronectin receptor proteins In some embodiments, the present disclosure relates to recombinant nucleic acids comprising one or more polynucleotides comprising a coding sequence for a vitronectin or vitronectin receptor gene. For example, the coding sequence for any vitronectin or vitronectin receptor gene (including any isoforms thereof) from any suitable species known in the art can be encoded by the polynucleotides of the present disclosure, including human vitronectin or vitronectin receptor genes (see, e.g., NCBI Gene IDs: 7448 and 3685), mouse vitronectin or vitronectin receptor genes (see, e.g., NCBI Gene IDs: 22370 and 16410), chimpanzee vitronectin or vitronectin receptor genes (see, e.g., NCBI Gene IDs: 738261 and 459807), rat vitronectin or vitronectin receptor genes (see, e.g., NCBI Gene IDs: 29169 and 257645), rabbit vitronectin or vitronectin receptor genes (see, e.g., NCBI Gene IDs: 100009128 and 100008956), and the like. Methods for identifying vitronectin or vitronectin receptor gene homologs / orthologs from additional species are known to those of skill in the art. In some embodiments, polynucleotides of the present disclosure comprise 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 the sequences of any of the vitronectin or vitronectin receptor genes (and / or their coding sequences) described herein or known in the art. In some embodiments, polynucleotides of the present disclosure comprise codon-optimized variants of any of the vitronectin or vitronectin receptor genes (and / or their coding sequences) described herein or known in the art.

[0118] In some embodiments, the present disclosure relates to one or more polynucleotides (i.e., one or more first polynucleotides and / or one or more second polynucleotides) comprising a coding sequence of a human vitronectin or vitronectin receptor gene. In some embodiments, a polynucleotide of the present disclosure comprises a coding sequence of a human VTN gene (or a codon-optimized variant thereof). In some embodiments, a polynucleotide of the present disclosure comprises a sequence having at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of SEQ ID NO:41 or SEQ ID NO:42. In some embodiments, a polynucleotide of the present disclosure comprises the sequence of SEQ ID NO:41 or SEQ ID NO:42.

[0119] In some embodiments, polynucleotides of the disclosure comprise a 5' truncation, a 3' truncation, or a fragment of the sequence of SEQ ID NO: 41 or SEQ ID NO: 42. In some embodiments, a 5' truncation, a 3' truncation, or a fragment of the sequence of SEQ ID NO: 41 or SEQ ID NO: 42 is a polynucleotide having at least 25, at least 50, at least 75, at least 100, at least 125, at least 150, at least 175, at least 200, at least 250, at least 300, or at least 350, at least 400, at least 450, at least 500, at least 750, at least 1000, at least about 1250, but fewer than 1437 contiguous nucleotides of SEQ ID NO: 41 or SEQ ID NO: 42. In some embodiments, a polynucleotide of the disclosure comprises a sequence having at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of nucleic acids 1-1034 of SEQ ID NO: 41 or SEQ ID NO: 42. In some embodiments, a polynucleotide of the disclosure comprises the sequence of nucleic acids 1-1034 of SEQ ID NO: 41 or SEQ ID NO: 42.

[0120] Polynucleotides encoding laminin proteins In some embodiments, the present disclosure relates to recombinant nucleic acids comprising one or more polynucleotides comprising a coding sequence of a laminin gene, such as the human laminin gene (see, e.g., NCBI Gene IDs: 284217, 3908, 3909, 3910, 3911, 3912, 3913, 3914, 3915, 3918, and 10319), the mouse laminin gene (see, e.g., NCBI Gene IDs: 16774, 16780, and 16782), the chimpanzee laminin gene (see, e.g., NCBI Gene IDs: 455339, 469668, and 457571), or the chimpanzee laminin gene (see, e.g., NCBI Gene IDs: 455339, 469668, and 457571). The coding sequence of any laminin gene (including any isoforms thereof) from any suitable species known in the art can be encoded by the disclosed polynucleotides, including the rat laminin gene (see, e.g., NCBI Gene IDs: 307582, 305078, and 192362), the rabbit laminin gene (see, e.g., NCBI Gene IDs: 100346886 and 100342905), etc. Methods for identifying laminin gene homologs / orthologs from additional species are known to those of skill in the art. In some embodiments, polynucleotides of the present disclosure comprise 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 to the sequence of any of the laminin genes (and / or their coding sequences) described herein or known in the art. In some embodiments, polynucleotides of the present disclosure comprise a codon-optimized variant of any of the laminin genes (and / or their coding sequences) described herein or known in the art.

[0121] In some embodiments, the present disclosure provides methods for encoding human laminin genes, such as the human LAMA1 gene (see, e.g., NCBI Gene ID: 284217), the human LAMA2 gene (see, e.g., NCBI Gene ID: 3908), the human LAMA3 gene (see, e.g., NCBI Gene ID: 3909), the human LAMA4 gene (see, e.g., NCBI Gene ID: 3910), the human LAMA5 gene (see, e.g., NCBI Gene ID: 3911), the human LAMB1 gene (see, e.g., NCBI Gene ID: 3912), the human The present invention relates to one or more polynucleotides (i.e., one or more first polynucleotides and / or one or more second polynucleotides) that comprise the coding sequence of the LAMB2 gene (see, e.g., NCBI Gene ID: 3913), the human LAMB3 gene (see, e.g., NCBI Gene ID: 3914), the human LAMC1 gene (see, e.g., NCBI Gene ID: 3915), the human LAMC2 gene (see, e.g., NCBI Gene ID: 3918), or the human LAMC3 gene (see, e.g., NCBI Gene ID: 10319).

[0122] In some embodiments, a polynucleotide of the present disclosure comprises a coding sequence of the human LAMA3 gene (or a codon-optimized variant thereof). In some embodiments, a polynucleotide of the present disclosure comprises a sequence having at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of SEQ ID NO:43 or SEQ ID NO:44. In some embodiments, a polynucleotide of the present disclosure comprises the sequence of SEQ ID NO:43 or SEQ ID NO:44.

[0123] In some embodiments, polynucleotides of the disclosure comprise a 5' truncation, a 3' truncation, or a fragment of the sequence of SEQ ID NO: 43 or SEQ ID NO: 44. In some embodiments, a 5' truncation, a 3' truncation, or a fragment of the sequence of SEQ ID NO: 43 or SEQ ID NO: 44 is a polynucleotide having at least 25, at least 50, at least 75, at least 100, at least 125, at least 150, at least 175, at least 200, at least 250, at least 300, or at least 350, at least 400, at least 450, at least 500, at least 750, at least 1000, at least 1250, at least 1500, at least 1750, at least 2000, at least 2500, at least 3000, at least 3500, at least 4000, at least about 4500, at least about 5000, but fewer than 5175 contiguous nucleotides of SEQ ID NO: 43 or SEQ ID NO: 44. In some embodiments, a polynucleotide of the disclosure comprises a sequence having at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of nucleic acids 1-5172 of SEQ ID NO: 43 or SEQ ID NO: 44. In some embodiments, a polynucleotide of the disclosure comprises the sequence of nucleic acids 1-5172 of SEQ ID NO: 43 or SEQ ID NO: 44.

[0124] In some embodiments, a polynucleotide of the present disclosure comprises a coding sequence of a human LAMB3 gene (or a codon-optimized variant thereof). In some embodiments, a polynucleotide of the present disclosure comprises a sequence having at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of SEQ ID NO:45 or SEQ ID NO:46. In some embodiments, a polynucleotide of the present disclosure comprises the sequence of SEQ ID NO:45 or SEQ ID NO:46.

[0125] In some embodiments, polynucleotides of the disclosure comprise a 5' truncation, a 3' truncation, or a fragment of the sequence of SEQ ID NO: 45 or SEQ ID NO: 46. In some embodiments, a 5' truncation, a 3' truncation, or a fragment of the sequence of SEQ ID NO: 45 or SEQ ID NO: 46 is a polynucleotide having at least 25, at least 50, at least 75, at least 100, at least 125, at least 150, at least 175, at least 200, at least 250, at least 300, or at least 350, at least 400, at least 450, at least 500, at least 750, at least 1000, at least 1250, at least 1500, at least 1750, at least 2000, at least 2500, at least 3000, at least 3500, but fewer than 3519 contiguous nucleotides of SEQ ID NO: 45 or SEQ ID NO: 46. In some embodiments, a polynucleotide of the disclosure comprises a sequence having at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of nucleic acids 1-3516 of SEQ ID NO: 45 or SEQ ID NO: 46. In some embodiments, a polynucleotide of the disclosure comprises the sequence of nucleic acids 1-3516 of SEQ ID NO: 45 or SEQ ID NO: 46.

[0126] In some embodiments, a polynucleotide of the present disclosure comprises a coding sequence of the human LAMC2 gene (or a codon-optimized variant thereof). In some embodiments, a polynucleotide of the present disclosure comprises a sequence having at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of SEQ ID NO:47 or SEQ ID NO:48. In some embodiments, a polynucleotide of the present disclosure comprises the sequence of SEQ ID NO:47 or SEQ ID NO:48.

[0127] In some embodiments, polynucleotides of the disclosure comprise a 5' truncation, a 3' truncation, or a fragment of the sequence of SEQ ID NO: 47 or SEQ ID NO: 48. In some embodiments, a 5' truncation, a 3' truncation, or a fragment of the sequence of SEQ ID NO: 47 or SEQ ID NO: 48 is a polynucleotide having at least 25, at least 50, at least 75, at least 100, at least 125, at least 150, at least 175, at least 200, at least 250, at least 300, or at least 350, at least 400, at least 450, at least 500, at least 750, at least 1000, at least 1250, at least 1500, at least 1750, at least 2000, at least 2500, at least 3000, at least 3500, but fewer than 3582 contiguous nucleotides of SEQ ID NO: 47 or SEQ ID NO: 48. In some embodiments, a polynucleotide of the disclosure comprises a sequence having at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of nucleic acids 1-3579 of SEQ ID NO: 47 or SEQ ID NO: 48. In some embodiments, a polynucleotide of the disclosure comprises the sequence of nucleic acids 1-3579 of SEQ ID NO: 47 or SEQ ID NO: 48.

[0128] Polynucleotides encoding neuromodulatory proteins In some embodiments, the present disclosure relates to recombinant nucleic acids comprising one or more polynucleotides comprising a coding sequence of a neuromodulatory gene. For example, the coding sequence of any neuromodulatory gene (including any isoforms thereof) from any suitable species known in the art can be encoded by the disclosed polynucleotides, including Clostridium botulinum neuromodulatory genes (see, e.g., NCBI Gene IDs: 5185061 and 39483740). Methods for identifying neuromodulatory gene homologs / orthologs from additional species are known to those of skill in the art. In some embodiments, polynucleotides of the present disclosure comprise 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 to the sequence of any of the neuromodulatory genes (and / or their coding sequences) described herein or known in the art. In some embodiments, polynucleotides of the present disclosure comprise a codon-optimized variant of any of the neuromodulatory genes (and / or their coding sequences) described herein or known in the art.

[0129] In some embodiments, the present disclosure relates to one or more polynucleotides (i.e., one or more first polynucleotides and / or one or more second polynucleotides) comprising a coding sequence of a Clostridium botulinum neuromodulatory gene.

[0130] In some embodiments, a polynucleotide of the present disclosure comprises the coding sequence of the Clostridium botulinum botA gene (or a codon-optimized variant thereof). In some embodiments, a polynucleotide of the present disclosure comprises a sequence having at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of SEQ ID NO:49 or SEQ ID NO:50. In some embodiments, a polynucleotide of the present disclosure comprises the sequence of SEQ ID NO:49 or SEQ ID NO:50.

[0131] In some embodiments, polynucleotides of the disclosure comprise a 5' truncation, a 3' truncation, or a fragment of the sequence of SEQ ID NO: 49 or SEQ ID NO: 50. In some embodiments, a 5' truncation, a 3' truncation, or a fragment of the sequence of SEQ ID NO: 49 or SEQ ID NO: 50 is a polynucleotide having at least 25, at least 50, at least 75, at least 100, at least 125, at least 150, at least 175, at least 200, at least 250, at least 300, or at least 350, at least 400, at least 450, at least 500, at least 750, at least 1000, at least about 1250, at least 1500, at least 1750, at least 2000, at least 2500, at least 3000, at least 3500, but fewer than 3891 contiguous nucleotides of SEQ ID NO: 49 or SEQ ID NO: 50. In some embodiments, a polynucleotide of the disclosure comprises a sequence having at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of nucleic acids 1-3888 of SEQ ID NO: 49 or SEQ ID NO: 50. In some embodiments, a polynucleotide of the disclosure comprises the sequence of nucleic acids 1-3888 of SEQ ID NO: 49 or SEQ ID NO: 50.

[0132] In some embodiments, a polynucleotide of the present disclosure comprises a coding sequence of a Clostridium botulinum botB gene (or a codon-optimized variant thereof). In some embodiments, a polynucleotide of the present disclosure comprises a sequence having at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of SEQ ID NO:51 or SEQ ID NO:52. In some embodiments, a polynucleotide of the present disclosure comprises the sequence of SEQ ID NO:51 or SEQ ID NO:52.

[0133] In some embodiments, polynucleotides of the disclosure comprise a 5' truncation, a 3' truncation, or a fragment of the sequence of SEQ ID NO: 51 or SEQ ID NO: 52. In some embodiments, a 5' truncation, a 3' truncation, or a fragment of the sequence of SEQ ID NO: 51 or SEQ ID NO: 52 is a polynucleotide having at least 25, at least 50, at least 75, at least 100, at least 125, at least 150, at least 175, at least 200, at least 250, at least 300, or at least 350, at least 400, at least 450, at least 500, at least 750, at least 1000, at least about 1250, at least 1500, at least 1750, at least 2000, at least 2500, at least 3000, at least 3500, but fewer than 3876 contiguous nucleotides of SEQ ID NO: 51 or SEQ ID NO: 52. In some embodiments, a polynucleotide of the disclosure comprises a sequence having at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of nucleic acids 1-3873 of SEQ ID NO: 51 or SEQ ID NO: 52. In some embodiments, a polynucleotide of the disclosure comprises the sequence of nucleic acids 1-3873 of SEQ ID NO: 51 or SEQ ID NO: 52.

[0134] Polynucleotides encoding fibrillin proteins In some embodiments, the present disclosure relates to recombinant nucleic acids comprising one or more polynucleotides comprising a coding sequence of a fibrillin gene. For example, the coding sequence of any fibrillin gene (including any isoforms thereof) from any suitable species known in the art can be encoded by a polynucleotide of the present disclosure, including the human fibrillin gene (see, e.g., NCBI Gene IDs: 2200, 2201, and 84467), mouse fibrillin gene (see, e.g., NCBI Gene IDs: 14118 and 14119), chimpanzee fibrillin gene (see, e.g., NCBI Gene IDs: 453411, 471621, and 455669), rat fibrillin gene (see, e.g., NCBI Gene IDs: 83727 and 689008), and rabbit fibrillin gene (see, e.g., NCBI Gene IDs: 100350931, 100357126, and 100359336). Methods for identifying fibrillin gene homologs / orthologs from additional species are known to those of skill in the art. In some embodiments, the polynucleotides of the present disclosure comprise 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 to the sequence of any of the fibrillin genes (and / or their coding sequences) described herein or known in the art. In some embodiments, the polynucleotides of the present disclosure comprise a codon-optimized variant of any of the fibrillin genes (and / or their coding sequences) described herein or known in the art.

[0135] In some embodiments, the present disclosure relates to one or more polynucleotides (i.e., one or more first polynucleotides and / or one or more second polynucleotides) comprising the coding sequence of a human fibrillin gene, such as the human FBN1 gene (see, e.g., NCBI Gene ID: 2200), the human FBN2 gene (see, e.g., NCBI Gene ID: 2201), or the human FBN3 gene (see, e.g., NCBI Gene ID: 84467).

[0136] Exemplary Polynucleotides In some embodiments, polynucleotides of the present disclosure encoding one or more cosmetic proteins (e.g., a first cosmetic protein, a further cosmetic protein, an additional cosmetic protein, and / or a second cosmetic protein) 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 to a nucleic acid sequence selected from SEQ ID NOs: 1-14 or 35-52. In some embodiments, polynucleotides of the present disclosure encoding one or more cosmetic proteins (e.g., a first cosmetic protein, a further cosmetic protein, an additional cosmetic protein, and / or a second cosmetic protein) comprise a sequence selected from SEQ ID NOs: 1-14 or 35-52.

[0137] In some embodiments, polynucleotides of the present disclosure encoding one or more cosmetic proteins (e.g., a first cosmetic protein, a further cosmetic protein, an additional cosmetic protein, and / or a second cosmetic protein) 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 to a nucleic acid sequence selected from SEQ ID NOs: 1-14, 35-38, or 43-48. In some embodiments, polynucleotides of the present disclosure encoding one or more cosmetic proteins (e.g., a first cosmetic protein, a further cosmetic protein, an additional cosmetic protein, and / or a second cosmetic protein) comprise a sequence selected from SEQ ID NOs: 1-14, 35-38, or 43-48.

[0138] Polynucleotides of the present disclosure encoding cosmetic proteins (e.g., human collagen proteins) may further encode additional coding and non-coding sequences, including, but not limited to, sequences encoding additional polypeptide tags (e.g., encoded in frame with the cosmetic protein to produce a fusion protein), introns (e.g., natural, modified, or heterologous introns), 5'UTRs and / or 3'UTRs (e.g., natural, modified, or heterologous 5'UTRs and / or 3'UTRs), etc. Examples of suitable polypeptide tags include, but are not limited to, purification tags, e.g., his-tag, flag-tag, maltose-binding protein, and glutathione-S-transferase tags; detection tags, e.g., tags that can be detected photometrically (e.g., green fluorescent protein, red fluorescent protein, etc.) and tags with detectable enzymatic activity (e.g., alkaline phosphatase, etc.); any combination of tags including secretory sequences, signal sequences, leader sequences, and / or stabilizing sequences, protease cleavage sites (e.g., furan cleavage sites, TEV cleavage sites, thrombin cleavage sites, etc.); in some embodiments, the 5' UTR and / or 3' UTR increase the stability, localization, and / or translation efficiency of the polynucleotide; in some embodiments, the 5' UTR and / or 3' UTR improve protein expression levels and / or duration. In some embodiments, the 5'UTR and / or 3'UTR contain elements (e.g., one or more miRNA binding sites) that can block or reduce off-target expression (e.g., inhibiting expression in a particular cell type (e.g., neuronal cells), inhibiting expression at a particular point in the cell cycle, inhibiting expression at a particular developmental stage, etc.). In some embodiments, the 5'UTR and / or 3'UTR contain elements (e.g., one or more miRNA binding sites) that can enhance cosmetic protein expression in a particular cell type (e.g., human keratinocytes and / or fibroblasts).

[0139] In some embodiments, a polynucleotide of the present disclosure encoding a cosmetic protein (e.g., a human collagen protein) is operably linked to one or more (e.g., one or more, two or more, three or more, four or more, five or more, ten or more, etc.) regulatory sequences. The term "regulatory sequence" may include enhancers, insulators, promoters, and other expression control 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., the SV40 enhancer on the late side of the replication origin (bp 100-270), the cytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the replication origin, adenovirus enhancers, etc.), and any combination thereof. Any suitable insulator(s) known in the art may be used, including, for example, the HSV chromatin boundary (CTRL / CTCF binding / insulator) elements CTRL1 and / or CTRL2 from the human interferon beta gene (IFNB1), the chicken hypersensitive site 4 insulator (cHS4), the human HNRPA2B1-CBX3 ubiquitous chromatin opening element (UCOE), the scaffold / matrix attachment region (S / MAR), and any combination thereof.Any suitable promoter known in the art (e.g., a promoter suitable for transcription in a mammalian host cell) may be used, provided that it is compatible with the host cell, including, for example, promoters derived from the genome of viruses (e.g., polyomavirus, fowlpox virus, adenovirus (e.g., adenovirus 2), bovine papilloma virus, avian sarcoma virus, cytomegalovirus, retrovirus, hepatitis B virus, simian virus 40 (SV40), etc.), promoters derived from heterologous mammalian genes (e.g., actin promoters (e.g., β-actin promoter), ubiquitin promoters (e.g., ubiquitin C (UbC) promoter), phosphoglycerate kinase (PGK) promoter, immunoglobulin promoter, heat shock promoter, etc.), promoters derived from homologous mammalian genes (e.g., native human collagen, fibronectin, elastin, lumican, vitronectramine, laminin, and / or fibrillin promoter, etc.), synthetic promoters (e.g., CAGG promoter), and any combination thereof. Regulatory sequences can include sequences that direct constitutive expression of the nucleic acid, as well as tissue-specific regulatory sequences and / or inducible or repressible sequences.

[0140] In some embodiments, a polynucleotide of the present disclosure encoding a cosmetic protein (e.g., a human collagen protein) is operably linked to one or more heterologous promoters. In some embodiments, the one or more heterologous promoters are one or more of a constitutive promoter, a tissue-specific promoter, a temporal promoter, a spatial promoter, an inducible promoter, and a repressible promoter. In some embodiments, the one or more heterologous promoters are one or more of a human cytomegalovirus (HCMV) immediate-early promoter, a human elongation factor-1 (EF1) promoter, a human β-actin promoter, a human UbC promoter, a human PGF promoter, a synthetic CAGG promoter, and any combination thereof. In some embodiments, a polynucleotide of the present disclosure encoding a cosmetic protein (e.g., a human collagen protein) is operably linked to an HCMV promoter.

[0141] In some embodiments, a polynucleotide of the present disclosure does not include a coding sequence for a collagen alpha-1 (VII) chain polypeptide (COL7) (e.g., a transgene encoding same). In some embodiments, a polynucleotide of the present disclosure does not include a coding sequence for a lysyl hydroxylase 3 polypeptide (LH3) (e.g., a transgene encoding same). In some embodiments, a polynucleotide of the present disclosure does not include a coding sequence for a keratin type I cytoskeletal 17 polypeptide (KRT17) (e.g., a transgene encoding same). In some embodiments, a polynucleotide of the present disclosure does not include a coding sequence for a transglutaminase (TGM) polypeptide (e.g., a human transglutaminase polypeptide, such as a human TGM1 polypeptide) (e.g., a transgene encoding same). In some embodiments, a polynucleotide of the present disclosure does not include a coding sequence for a laminin subunit beta-3 polypeptide (LAMB3) (e.g., a transgene encoding same). In some embodiments, a polynucleotide of the present disclosure does not comprise a coding sequence for a collagen alpha-1(VII) chain polypeptide, a lysyl hydroxylase 3 polypeptide, a keratin type I cytoskeletal 17 polypeptide, and / or any chimeric polypeptides thereof (e.g., a transgene encoding the same). In some embodiments, a polynucleotide of the present disclosure does not comprise a coding sequence for a collagen alpha-1(VII) chain polypeptide, a lysyl hydroxylase 3 polypeptide, a keratin type I cytoskeletal 17 polypeptide, a transglutaminase (TGM) polypeptide (e.g., a human transglutaminase polypeptide such as human TGM1 polypeptide), a laminin subunit beta-3 (LAMB3) polypeptide (e.g., a human LamB3 polypeptide), and / or any chimeric polypeptides thereof (e.g., a transgene encoding the same).

[0142] Cosmetic Protein Collagen protein In some embodiments, the present disclosure relates to one or more polynucleotides encoding full-length collagen proteins or any isoforms or portions thereof, such as human collagen proteins (see, e.g., UniProt Accession Nos. P02452, P08123, P02461, P02462, P08572, P12109, Q02388, Q9UMD9, etc.), mouse collagen proteins (see, e.g., UniProt Accession Nos. P11087, Q01149, P08121, P02463, P08122, Q04857, Q63870, Q07563, etc.), chimpanzee collagen proteins (see, e.g., UniProt Accession Nos. A0A2I3SM98, A0A2J8L483, H2QJ46, K7C8P4, K7C8W0 ... Any collagen protein from any suitable species known in the art can be encoded by the polynucleotides of the present disclosure, including, for example, collagen proteins from any suitable species known in the art, including, for example, collagen proteins from any suitable species (e.g., see UniProt Accession Nos. P02454, P02466, P13941, P02466, F1M6Q3, D3ZUL3, D3ZE04, D3ZE04, etc.), rat collagen proteins (e.g., see UniProt Accession Nos. G1T4A5, Q28668, G1T8J0, G1U9R7, G1T548, G1T380, G1T548, etc.), and rabbit collagen proteins (e.g., see UniProt Accession Nos. G1T4A5, Q28668, G1T8J0, G1U9R7, G1T548, G1T380, G1T548, etc.). Methods for identifying collagen protein homologs / orthologs from additional species are known to those of skill in the art, including, for example, the use of amino acid sequence alignment programs such as the BLAST® blastp suite or OrthoDB. In some embodiments, a collagen polypeptide of the present disclosure comprises a sequence having at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of any of the collagen polypeptides described herein or known in the art.

[0143] In some embodiments, the present disclosure relates to one or more polynucleotides encoding human collagen proteins, such as collagen alpha-1(I) chain polypeptide (COL1-1) (see, e.g., UniProt Accession No. P02452, SEQ ID NO: 15), collagen alpha-2(I) chain polypeptide (COL1-2) (see, e.g., UniProt Accession No. P08123, SEQ ID NO: 16), collagen alpha-1(II) chain polypeptide (COL2) (see, e.g., UniProt Accession No. P02458), collagen alpha-1(III) chain polypeptide (COL3) (see, e.g., UniProt Accession No. P02459), collagen alpha-1(III) chain polypeptide (COL4) (see, e.g., UniProt Accession No. P02459), collagen alpha-1(III) chain polypeptide (COL5) (see, e.g., UniProt Accession No. P02459), collagen alpha-1(III) chain polypeptide (COL6) (see, e.g., UniProt Accession No. P02459), collagen alpha-1(III) chain polypeptide (COL7) (see, e.g., UniProt Accession No. P02459), collagen alpha-1(III) chain polypeptide (COL8) (see, e.g., UniProt Accession No. P02459), collagen alpha-1(III) chain polypeptide (COL9) (see, e.g., UniProt Accession No. P02459), collagen alpha-1(III) chain polypeptide (COL10) (see, e.g., UniProt Accession No. P02459), collagen alpha-1(III) chain polypeptide (COL11) (see, e.g., UniProt Accession No. P02459), collagen alpha-1(III) chain polypeptide (COL12) (see, e.g., UniProt Accession No. P02 rot accession number P2461, SEQ ID NO: 17), collagen alpha-1(IV) chain polypeptide (COL4-1) (see, e.g., UniProt accession number P02462, SEQ ID NO: 18), collagen alpha-2(IV) chain polypeptide (COL4-2) (see, e.g., UniProt accession number P08572), collagen alpha-3(IV) chain polypeptide (COL4-3) (see, e.g., UniProt accession number Q01955), collagen alpha-4(IV) chain polypeptide peptide (COL4-4) (see, e.g., UniProt accession number P53420), collagen alpha-5(IV) chain polypeptide (COL4-5) (see, e.g., UniProt accession number 29400), collagen alpha-6(IV) chain polypeptide (COL4-6) (see, e.g., UniProt accession number Q14031), collagen alpha-1(V) chain polypeptide (COL5-1) (see, e.g., UniProt accession number P20908), collagen alpha-2( collagen alpha-V) chain polypeptide (COL5-2) (see, e.g., UniProt accession number P05997), collagen alpha-3(V) chain polypeptide (COL5-3) (see, e.g., UniProt accession number P25940), collagen alpha-1(VI) chain polypeptide (COL6-1) (see, e.g., UniProt accession number P12109, SEQ ID NO: 19), collagen alpha-2(VI) chain polypeptide (COL6-2) (see, e.g., UniProt accession number P12110),Collagen alpha-3(VI) chain polypeptide (COL6-3) (see, e.g., UniProt accession number P12111), collagen alpha-4(VI) chain polypeptide (COL6-4), collagen alpha-5(VI) chain polypeptide (COL6-5) (see, e.g., UniProt accession number A8TX70), collagen alpha-6(VI) chain polypeptide (COL6-6) (see, e.g., UniProt accession number A6NMZ7), collagen alpha-1(VII) chain polypeptide (COL7) (see, e.g., UniProt accession number rot accession number Q02388, SEQ ID NO: 20), collagen alpha-1(VIII) chain polypeptide (COL8) (see, e.g., UniProt accession number P27658), collagen alpha-1(IX) chain polypeptide (COL9-1) (see, e.g., UniProt accession number P20849), collagen alpha-2(IX) chain polypeptide (COL9-2) (see, e.g., UniProt accession number Q14055), collagen alpha-3(IX) chain polypeptide (COL9-3) (see, e.g., UniProt accession number Q14056), Collagen alpha-1(X) chain polypeptide (COL10) (see, e.g., UniProt accession number Q03692), collagen alpha-1(XI) chain polypeptide (COL11-1) (see, e.g., UniProt accession number P12107), collagen alpha-2(XI) chain polypeptide (COL11-2) (see, e.g., UniProt accession number P13942), collagen alpha-1(XII) chain polypeptide (COL12) (see, e.g., UniProt accession number Q997 15), collagen alpha-1(XIII) chain polypeptide (COL13) (see, e.g., UniProt accession number Q5TAT6), collagen alpha-1(XIV) chain polypeptide (COL14) (see, e.g., UniProt accession number Q05707), collagen alpha-1(XV) chain polypeptide (COL15) (see, e.g., UniProt accession number P39059), collagen alpha-1(XVI) chain polypeptide (COL16) (see, e.g., UniProt accession number Q07092),Collagen alpha-1(XVII) chain polypeptide (COL17) (see, e.g., UniProt accession number Q9UMD9, SEQ ID NO: 21), collagen alpha-1(XVIII) chain polypeptide (COL18) (see, e.g., UniProt accession number P39060), collagen alpha-1(XIX) chain polypeptide (COL19) (see, e.g., UniProt accession number Q14993), collagen alpha-1(XX) chain polypeptide (COL20) (see, e.g., UniProt accession number Q9P218), collagen alpha-1(XXI) chain polypeptide (COL21) (see, e.g., UniProt accession number Q96P44), collagen alpha-1(XXII) chain polypeptide (COL22) (see, e.g., UniProt accession number Q8NFW1), collagen alpha-1(XXIII) chain polypeptide (COL Any suitable human collagen protein known in the art can be encoded by the polynucleotides of the present disclosure, including collagen alpha-1(XXIV) chain polypeptide (COL23) (see, e.g., UniProt Accession No. Q86Y22), collagen alpha-1(XXIV) chain polypeptide (COL24) (see, e.g., UniProt Accession No. Q17RW2), collagen alpha-1(XXV) chain polypeptide (COL25) (see, e.g., UniProt Accession No. Q9BXS0), collagen alpha-1(XXVI) chain polypeptide (COL26) (see, e.g., UniProt Accession No. Q96A83), collagen alpha-1(XXVII) chain polypeptide (COL27) (see, e.g., UniProt Accession No. Q8IZC6), collagen alpha-1(XXVIII) chain polypeptide (COL28) (see, e.g., UniProt Accession No. Q2UY09), and the like. In some embodiments, the polynucleotides of the present disclosure have 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%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%, at least 107%, at least 108%, at least 109%, at least 110%, at least 111%, at least 112%, at least 113%, at least 114%, at least 115%, at least 116%, at least 117%, at least 118%, at least 119%, at least 120%, at least 121%, at least 122%, at least 123%, at least 124%, at least 125%, at least 126%, at least 127%, at least 128%, at least 129%, at least 130%, at least 131%, at least 132%, at least 133%, at least 134%, at least 135%, at least 136%, at least 137%, at least 138%, at least 139%, at least 140%, at least 141%, at least 142%, at least 143%, at least 144%, at least 145%, at least 146%, at least 147%, at least 148%, at least 149%, at least 149, at least 150%, at least 151%, at least 152%, at least 153%, at least 154%, at least 1These include sequences with at least 97%, at least 98%, at least 99%, or 100% sequence identity. Methods for identifying additional human collagen or collagen-like polypeptide homologs / orthologs are known to those of skill in the art, including, for example, using amino acid sequence alignment programs such as the BLAST® blastp suite or OrthoDB.

[0144] In some embodiments, the polynucleotide of the present disclosure encodes a human COL1-1 protein. In some embodiments, the polynucleotide encoding the COL1-1 protein is a polynucleotide that encodes 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% sequence identity to the sequence of SEQ ID NO: 15. In some embodiments, the polynucleotide encoding the human COL1-1 protein is a polynucleotide that encodes a polypeptide comprising the amino acid sequence of SEQ ID NO: 15.

[0145] In some embodiments, the polynucleotide encoding the COL1-1 protein is a polynucleotide encoding an N-terminal truncation, a C-terminal truncation, or a fragment of the amino acid sequence of SEQ ID NO: 15. 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, 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 1100, at least 1200, at least 1300, or at least 1400, but fewer than 1464, contiguous amino acids of SEQ ID NO: 15.

[0146] In some embodiments, the polynucleotide of the present disclosure encodes a human COL1-2 protein. In some embodiments, the polynucleotide encoding the COL1-2 protein is a polynucleotide that encodes 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% sequence identity to the sequence of SEQ ID NO: 16. In some embodiments, the polynucleotide encoding the human COL1-2 protein is a polynucleotide that encodes a polypeptide comprising the amino acid sequence of SEQ ID NO: 16.

[0147] In some embodiments, the polynucleotide encoding the COL1-2 protein is a polynucleotide encoding an N-terminal truncation, a C-terminal truncation, or a fragment of the amino acid sequence of SEQ ID NO: 16. 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, 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 1100, at least 1200, or at least 1300, but fewer than 1366, contiguous amino acids of SEQ ID NO: 16.

[0148] In some embodiments, the polynucleotide of the present disclosure encodes a human COL3 protein. In some embodiments, the polynucleotide encoding the COL3 protein is a polynucleotide that encodes 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% sequence identity to the sequence of SEQ ID NO: 17. In some embodiments, the polynucleotide encoding the human COL3 protein is a polynucleotide that encodes a polypeptide comprising the amino acid sequence of SEQ ID NO: 17.

[0149] In some embodiments, the polynucleotide encoding the COL3 protein is a polynucleotide encoding an N-terminal truncation, a C-terminal truncation, or a fragment of the amino acid sequence of SEQ ID NO: 17. 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, 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 1100, at least 1200, at least 1300, at least 1400, but fewer than 1466 contiguous amino acids of SEQ ID NO: 17.

[0150] In some embodiments, the polynucleotide of the present disclosure encodes a human COL4-1 protein. In some embodiments, the polynucleotide encoding the COL4-1 protein is a polynucleotide that encodes 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% sequence identity to the sequence of SEQ ID NO: 18. In some embodiments, the polynucleotide encoding the human COL4-1 protein is a polynucleotide that encodes a polypeptide comprising the amino acid sequence of SEQ ID NO: 18.

[0151] In some embodiments, the polynucleotide encoding the COL4-1 protein is a polynucleotide encoding an N-terminal truncation, a C-terminal truncation, or a fragment of the amino acid sequence of SEQ ID NO: 18. 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, 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 1100, at least 1200, at least 1300, at least 1400, at least 1500, at least 1600, but fewer than 1669 contiguous amino acids of SEQ ID NO: 18.

[0152] In some embodiments, the polynucleotide of the present disclosure encodes a human COL6-1 protein. In some embodiments, the polynucleotide encoding the COL6-1 protein is a polynucleotide that encodes 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% sequence identity to the sequence of SEQ ID NO: 19. In some embodiments, the polynucleotide encoding the human COL6-1 protein is a polynucleotide that encodes a polypeptide comprising the amino acid sequence of SEQ ID NO: 19.

[0153] In some embodiments, the polynucleotide encoding the COL6-1 protein is a polynucleotide encoding an N-terminal truncation, a C-terminal truncation, or a fragment of the amino acid sequence of SEQ ID NO: 19. 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, 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, or at least 1000, but fewer than 1028, consecutive amino acids of SEQ ID NO: 19.

[0154] In some embodiments, the polynucleotide of the present disclosure encodes a human COL7 protein. In some embodiments, the polynucleotide encoding the COL7 protein is a polynucleotide that encodes 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% sequence identity to the sequence of SEQ ID NO: 20. In some embodiments, the polynucleotide encoding the human COL7 protein is a polynucleotide that encodes a polypeptide comprising the amino acid sequence of SEQ ID NO: 20.

[0155] In some embodiments, the polynucleotide encoding the COL7 protein is a polynucleotide that encodes an N-terminal truncation, a C-terminal truncation, or a fragment of the amino acid sequence of SEQ ID NO:20. N-terminal truncations, C-terminal truncations, or fragments may comprise at least 10, at least 12, at least 14, at least 16, at least 18, at least 20, at least 30, at least 40, at least 50, at least 75, at least 100, at least 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 1100, at least 1200, at least 1300, at least 1400, at least 1500, at least 1600, at least 1700, at least 1800, at least 1900, at least 2000, at least 2100, at least 2200, at least 2300, at least 2400, at least 2500, at least 2600, at least 2700, at least 2800, at least 2900, but fewer than 2944 consecutive amino acids of SEQ ID NO:20.

[0156] In some embodiments, the polynucleotide of the present disclosure encodes a human COL17 protein. In some embodiments, the polynucleotide encoding the COL17 protein is a polynucleotide that encodes 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% sequence identity to the sequence of SEQ ID NO: 21. In some embodiments, the polynucleotide encoding the human COL17 protein is a polynucleotide that encodes a polypeptide comprising the amino acid sequence of SEQ ID NO: 21.

[0157] In some embodiments, the polynucleotide encoding the COL17 protein is a polynucleotide encoding an N-terminal truncation, a C-terminal truncation, or a fragment of the amino acid sequence of SEQ ID NO: 21. 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, 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 1100, at least 1200, at least 1300, at least 1400, but fewer than 1497 contiguous amino acids of SEQ ID NO: 21.

[0158] In some embodiments, one or more human collagen proteins of the present disclosure (e.g., the first human collagen protein, the further human collagen protein, the additional human collagen protein, and / or the second human collagen protein) comprise an amino acid sequence that comprises at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to an amino acid sequence selected from SEQ ID NOs: 15-21. In some embodiments, one or more human collagen proteins of the present disclosure (e.g., the first human collagen protein, the further human collagen protein, the additional human collagen protein, and / or the second human collagen protein) comprise a sequence selected from SEQ ID NOs: 15-21.

[0159] In some embodiments, one or more human collagen proteins of the present disclosure (e.g., the first human collagen protein, the further human collagen protein, the additional human collagen protein, and / or the second human collagen protein) comprise an amino acid sequence that comprises at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to an amino acid sequence selected from SEQ ID NOs: 15-17. In some embodiments, one or more human collagen proteins of the present disclosure (e.g., the first human collagen protein, the further human collagen protein, the additional human collagen protein, and / or the second human collagen protein) comprise a sequence selected from SEQ ID NOs: 15-17.

[0160] fibronectin protein In some embodiments, the present disclosure relates to one or more polynucleotides encoding full-length fibronectin proteins or any isoforms or portions thereof. For example, any fibronectin protein from any suitable species known in the art can be encoded by the polynucleotides of the present disclosure, including human fibronectin protein (e.g., see UniProt Accession No. P02751), mouse fibronectin protein (e.g., see UniProt Accession No. P11276), chimpanzee fibronectin protein (e.g., see UniProt Accession No. P11276), rat fibronectin protein (e.g., see UniProt Accession No. P04937), rabbit fibronectin protein (e.g., see UniProt Accession No. P04937), etc. Methods for identifying fibronectin protein homologs / orthologs from additional species are known to those skilled in the art. In some embodiments, fibronectin proteins of the present 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 the sequences of any of the fibronectin proteins described herein or known in the art.

[0161] In some embodiments, the polynucleotide of the present disclosure encodes a human fibronectin protein. In some embodiments, the polynucleotide encoding the human fibronectin protein 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% sequence identity to the sequence of SEQ ID NO: 53. In some embodiments, the polynucleotide encoding the human fibronectin protein is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 53.

[0162] In some embodiments, the polynucleotide encoding the human fibronectin protein is a polynucleotide encoding an N-terminal truncation, a C-terminal truncation, or a fragment of the amino acid sequence of SEQ ID NO: 53. 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, 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 1100, at least 1200, at least 1300, at least 1400, at least 1500, at least 1600, at least 1700, at least 1800, at least 1900, at least 2000, at least 2100, at least 2200, at least 2300, or at least 2400, but fewer than 2477, consecutive amino acids of SEQ ID NO: 53.

[0163] Elastin and related proteins Elastic fibers in the extracellular matrix provide tissue with elastic properties. Elastic fibers generally contain two morphologically distinct components: mature elastin fibers and microfibrils, which contain primarily fibrillin and associate with additional proteins such as microfibril-associated glycoprotein (MAGP), fibrillin, and elastin-microfibril interface-localized protein (EMILIN). Elastin and its soluble precursor, tropoelastin, are among the major structural proteins in the body.

[0164] In some embodiments, the present disclosure relates to one or more polynucleotides encoding elastin or elastin-related proteins, including tropoelastin, fibrillin, microfibril-associated glycoprotein, fibrillin, or elastin-microfibril interface-localized proteins. In some embodiments, the present disclosure relates to one or more polynucleotides encoding full-length elastin proteins or any isoforms or portions thereof. Any elastin protein from any suitable species known in the art can be encoded by the polynucleotides of the present disclosure, including, for example, human elastin protein (see, e.g., UniProt Accession No. P15502), mouse elastin protein (see, e.g., UniProt Accession No. P15502), chimpanzee elastin protein (see, e.g., UniProt Accession No. H2QUQ6), rat elastin protein (see, e.g., UniProt Accession No. Q99372), etc. Methods for identifying elastin protein homologs / orthologs from additional species are known to those of skill in the art. In some embodiments, elastin proteins of the present disclosure comprise 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 to the sequence of any of the elastin proteins described herein or known in the art.

[0165] In some embodiments, the polynucleotide of the present disclosure encodes a human elastin protein. In some embodiments, the polynucleotide encoding the human elastin protein is a polynucleotide that encodes 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% sequence identity to the sequence of SEQ ID NO: 54. In some embodiments, the polynucleotide encoding the human elastin protein is a polynucleotide that encodes a polypeptide comprising the amino acid sequence of SEQ ID NO: 54.

[0166] In some embodiments, the polynucleotide encoding the human elastin protein is a polynucleotide encoding an N-terminal truncation, C-terminal truncation, or fragment of the amino acid sequence of SEQ ID NO: 54. 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, at least 100, at least 200, at least 300, at least 400, at least 500, at least 600, at least 700, but fewer than 786 contiguous amino acids of SEQ ID NO: 54.

[0167] Lumican protein In some embodiments, the present disclosure relates to one or more polynucleotides encoding a full-length lumican protein or any isoform or portion thereof. For example, any lumican protein from any suitable species known in the art can be encoded by the polynucleotides of the present disclosure, including human lumican protein (e.g., see UniProt Accession No. P51884), mouse lumican protein (e.g., see UniProt Accession No. P51885), chimpanzee lumican protein (e.g., see UniProt Accession No. H2Q6L3), rat lumican protein (e.g., see UniProt Accession No. H2Q6L3), rabbit lumican protein (e.g., see UniProt Accession No. O46379), etc. Methods for identifying lumican protein homologs / orthologs from additional species are known to those skilled in the art. In some embodiments, a lumican protein of the present disclosure comprises a sequence having at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of any of the lumican proteins described herein or known in the art.

[0168] In some embodiments, the polynucleotide of the present disclosure encodes a human lumican protein. In some embodiments, the polynucleotide encoding the human lumican protein encodes 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% sequence identity to the sequence of SEQ ID NO: 55. In some embodiments, the polynucleotide encoding the human lumican protein encodes a polypeptide comprising the amino acid sequence of SEQ ID NO: 55.

[0169] In some embodiments, the polynucleotide encoding the human lumican protein is a polynucleotide encoding an N-terminal truncation, a C-terminal truncation, or a fragment of the amino acid sequence of SEQ ID NO: 55. 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, at least 100, at least 200, or at least 300, but fewer than 338, consecutive amino acids of SEQ ID NO: 55.

[0170] Vitronectin and vitronectin receptor protein In some embodiments, the present disclosure relates to one or more polynucleotides encoding full-length vitronectin or vitronectin receptor proteins, or any isoforms or portions thereof. Any vitronectin or vitronectin receptor protein from any suitable species known in the art can be encoded by a polynucleotide of the present disclosure, including, for example, human vitronectin or vitronectin receptor protein (see, e.g., UniProt Accession Nos. P04004 and P06756), mouse vitronectin or vitronectin receptor protein (see, e.g., UniProt Accession Nos. P29788 and P43406), chimpanzee vitronectin or vitronectin receptor protein (see, e.g., UniProt Accession Nos. H2QCH3 and H2R6C3), rat vitronectin or vitronectin receptor protein (see, e.g., UniProt Accession No. Q7TQ11), rabbit vitronectin or vitronectin receptor protein (see, e.g., UniProt Accession No. P22458), etc. Methods for identifying vitronectin or vitronectin receptor protein homologs / orthologs from additional species are known to those of skill in the art. In some embodiments, the vitronectin or vitronectin receptor proteins of the present disclosure comprise 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 to the sequence of any of the vitronectin or vitronectin receptor proteins described herein or known in the art.

[0171] In some embodiments, the polynucleotide of the present disclosure encodes a human vitronectin protein. In some embodiments, the polynucleotide encoding the human vitronectin protein is a polynucleotide that encodes 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% sequence identity to the sequence of SEQ ID NO: 56. In some embodiments, the polynucleotide encoding the human vitronectin protein is a polynucleotide that encodes a polypeptide comprising the amino acid sequence of SEQ ID NO: 56.

[0172] In some embodiments, the polynucleotide encoding the human vitronectin protein is a polynucleotide encoding an N-terminal truncation, a C-terminal truncation, or a fragment of the amino acid sequence of SEQ ID NO: 56. 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, at least 100, at least 200, at least 300, at least 400, but fewer than 478 consecutive amino acids of SEQ ID NO: 56.

[0173] Laminin Protein In some embodiments, the present disclosure relates to one or more polynucleotides encoding full-length laminin proteins or any isoforms or portions thereof, such as human laminin proteins (see, e.g., UniProt Accession Nos. P25391, P24043, Q16787, Q16363, O15230, P07942, P55268, Q13751, P11047, Q13753, and Q9Y6N6), mouse laminin proteins (see, e.g., UniProt Accession Nos. Q61789, Q61087, and Q61092), chimpanzee laminin proteins (see, e.g., UniProt Accession Nos. Any laminin protein from any suitable species known in the art can be encoded by the polynucleotides of the present disclosure, including laminin proteins from any suitable species known in the art, including those from any species known in the art, including those from any suitable ... In some embodiments, laminin proteins of the present 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 the sequences of any of the laminin proteins described herein or known in the art.

[0174] In some embodiments, the polynucleotides of the disclosure are directed to a human laminin protein, such as a human laminin subunit alpha-1 (LamA1) polypeptide (see, e.g., UniProt Accession No. P25391), a human laminin subunit alpha-2 (LamA2) polypeptide (see, e.g., UniProt Accession No. P24043), a human laminin subunit alpha-3 (LamA3) polypeptide (see, e.g., UniProt Accession No. Q16787), a human laminin subunit alpha-4 (LamA4) polypeptide (see, e.g., UniProt Accession No. Q16363), a human laminin subunit alpha-5 (LamA5) polypeptide (see, e.g., UniProt Accession No. O15230), a human laminin subunit alpha-6 (LamA6) polypeptide (see, e.g., UniProt Accession No. O15231), a human laminin subunit alpha-7 (LamA7) polypeptide (see, e.g., UniProt Accession No. O15232), a human laminin subunit alpha-8 (LamA8) polypeptide (see, e.g., UniProt Accession No. O15233), a human laminin subunit alpha-9 (LamA9) polypeptide (see, e.g., UniProt Accession No. O15234), a human laminin subunit alpha-10 (LamA10) polypeptide (see, e.g., UniProt Accession No. O15235), a human laminin subunit alpha-11 (LamA11) polypeptide (see, e.g., UniProt Accession No. O15236), a human laminin subunit alpha-12 (LamA12) polypeptide (see, e.g., UniProt Accession No. O15237), a human laminin subunit alpha-13 (La and the like.

[0175] In some embodiments, the polynucleotide of the present disclosure encodes a human LamA3 polypeptide. In some embodiments, the polynucleotide encoding the human LamA3 polypeptide is a polynucleotide that encodes 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% sequence identity to the sequence of SEQ ID NO: 57. In some embodiments, the polynucleotide encoding the human LamA3 polypeptide is a polynucleotide that encodes a polypeptide comprising the amino acid sequence of SEQ ID NO: 57.

[0176] In some embodiments, the polynucleotide encoding the human LamA3 polypeptide is a polynucleotide encoding an N-terminal truncation, C-terminal truncation, or fragment of the amino acid sequence of SEQ ID NO: 57. 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, 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, at least 2500, at least 2750, at least 3000, or at least 3250, but fewer than 3333, contiguous amino acids of SEQ ID NO: 57.

[0177] In some embodiments, the polynucleotide of the present disclosure encodes a human LamB3 polypeptide. In some embodiments, the polynucleotide encoding the human LamB3 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% sequence identity to the sequence of SEQ ID NO: 58. In some embodiments, the polynucleotide encoding the human LamB3 polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 58.

[0178] In some embodiments, the polynucleotide encoding a LamB3 polypeptide is a polynucleotide encoding an N-terminal truncation, C-terminal truncation, or fragment of the amino acid sequence of SEQ ID NO: 58. 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, 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 1100, but fewer than 1172 consecutive amino acids of SEQ ID NO: 58.

[0179] In some embodiments, the polynucleotide of the present disclosure encodes a human LamC2 polypeptide. In some embodiments, the polynucleotide encoding the human LamC2 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% sequence identity to the sequence of SEQ ID NO: 59. In some embodiments, the polynucleotide encoding the human LamC2 polypeptide is a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 59.

[0180] In some embodiments, the polynucleotide encoding the LamC2 polypeptide is a polynucleotide encoding an N-terminal truncation, a C-terminal truncation, or a fragment of the amino acid sequence of SEQ ID NO: 59. 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, 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 1100, but fewer than 1193 consecutive amino acids of SEQ ID NO: 59.

[0181] Neuromodulatory Proteins In some embodiments, the present disclosure relates to one or more polynucleotides encoding a full-length neuromodulatory protein or any isoform or portion thereof. For example, any neuromodulatory protein from any suitable species known in the art can be encoded by a polynucleotide of the present disclosure, including Clostridium botulinum proteins (see, e.g., UniProt Accession Nos. P0DPI0, Q45894, P0DPI1, P10844, and B1INP5). Methods for identifying neuromodulator protein homologs / orthologs from additional species are known to those of skill in the art. In some embodiments, a neuromodulatory protein of the present disclosure comprises a sequence having at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of any neuromodulatory protein described herein or known in the art.

[0182] In some embodiments, a polynucleotide of the present disclosure encodes a Clostridium botulinum neuromodulatory protein.

[0183] In some embodiments, a polynucleotide of the present disclosure encodes a type A Clostridium botulinum neurotoxin protein. In some embodiments, the polynucleotide encoding a type A Clostridium botulinum neurotoxin protein encodes 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% sequence identity to the sequence of SEQ ID NO: 60. In some embodiments, the polynucleotide encoding a type A Clostridium botulinum neurotoxin protein encodes a polypeptide comprising the amino acid sequence of SEQ ID NO: 60. In some embodiments, the type A Clostridium botulinum neurotoxin protein of the present disclosure comprises an alanine to valine mutation at a position corresponding to position 27 of SEQ ID NO: 60.

[0184] In some embodiments, the polynucleotide encoding a type A Clostridium botulinum neurotoxin protein is a polynucleotide encoding an N-terminal truncation, a C-terminal truncation, or a fragment of the amino acid sequence of SEQ ID NO: 60. 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, 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 1100, or at least 1200, but fewer than 1296, contiguous amino acids of SEQ ID NO: 60.

[0185] In some embodiments, the polynucleotide of the present disclosure encodes a type B Clostridium botulinum neurotoxin protein. In some embodiments, the polynucleotide encoding the type B Clostridium botulinum neurotoxin protein encodes a polynucleotide 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% sequence identity to the sequence of SEQ ID NO: 61. In some embodiments, the polynucleotide encoding the type B Clostridium botulinum neurotoxin protein encodes a polypeptide comprising the amino acid sequence of SEQ ID NO: 61.

[0186] In some embodiments, the polynucleotide encoding a Clostridium botulinum type B neurotoxin protein is a polynucleotide encoding an N-terminal truncation, a C-terminal truncation, or a fragment of the amino acid sequence of SEQ ID NO: 61. 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, 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 1100, or at least 1200, but fewer than 1291, contiguous amino acids of SEQ ID NO: 61.

[0187] Fibrillin protein In some embodiments, the present disclosure relates to one or more polynucleotides encoding a full-length fibrillin protein or any isoform or portion thereof. Any fibrillin protein from any suitable species known in the art can be encoded by a polynucleotide of the present disclosure, including, for example, human fibrillin protein (see, e.g., UniProt Accession Nos. P35555, P35556, and Q75N90), mouse fibrillin protein (see, e.g., UniProt Accession Nos. Q61554 and Q61555), chimpanzee fibrillin protein (see, e.g., UniProt Accession Nos. A0A2I3RTE4 and K7CZX0), rat fibrillin protein (see, e.g., UniProt Accession Nos. G3V9M6 and F1M5Q4), rabbit fibrillin protein (see, e.g., UniProt Accession Nos. G1SKM2, G1SUS5, and G1T1H4), etc. Methods for identifying fibrillin protein homologs / orthologs from additional species are known to those of skill in the art. In some embodiments, a fibrillin protein of the present disclosure comprises a sequence having at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of any of the fibrillin proteins described herein or known in the art.

[0188] In some embodiments, the polynucleotides of the present disclosure encode human fibrillin proteins.

[0189] In some embodiments, the polynucleotide of the present disclosure encodes a human fibrillin-1 protein. In some embodiments, the polynucleotide encoding the human fibrillin-1 protein is a polynucleotide that encodes 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% sequence identity to the sequence of SEQ ID NO: 62. In some embodiments, the polynucleotide encoding the human fibrillin-1 protein is a polynucleotide that encodes a polypeptide comprising the amino acid sequence of SEQ ID NO: 62.

[0190] In some embodiments, the polynucleotide encoding the human fibrillin-1 protein is a polynucleotide encoding an N-terminal truncation, a C-terminal truncation, or a fragment of the amino acid sequence of SEQ ID NO: 62. 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, 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, at least 2500, at least 2750, but fewer than 2871 consecutive amino acids of SEQ ID NO: 62.

[0191] In some embodiments, the polynucleotide of the present disclosure encodes a human fibrillin-2 protein. In some embodiments, the polynucleotide encoding the human fibrillin-2 protein is a polynucleotide that encodes 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% sequence identity to the sequence of SEQ ID NO: 63. In some embodiments, the polynucleotide encoding the human fibrillin-2 protein is a polynucleotide that encodes a polypeptide comprising the amino acid sequence of SEQ ID NO: 63.

[0192] In some embodiments, the polynucleotide encoding the human fibrillin-2 protein is a polynucleotide encoding an N-terminal truncation, a C-terminal truncation, or a fragment of the amino acid sequence of SEQ ID NO: 63. 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, 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, at least 2500, at least 2750, but fewer than 2912 consecutive amino acids of SEQ ID NO: 63.

[0193] In some embodiments, the polynucleotide of the present disclosure encodes a human fibrillin-3 protein. In some embodiments, the polynucleotide encoding the human fibrillin-3 protein is a polynucleotide that encodes 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% sequence identity to the sequence of SEQ ID NO: 64. In some embodiments, the polynucleotide encoding the human fibrillin-3 protein is a polynucleotide that encodes a polypeptide comprising the amino acid sequence of SEQ ID NO: 64.

[0194] In some embodiments, the polynucleotide encoding the human fibrillin-3 protein is a polynucleotide encoding an N-terminal truncation, a C-terminal truncation, or a fragment of the amino acid sequence of SEQ ID NO: 64. 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, 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, at least 2500, at least 2750, but fewer than 2809, consecutive amino acids of SEQ ID NO: 64.

[0195] Exemplary Cosmetic Polypeptides In some embodiments, one or more cosmetic proteins of the present disclosure (e.g., the first cosmetic protein, the further cosmetic protein, the additional cosmetic protein, and / or the second cosmetic protein) comprise an amino acid sequence that comprises at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to an amino acid sequence selected from SEQ ID NOs: 15-21 or 53-64. In some embodiments, one or more cosmetic proteins of the present disclosure (e.g., the first cosmetic protein, the further cosmetic protein, the additional cosmetic protein, and / or the second cosmetic protein) comprise a sequence selected from SEQ ID NOs: 15-21 or 53-64.

[0196] In some embodiments, one or more cosmetic proteins of the present disclosure (e.g., the first cosmetic protein, the further cosmetic protein, the additional cosmetic protein, and / or the second cosmetic protein) comprise an amino acid sequence that comprises at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to an amino acid sequence selected from SEQ ID NOs: 15-21, 53-54, or 57-59. In some embodiments, one or more cosmetic proteins of the present disclosure (e.g., the first cosmetic protein, the further cosmetic protein, the additional cosmetic protein, and / or the second cosmetic protein) comprise a sequence selected from SEQ ID NOs: 15-21, 53-54, or 57-59.

[0197] First Polynucleotide In some embodiments, the present disclosure relates to a recombinant nucleic acid comprising a first polynucleotide encoding a first polypeptide comprising a first cosmetic protein. The first cosmetic protein can be any of the cosmetic proteins described herein or known in the art, including, for example, collagen proteins, fibronectin, elastin, lumican, vitronectin / vitronectin receptor, laminin, neuromodulators, fibrillin, etc. In some embodiments, the first cosmetic protein is a structural extracellular matrix protein (e.g., collagen, elastin, fibronectin, laminin, fibrillin, etc.). In some embodiments, the first cosmetic protein is a collagen, elastin, fibronectin, or laminin protein (e.g., human collagen, elastin, fibronectin, or laminin protein).

[0198] In some embodiments, a recombinant nucleic acid of the disclosure comprises one copy of a first polynucleotide. In some embodiments, a recombinant nucleic acid of the disclosure comprises two or more (e.g., two or more, three or more, four or more, five or more, ten or more, etc.) copies of a first polynucleotide. In some embodiments, a recombinant nucleic acid of the disclosure comprises two copies of a first polynucleotide.

[0199] In some embodiments, the first cosmetic protein is a first human collagen protein. The first human collagen protein can be any of the human collagen proteins described herein or known in the art. In some embodiments, the first human collagen protein is selected from COL1-1, COL1-2, COL2, COL3, COL4-1, COL4-2, COL4-3, COL4-4, COL4-5, COL4-6, COL5-1, COL5-2, COL5-3, COL6-1, COL6-2, COL6-3, COL6-4, COL6-5, COL6-6, COL7, COL8, COL9-1, COL9-2, COL9-3, COL10, COL11-1, COL11-2, COL12, COL13, COL14, COL15, COL16, COL17, COL18, COL19, COL20, COL21, COL22, COL23, COL24, COL25, COL26, COL27, or COL28. In some embodiments, the first human collagen protein is selected from COL1-1, COL1-2, COL3, COL4-1, COL4-2, COL6-1, COL7, or COL17. In some embodiments, the first human collagen protein is COL1-1. In some embodiments, the first human collagen protein is COL1-2. In some embodiments, the first human collagen protein is COL3. In some embodiments, the first human collagen protein is COL4-1. In some embodiments, the first human collagen protein is COL4-2. In some embodiments, the first human collagen protein is COL6-1. In some embodiments, the first human collagen protein is COL7. In some embodiments, the first human collagen protein is not COL7. In some embodiments, the first human collagen protein is COL17.

[0200] In some embodiments, the first polypeptide consists essentially of a first cosmetic protein. In some embodiments, the first polypeptide consists of a first cosmetic protein. In some embodiments, the first polypeptide is a first cosmetic protein.

[0201] Chimeric Polypeptides In some embodiments, the first polypeptide is a chimeric polypeptide comprising a first cosmetic protein. In some embodiments, the first polypeptide is a chimeric polypeptide comprising a first cosmetic protein and an additional cosmetic protein. In some embodiments, the chimeric polypeptide comprises a linker polypeptide connecting the first cosmetic protein and the additional cosmetic protein. In some embodiments, the chimeric polypeptide comprises, from N-terminus to C-terminus, the first cosmetic protein-linker polypeptide-additional cosmetic protein. The first cosmetic protein and / or the additional cosmetic protein can be any of the cosmetic proteins described herein or known in the art, including, for example, collagen proteins, fibronectin, elastin, lumican, vitronectin / vitronectin receptor, laminin, neuromodulators, fibrillin, etc. In some embodiments, the first cosmetic protein and / or the additional cosmetic protein is a structural extracellular matrix protein (e.g., collagen, elastin, fibronectin, laminin, fibrillin, etc.). In some embodiments, the first cosmetic protein and / or the additional cosmetic protein is a collagen, elastin, fibronectin, or laminin protein (e.g., human collagen, elastin, fibronectin, or laminin protein). In some embodiments, the first cosmetic protein and the additional cosmetic protein are the same. In some embodiments, the first cosmetic protein and the additional cosmetic protein are different.

[0202] In some embodiments, the linker polypeptide is a cleavable linker polypeptide. Any cleavable linker polypeptide known in the art can be used in the chimeric polypeptides of the present disclosure, including, for example, a T2A linker, a P2A linker, an E2A linker, an F2A linker, etc. In some embodiments, the linker polypeptide is a T2A linker polypeptide. An exemplary nucleic acid sequence encoding a T2A linker polypeptide is provided as SEQ ID NO:24. An exemplary amino acid sequence of a T2A linker polypeptide is provided as SEQ ID NO:28. In some embodiments, the linker polypeptide is a P2A linker polypeptide. An exemplary nucleic acid sequence encoding a P2A linker polypeptide is provided as SEQ ID NO:25. An exemplary amino acid sequence of a P2A linker polypeptide is provided as SEQ ID NO:29. In some embodiments, the linker polypeptide is an E2A linker polypeptide. An exemplary nucleic acid sequence encoding an E2A linker polypeptide is provided as SEQ ID NO:26. An exemplary amino acid sequence of an E2A linker polypeptide is provided as SEQ ID NO:30. In some embodiments, the linker polypeptide is an F2A linker polypeptide. An exemplary nucleic acid sequence encoding an F2A linker polypeptide is provided as SEQ ID NO: 27. An exemplary amino acid sequence of an F2A linker polypeptide is provided as SEQ ID NO: 31.

[0203] In some embodiments, the linker 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 to an amino acid sequence selected from SEQ ID NOs: 28-31. In some embodiments, the linker polypeptide comprises a sequence selected from SEQ ID NOs: 28-31.

[0204] In some embodiments, the first cosmetic protein is a first collagen protein (e.g., a first human collagen protein) and the additional cosmetic protein is an additional collagen protein (e.g., an additional human collagen protein). An exemplary nucleic acid sequence encoding a chimeric polypeptide comprising a first human collagen protein, a linker polypeptide, and an additional human collagen protein is provided as SEQ ID NO:32.

[0205] In some embodiments, the first cosmetic protein is a first human collagen protein and the additional cosmetic protein is an additional human collagen protein. The additional human collagen protein can be any of the human collagen proteins described herein or known in the art. In some embodiments, the additional human collagen protein is selected from COL1-1, COL1-2, COL2, COL3, COL4-1, COL4-2, COL4-3, COL4-4, COL4-5, COL4-6, COL5-1, COL5-2, COL5-3, COL6-1, COL6-2, COL6-3, COL6-4, COL6-5, COL6-6, COL7, COL8, COL9-1, COL9-2, COL9-3, COL10, COL11-1, COL11-2, COL12, COL13, COL14, COL15, COL16, COL17, COL18, COL19, COL20, COL21, COL22, COL23, COL24, COL25, COL26, COL27, or COL28. In some embodiments, the additional human collagen protein is selected from COL1-1, COL1-2, COL3, COL4-1, COL4-2, COL6-1, COL7, or COL17. In some embodiments, the additional human collagen protein is COL1-1. In some embodiments, the additional human collagen protein is COL1-2. In some embodiments, the additional human collagen protein is COL3. In some embodiments, the additional human collagen protein is COL4-1. In some embodiments, the additional human collagen protein is COL4-2. In some embodiments, the additional human collagen protein is COL6-1. In some embodiments, the additional human collagen protein is COL7. In some embodiments, the additional human collagen protein is not COL7. In some embodiments, the additional human collagen protein is COL17. In some embodiments, the first human collagen protein and the additional human collagen protein are the same.In some embodiments, the first human collagen protein and the additional human collagen protein are different.

[0206] In some embodiments, the first human collagen protein is COL1-1 and the additional human collagen protein is selected from COL1-2, COL3, COL4-1, COL4-2, COL6-1, COL7, or COL17. In some embodiments, the first human collagen protein is COL1-1 and the additional human collagen protein is COL1-2. In some embodiments, the first human collagen protein is COL1-1 and the additional human collagen protein is COL3.

[0207] In some embodiments, the first human collagen protein is COL1-2 and the additional human collagen protein is COL1-1, COL3, COL4-1, COL4-2, COL6-1, COL7, or COL17. In some embodiments, the first human collagen protein is COL1-2 and the additional human collagen protein is COL1-1.

[0208] In some embodiments, the first human collagen protein is COL3 and the additional human collagen protein is selected from COL1-1, COL1-2, COL4-1, COL4-2, COL6-1, COL7, or COL17.

[0209] In some embodiments, the first human collagen protein is COL4-1 and the additional human collagen protein is COL1-1, COL1-2, COL3, COL4-2, COL6-1, COL7, or COL17. In some embodiments, the first human collagen protein is COL4-1 and the additional human collagen protein is COL4-2.

[0210] In some embodiments, the first human collagen protein is COL6-1 and the additional human collagen protein is selected from COL1-1, COL1-2, COL3, COL4-1, COL4-2, COL7, or COL17.

[0211] In some embodiments, the first human collagen protein is COL7 and the additional human collagen protein is COL1-1, COL1-2, COL3, COL4-1, COL4-2, COL6-1, or COL17.

[0212] In some embodiments, the first human collagen protein is COL17 and the additional human collagen protein is COL1-1, COL1-2, COL3, COL4-1, COL4-2, COL6-1, or COL7.

[0213] In some embodiments, the first cosmetic protein is a first laminin protein (e.g., a first human laminin protein) and the additional cosmetic protein is an additional laminin protein (e.g., an additional human laminin protein). In some embodiments, the first cosmetic protein is a first human laminin protein and the additional cosmetic protein is an additional human laminin protein. The additional human laminin protein can be any of the human laminin proteins described herein or known in the art. In some embodiments, the first human laminin protein is a human LamA3 polypeptide and the additional human laminin protein is a human LamB3 polypeptide. In some embodiments, the first human laminin protein is a human LamA3 polypeptide and the additional human laminin protein is a human LamC2 polypeptide. In some embodiments, the first human laminin protein is a human LamB3 polypeptide and the additional human laminin protein is a human LamC2 polypeptide.

[0214] In some embodiments, the first polynucleotide encodes a monocistronic mRNA. In some embodiments, the monocistronic mRNA comprises an open reading frame (ORF) encoding the first polypeptide.

[0215] In some embodiments, the first polynucleotide encodes a polycistronic mRNA. In some embodiments, the polycistronic mRNA comprises an open reading frame (ORF) encoding the first polypeptide.

[0216] Polycistronic mRNA In some embodiments, the first polynucleotide encodes a polycistronic mRNA. In some embodiments, the polycistronic mRNA comprises an open reading frame (ORF) encoding a first polypeptide. In some embodiments, the first polynucleotide encodes a polycistronic mRNA comprising (1) a first open reading frame (ORF) encoding the first polypeptide and (2) a second open reading frame (ORF) encoding an additional cosmetic protein. In some embodiments, the polycistronic mRNA further comprises an internal ribosome entry site (IRES) separating the first ORF and the second ORF. In some embodiments, the polycistronic mRNA comprises, in the 5' to 3' direction: a first ORF encoding the first polypeptide, an IRES, and a second ORF encoding the additional cosmetic protein. The first polypeptide can be any of the first polypeptides described herein. The additional cosmetic protein can be any of the cosmetic proteins described herein or known in the art, including, for example, collagen proteins, fibronectin, elastin, lumican, vitronectin / vitronectin receptor, laminin, neuromodulators, fibrillin, etc. In some embodiments, the additional cosmetic protein is a structural extracellular matrix protein (e.g., collagen, elastin, fibronectin, laminin, fibrillin, etc.). In some embodiments, the additional cosmetic protein is a collagen, elastin, fibronectin, or laminin protein (e.g., human collagen, elastin, fibronectin, or laminin protein).

[0217] For example, virus-derived IRES (e.g., IRES derived from poliovirus, rhinovirus, encephalomyocarditis virus (EMCV), foot-and-mouth disease virus, hepatitis C virus, classical swine fever virus, Rous sarcoma virus, human immunodeficiency virus, cricket paralysis virus, Kaposi's sarcoma-associated herpesvirus, etc.), cellular mRNA-derived IRES (e.g., IRES derived from growth factor mRNAs such as fibroblast growth factor 2, platelet-derived growth factor B, and vascular endothelial growth factor, IRES derived from transcription factor mRNAs such as antennapedia, ultrathorax, and NF-κB inhibitor, c-myc, pim-1, and protein kinase p58), PITSLRE Any suitable IRES known in the art can be used in the polycistronic mRNAs of the present disclosure, including IRESs derived from oncogene mRNAs such as IgG148, IgG24, IgG3, IgG4, IgG5, IgG6, IgG7, IgG8, IgG9, IgG10, IgG11, IgG12, IgG13, IgG14, IgG15, IgG16, IgG17, IgG18, IgG19, IgG20, IgG21, IgG22, IgG23, IgG24, IgG25, IgG26, IgG27, IgG28, IgG29, IgG30, IgG40, IgG41, IgG42, IgG43, IgG44, IgG45, IgG46, IgG47, IgG48, IgG49, IgG41, IgG41, IgG42, IgG45, IgG46, IgG47, IgG48, IgG49, IgG50, IgG41, IgG42, IgG45, IgG46, IgG47, IgG48, IgG49 ...3, IgG44, IgG45, IgG45, IgG46, IgG47, IgG48, IgG49, IgG41, IgG42, IgG44, IgG45, IgG46, IgG47, IgG48, IgG49, IgG41,

[0218] In some embodiments, the nucleic acid sequence encoding an IRES 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 to a nucleic acid sequence selected from SEQ ID NO: 22 or SEQ ID NO: 23. In some embodiments, the nucleic acid sequence encoding an IRES comprises the sequence of SEQ ID NO: 22 or SEQ ID NO: 23.

[0219] In some embodiments, the first polypeptide is a first collagen protein (e.g., a first human collagen protein) and the additional cosmetic protein is an additional collagen protein (e.g., an additional human collagen protein). An exemplary nucleic acid encoding a polycistronic mRNA comprising a first ORF, an IRES, and a second ORF is provided as SEQ ID NO: 33 or SEQ ID NO: 34. The additional human collagen protein can be any of the human collagen proteins described herein. In some embodiments, the additional human collagen protein is selected from COL1-1, COL1-2, COL2, COL3, COL4-1, COL4-2, COL4-3, COL4-4, COL4-5, COL4-6, COL5-1, COL5-2, COL5-3, COL6-1, COL6-2, COL6-3, COL6-4, COL6-5, COL6-6, COL7, COL8, COL9-1, COL9-2, COL9-3, COL10, COL11-1, COL11-2, COL12, COL13, COL14, COL15, COL16, COL17, COL18, COL19, COL20, COL21, COL22, COL23, COL24, COL25, COL26, COL27, or COL28. In some embodiments, the additional human collagen protein is selected from COL1-1, COL1-2, COL3, COL4-1, COL4-2, COL6-1, COL7, or COL17. In some embodiments, the additional human collagen protein is COL1-1. In some embodiments, the additional human collagen protein is COL1-2. In some embodiments, the additional human collagen protein is COL3. In some embodiments, the additional human collagen protein is COL4-1. In some embodiments, the additional human collagen protein is COL4-2. In some embodiments, the additional human collagen protein is COL6-1. In some embodiments, the additional human collagen protein is COL7. In some embodiments, the additional human collagen protein is not COL7. In some embodiments, the additional human collagen protein is COL17.In some embodiments, the first human collagen protein and the additional human collagen protein are the same. In some embodiments, the first human collagen protein and the additional human collagen protein are different.

[0220] In some embodiments, the first human collagen protein is COL1-1 and the additional human collagen protein is selected from COL1-2, COL3, COL4-1, COL4-2, COL6-1, COL7, or COL17. In some embodiments, the first human collagen protein is COL1-1 and the additional human collagen protein is COL1-2. In some embodiments, the first human collagen protein is COL1-1 and the additional human collagen protein is COL3.

[0221] In some embodiments, the first human collagen protein is COL1-2 and the additional human collagen protein is selected from COL1-1, COL3, COL4-1, COL4-2, COL6-1, COL7, or COL17. In some embodiments, the first human collagen protein is COL1-2 and the additional human collagen protein is COL1-1.

[0222] In some embodiments, the first human collagen protein is COL3 and the additional human collagen protein is selected from COL1-1, COL1-2, COL4-1, COL4-2, COL6-1, COL7, or COL17.

[0223] In some embodiments, the first human collagen protein is COL4-1 and the additional human collagen protein is selected from COL1-1, COL1-2, COL3, COL4-2, COL6-1, COL7, or COL17. In some embodiments, the first human collagen protein is COL4-1 and the additional human collagen protein is COL4-2.

[0224] In some embodiments, the first human collagen protein is COL6-1 and the additional human collagen protein is selected from COL1-1, COL1-2, COL3, COL4-1, COL4-2, COL7, or COL17.

[0225] In some embodiments, the first human collagen protein is COL7 and the additional human collagen protein is selected from COL1-1, COL1-2, COL3, COL4-1, COL4-2, COL6-1, or COL17.

[0226] In some embodiments, the first human collagen protein is COL17 and the additional human collagen protein is selected from COL1-1, COL1-2, COL3, COL4-1, COL4-2, COL6-1, or COL7.

[0227] In some embodiments, the first polypeptide is a first collagen protein (eg, a first human collagen protein) and the additional cosmetic protein is an additional collagen protein (eg, an additional human collagen protein).

[0228] In some embodiments, the first polypeptide is a first laminin protein (e.g., a first human laminin protein) and the additional cosmetic protein is an additional laminin protein (e.g., an additional human laminin protein). In some embodiments, the first polypeptide is a first human laminin protein and the additional cosmetic protein is an additional human laminin protein. The additional human laminin protein can be any of the human laminin proteins described herein or known in the art. In some embodiments, the first human laminin protein is a human LamA3 polypeptide and the additional human laminin protein is a human LamB3 polypeptide. In some embodiments, the first human laminin protein is a human LamA3 polypeptide and the additional human laminin protein is a human LamC2 polypeptide. In some embodiments, the first human laminin protein is a human LamB3 polypeptide and the additional human laminin protein is a human LamC2 polypeptide.

[0229] Second Polynucleotide In some embodiments, the present disclosure relates to a recombinant nucleic acid further comprising a second polynucleotide encoding a second cosmetic protein. The second cosmetic protein can be any of the cosmetic proteins described herein or known in the art, including, for example, collagen proteins, fibronectin, elastin, lumican, vitronectin / vitronectin receptor, laminin, neuromodulators, fibrillin, etc. In some embodiments, the second cosmetic protein is a structural extracellular matrix protein (e.g., collagen, elastin, fibronectin, laminin, fibrillin, etc.). In some embodiments, the second cosmetic protein is a collagen, elastin, fibronectin, or laminin protein (e.g., human collagen, elastin, fibronectin, or laminin protein). In some embodiments, the first cosmetic protein and the second cosmetic protein are the same. In some embodiments, the first cosmetic protein and the second cosmetic protein are different. In some embodiments, the recombinant nucleic acid comprises one copy of the second polynucleotide. In some embodiments, the recombinant nucleic acid comprises two or more (e.g., two or more, three or more, four or more, five or more, ten or more, etc.) copies of the second polynucleotide. In some embodiments, the recombinant nucleic acid comprises two copies of the second polynucleotide.

[0230] In some embodiments, the second cosmetic protein is a collagen protein. In some embodiments, the second cosmetic protein is a second human collagen protein. The second human collagen protein can be any of the human collagen proteins described herein. In some embodiments, the second human collagen protein is selected from COL1-1, COL1-2, COL2, COL3, COL4-1, COL4-2, COL4-3, COL4-4, COL4-5, COL4-6, COL5-1, COL5-2, COL5-3, COL6-1, COL6-2, COL6-3, COL6-4, COL6-5, COL6-6, COL7, COL8, COL9-1, COL9-2, COL9-3, COL10, COL11-1, COL11-2, COL12, COL13, COL14, COL15, COL16, COL17, COL18, COL19, COL20, COL21, COL22, COL23, COL24, COL25, COL26, COL27, or COL28. In some embodiments, the second human collagen protein is selected from COL1-1, COL1-2, COL3, COL4-1, COL6-1, COL7, or COL17. In some embodiments, the second human collagen protein is COL1-1. In some embodiments, the second human collagen protein is COL1-2. In some embodiments, the second human collagen protein is COL3. In some embodiments, the second human collagen protein is COL4-1. In some embodiments, the second human collagen protein is COL4-2. In some embodiments, the second human collagen protein is COL6-1. In some embodiments, the second human collagen protein is COL7. In some embodiments, the second human collagen protein is not COL7. In some embodiments, the second human collagen protein is COL17.

[0231] In some embodiments, the first polynucleotide encodes a first collagen protein and the second polynucleotide encodes a second collagen protein. In some embodiments, the first polynucleotide encodes a first human collagen protein and the second polynucleotide encodes a second human collagen protein. In some embodiments, the first human collagen protein (encoded by the first polynucleotide) and the second human collagen protein (encoded by the second polynucleotide) are the same. In some embodiments, the first human collagen protein (encoded by the first polynucleotide) and the second human collagen protein (encoded by the second polynucleotide) are different.

[0232] In some embodiments, the first human collagen protein is COL1-1 and the second human collagen protein is selected from COL1-2, COL3, COL4-1, COL4-2, COL6-1, COL7, or COL17. In some embodiments, the first human collagen protein is COL1-1 and the second human collagen protein is COL1-2. In some embodiments, the first human collagen protein is COL1-1 and the second human collagen protein is COL3.

[0233] In some embodiments, the first human collagen protein is COL1-2 and the second human collagen protein is selected from COL1-1, COL3, COL4-1, COL4-2, COL6-1, COL7, or COL17. In some embodiments, the first human collagen protein is COL1-2 and the second human collagen protein is COL1-1.

[0234] In some embodiments, the first human collagen protein is COL3 and the second human collagen protein is selected from COL1-1, COL1-2, COL4-1, COL4-2, COL6-1, COL7, or COL17.

[0235] In some embodiments, the first human collagen protein is COL4-1 and the second human collagen protein is selected from COL1-2, COL1-2, COL3, COL4-2, COL6-1, COL7, or COL17. In some embodiments, the first human collagen protein is COL4-1 and the second human collagen protein is COL4-2.

[0236] In some embodiments, the first human collagen protein is COL6-1 and the second human collagen protein is selected from COL1-1, COL1-2, COL3, COL4-1, COL4-2, COL7, or COL17.

[0237] In some embodiments, the first human collagen protein is COL7 and the second human collagen protein is selected from COL1-1, COL1-2, COL3, COL4-1, COL4-2, COL6-1, or COL17.

[0238] In some embodiments, the first human collagen protein is COL17 and the second human collagen protein is selected from COL1-1, COL1-2, COL3, COL4-1, COL4-2, COL6-1, or COL7.

[0239] In some embodiments, the first polynucleotide encodes a first laminin protein (e.g., a first human laminin protein), and the second polynucleotide encodes a second laminin protein (e.g., a second human laminin protein). In some embodiments, the first polynucleotide encodes a first human laminin polypeptide, and the second polynucleotide encodes a second human laminin protein. The second human laminin protein can be any of the human laminin proteins described herein or known in the art. In some embodiments, the first human laminin protein is a human LamA3 polypeptide, and the second human laminin protein is a human LamB3 polypeptide. In some embodiments, the first human laminin protein is a human LamA3 polypeptide, and the second human laminin protein is a human LamC2 polypeptide. In some embodiments, the first human laminin protein is a human LamB3 polypeptide, and the second human laminin protein is a human LamC2 polypeptide.

[0240] Recombinant nucleic acids In some embodiments, the present disclosure relates to a recombinant nucleic acid comprising any one or more of the polynucleotides described herein. In some embodiments, the recombinant nucleic acid comprises one copy of a first polynucleotide. In some embodiments, the recombinant nucleic acid comprises two copies of a first polynucleotide. In some embodiments, the recombinant nucleic acid comprises one copy of a first polynucleotide and one copy of a second polynucleotide. In some embodiments, the recombinant nucleic acid comprises one copy of a first polynucleotide and two copies of a second polynucleotide. In some embodiments, the recombinant nucleic acid comprises two copies of a first polynucleotide and one copy of a second polynucleotide. In some embodiments, the recombinant nucleic acid comprises two copies of a first polynucleotide and two copies of a second polynucleotide.

[0241] 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, any vector suitable for maintaining, propagating, and / or expressing a polynucleotide to produce one or more polypeptides in a subject can be used. Examples of suitable vectors can include, for example, plasmids, cosmids, episomes, transposons, and viral vectors (e.g., adenoviral vectors, adeno-associated viral vectors, vaccinia viral vectors, Sindbis viral vectors, measles vectors, herpes viral vectors, lentiviral vectors, retroviral vectors, etc.). In some embodiments, the vector is a herpes viral vector. In some embodiments, the vector is capable of autonomous replication in a host cell. In some embodiments, the vector is not capable of autonomous replication in a host cell. In some embodiments, the vector is capable of integration into host DNA. In some embodiments, the vector is not capable of integration into host DNA (e.g., is episomal). Those skilled in the art are familiar with methods for preparing vectors containing one or more polynucleotides of interest, for example, by chemical synthesis or by the artificial manipulation of isolated segments of nucleic acid (e.g., by genetic engineering techniques).

[0242] In some embodiments, the recombinant nucleic acid of the present disclosure is a herpes simplex virus (HSV) amplicon. Herpes virus amplicons, including structural features and methods of making them, are generally known to those of skill in the art (see, e.g., 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, an HSV / AAV hybrid amplicon, an HSV / EBV hybrid amplicon, an HSV / EBV / RV hybrid amplicon, and / or an HSV / Sleeping Beauty hybrid amplicon. In some embodiments, the amplicon is an HSV / AAV hybrid amplicon. In some embodiments, the amplicon is an HSV / Sleeping Beauty hybrid amplicon.

[0243] In some embodiments, the recombinant nucleic acid of the present disclosure is a recombinant herpesvirus genome. For example, the recombinant herpesvirus genome can be a recombinant genome from any member of the Herpesviridae family of DNA viruses known in the art, including a recombinant herpes simplex virus genome, a recombinant varicella-zoster virus genome, a recombinant human cytomegalovirus genome, a recombinant herpesvirus 6A genome, a recombinant herpesvirus 6B genome, a recombinant herpesvirus 7 genome, a recombinant Kaposi's sarcoma-associated herpesvirus genome, and any combination or derivative thereof. In some embodiments, the recombinant herpesvirus genome comprises 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, the 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 a corresponding wild-type herpesvirus genome). In some embodiments, the recombinant herpesvirus genome is replication-competent. In some embodiments, the recombinant herpesvirus genome is replication-deficient.

[0244] 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 herpes simplex virus genome is replication-competent. In some embodiments, the recombinant herpes simplex virus genome is replication-deficient. In some embodiments, the recombinant herpes simplex virus genome comprises 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, the 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 or regulon product (RNA or protein) with reduced, undetectable, or eliminated amount and / or function (e.g., compared to the corresponding sequence lacking the inactivating mutation). Examples of inactivating mutations include, but are not limited to, deletions, insertions, point mutations, and rearrangements of transcription control sequences (promoters, enhancers, insulators, etc.) and / or coding sequences of a given gene or regulon. Any suitable method for measuring the amount of a gene or regulon product known in the art may be used, including, for example, qPCR, Northern blot, RNAseq, Western blot, ELISA, etc.

[0245] In some embodiments, the recombinant herpes simplex virus genome comprises 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 all eight of the infected cell protein (or infected 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 comprise an inactivating mutation in the ICP34.5 herpes simplex virus gene and / or the ICP47 herpes simplex virus gene (e.g., to avoid production of immunostimulatory virus). In some embodiments, the recombinant herpes simplex virus genome does not comprise an inactivating mutation in the ICP34.5 herpes simplex virus gene (one or both copies). In some embodiments, the recombinant herpes simplex virus genome does not comprise an inactivating mutation in the ICP47 herpes simplex virus gene. In some embodiments, the recombinant herpes simplex virus genome does not comprise 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.

[0246] In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP0 gene (one or both copies). In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP0 gene (one or both copies) and further comprises an initiation mutation in the ICP4 (one or both copies), ICP22, ICP27, ICP47, UL41, and / or UL55 gene. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP0 gene (one or both copies) and an inactivating mutation in the ICP4 gene (one or both copies). In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP0 gene (one or both copies) and an inactivating mutation in the ICP22 gene. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP0 gene (one or both copies) and an inactivating mutation in the UL41 gene. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP0 gene (one or both copies), an inactivating mutation in the ICP4 gene (one or both copies), and an inactivating mutation in the ICP22 gene. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP0 gene (one or both copies), an inactivating mutation in the ICP4 gene (one or both copies), and an inactivating mutation in the UL41 gene. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP0 gene (one or both copies), an inactivating mutation in the ICP22 gene, and an inactivating mutation in the UL41 gene. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP0 gene (one or both copies), an inactivating mutation in the ICP4 gene (one or both copies), an inactivating mutation in the ICP22 gene, and an inactivating mutation in the UL41 gene. In some embodiments, the inactivating mutation is a deletion of the coding sequence of the ICP0 (one or both copies), ICP4 (one or both copies), ICP22, and / or UL41 gene.In some embodiments, the recombinant herpes simplex virus genome further comprises an inactivating mutation in the ICP27, ICP47, and / or UL55 gene.

[0247] In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP4 gene (one or both copies). In some embodiments, the recombinant herpes complex virus genome comprises an inactivating mutation in ICP4 (one or both copies) and further comprises an inactivating mutation in the ICP0 (one or both copies), ICP22, ICP27, ICP47, UL41, and / or UL55 gene. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP4 gene (one or both copies) and an inactivating mutation in the ICP22 gene. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP4 gene (one or both copies) and an inactivating mutation in the UL41 gene. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP4 gene (one or both copies), an inactivating mutation in the ICP22 gene, and an inactivating mutation in the UL41 gene. In some embodiments, the inactivating mutation is a deletion of the coding sequence of the ICP4 (one or both copies), ICP22, and / or UL41 gene. In some embodiments, the recombinant herpes simplex virus genome further comprises an inactivating mutation in the ICP0, ICP27, ICP47, and / or UL55 gene.

[0248] In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP22 gene. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP22 gene and further comprises an inactivating mutation in an ICP0 (one or both copies), ICP4 (one or both copies), ICP27, ICP47, UL41, and / or UL55 gene. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP22 gene and comprises an inactivating mutation in the UL41 gene. In some embodiments, the inactivating mutation is a deletion of the coding sequence of the ICP22 and / or UL41 gene. In some embodiments, the recombinant herpes simplex virus genome further comprises an inactivating mutation in an ICP0 (one or both copies), ICP4 (one or both copies), ICP27, ICP47, and / or UL55 gene.

[0249] In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP27 gene. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP27 gene and further comprises an inactivating mutation in an ICP0 (one or both copies), ICP4 (one or both copies), ICP22, ICP47, UL41, and / or UL55 gene. In some embodiments, the inactivating mutation is a deletion of the coding sequence of the ICP27 gene.

[0250] In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP47 gene. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP47 gene and further comprises an inactivating mutation in an ICP0 (one or both copies), ICP4 (one or both copies), ICP22, ICP27, UL41, and / or UL55 gene. In some embodiments, the inactivating mutation is a deletion of the coding sequence of the ICP47 gene.

[0251] In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the UL41 gene. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the UL41 gene and further comprises an inactivating mutation in an ICP0 (one or both copies), ICP4 (one or both copies), ICP22, ICP27, ICP47, and / or UL55 gene. In some embodiments, the inactivating mutation is a deletion of the coding sequence of the UL41 gene.

[0252] In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the UL55 gene. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the UL55 gene and further comprises an inactivating mutation in an ICP0 (one or both copies), ICP4 (one or both copies), ICP22, ICP27, ICP47, and / or UL41 gene. In some embodiments, the inactivating mutation is a deletion of the coding sequence of the UL55 gene.

[0253] In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation (e.g., deletion) in the internal repeat (junction) region, which includes the IRL (internal repeat long) and IRS (internal repeat short) regions. In some embodiments, inactivation (e.g., deletion) of the junction region eliminates one copy each of the ICP4 gene and the ICP0 gene. In some embodiments, inactivation (e.g., deletion) of the junction region further inactivates (e.g., deletes) the promoters of the ICP22 and ICP47 genes. If desired, expression of one or both of these genes can be restored by insertion of an immediate-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). Without wishing to be bound by theory, it is believed that inactivating (e.g., deleting) the junction region may contribute to the stability of the recombinant herpes simplex virus genome and / or allow the recombinant herpes simplex virus genome to accommodate more and / or larger transgenes.

[0254] In some embodiments, the recombinant herpes simplex virus genome comprises inactivating mutations in the ICP4 (one or both copies), ICP22, and ICP27 genes. In some embodiments, the recombinant herpes simplex virus genome comprises inactivating mutations in the ICP4 (one or both copies), ICP27, and UL55 genes. In some embodiments, the recombinant herpes simplex virus genome comprises inactivating mutations in the ICP4 (one or both copies), ICP22, ICP27, ICP47, and UL55 genes. In some embodiments, the inactivating mutations in the ICP4 (one or both copies), ICP27, and / or UL55 genes are deletions of the coding sequence of the ICP4 (one or both copies), ICP27, and / or UL55 genes. In some embodiments, the inactivating mutations in the ICP22 and ICP47 genes are deletions of the promoter regions of the ICP22 and ICP47 genes (e.g., the ICP22 and ICP47 coding sequences are intact but not transcriptionally active). In some embodiments, the recombinant herpes simplex virus genome comprises a deletion of the coding sequences of the ICP4 (one or both copies), ICP27, and UL55 genes, and a deletion of the promoter regions of the ICP22 and ICP47 genes. In some embodiments, the recombinant herpes simplex virus genome further comprises an inactivating mutation in the ICP0 gene and / or the UL41 gene.

[0255] In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP0 (one or both copies) gene. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP0 (one or both copies) and ICP4 (one or both copies) genes. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP0 (one or both copies), ICP4 (one or both copies), and ICP22 genes. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP0 (one or both copies), ICP4 (one or both copies), ICP22, and ICP27 genes. In some embodiments, the recombinant herpes simplex virus genome comprises an inactivating mutation in the ICP0 (one or both copies), ICP4 (one or both copies), ICP22, ICP27, and UL55 genes. In some embodiments, the inactivating mutations in the ICP0 (one or both copies), ICP4 (one or both copies), ICP22, ICP27, and / or UL55 genes comprise a deletion of the coding sequence of the ICP0, ICP4 (one or both copies), ICP22, ICP27, and / or UL55 genes. In some embodiments, the recombinant herpes simplex virus genome further comprises an inactivating mutation in the ICP47 gene and / or the UL41 gene.

[0256] In some embodiments, a recombinant herpes simplex virus genome comprises one or more polynucleotides of the present disclosure within one, two, three, four, five, six, seven, or more viral loci. Examples of suitable viral loci include, but are not limited to, the ICP0 (one or both copies), ICP4 (one or both copies), ICP22, ICP27, ICP47, tk, UL41, and UL55 herpes simplex virus loci. In some embodiments, a recombinant herpes simplex virus genome comprises one or more polynucleotides of the present disclosure within one or both viral ICP4 loci (e.g., a recombinant virus harboring a first polynucleotide encoding a first human collagen protein within one or both ICP4 loci, a recombinant virus harboring a second polynucleotide encoding a second human collagen protein within one or both ICP4 loci, etc.). In some embodiments, the recombinant herpes simplex virus genome comprises one or more polynucleotides of the present disclosure within the viral ICP22 locus (e.g., a recombinant virus harboring a first polynucleotide encoding a first human collagen protein at the ICP22 locus, a recombinant virus harboring a second polynucleotide encoding a second human collagen protein at the ICP22 locus, etc.). In some embodiments, the recombinant herpes simplex virus genome comprises one or more polynucleotides of the present disclosure within the viral UL41 locus (e.g., a recombinant virus harboring a first polynucleotide encoding a first human collagen protein at the UL41 locus, a recombinant virus harboring a second polynucleotide encoding a second human collagen protein at the UL41 locus, etc.).In some embodiments, the recombinant herpes simplex virus genome comprises one or more polynucleotides of the present disclosure within one or both of the viral ICP4 loci and one or more polynucleotides of the present disclosure within one or both of the viral ICP22 loci (e.g., a recombinant virus harboring a first polynucleotide encoding a first human collagen protein at one or both of the ICP4 loci and a second polynucleotide encoding a second human collagen protein at the ICP22 locus; a recombinant virus harboring a second polynucleotide encoding a second human collagen protein at one or both of the ICP4 loci and a first polynucleotide encoding a first human collagen protein at the ICP22 locus, etc.). In some embodiments, the recombinant herpes simplex virus genome comprises one or more polynucleotides of the present disclosure within one or both of the viral ICP4 loci and one or more polynucleotides of the present disclosure within one or both of the viral UL41 loci (e.g., a recombinant virus harboring a first polynucleotide encoding a first human collagen protein within one or both of the ICP4 loci and a second polynucleotide encoding a second human collagen protein within the UL41 locus; a recombinant virus harboring a second polynucleotide encoding a second human collagen protein within one or both of the ICP4 loci and a first polynucleotide encoding a first human collagen protein within the UL41 locus, etc.).In some embodiments, the recombinant herpes simplex virus genome comprises one or more polynucleotides of the present disclosure within one or both of the viral ICP4 loci, comprises one or more polynucleotides of the present disclosure within the viral ICP22 locus, and comprises one or more polynucleotides of the present disclosure within the viral UL41 locus (e.g., a recombinant virus harboring a first polynucleotide encoding a first human collagen protein within one or both of the ICP4 loci and a second polynucleotide encoding a second human collagen protein within the ICP22 locus and the UL41 locus; a recombinant virus harboring a second polynucleotide encoding a second human collagen protein within one or both of the ICP4 loci and a first polynucleotide encoding a first human collagen protein within the ICP22 locus and the UL41 locus, etc.).

[0257] In some embodiments, the recombinant herpesvirus genome (e.g., recombinant herpes simplex virus genome) has been engineered to reduce or eliminate expression of one or more toxic herpes simplex genes (one or both copies of the HSV ICP0 gene, one or both copies of the HSV ICP4 gene, the ICP22 gene, and / or the UL41 gene). In some embodiments, the recombinant herpesvirus genome (e.g., recombinant herpes simplex virus genome) has been engineered to reduce the cytotoxicity of the recombinant genome (e.g., when introduced into a target cell) compared to a corresponding wild-type herpesvirus genome (e.g., a wild-type herpes simplex virus genome). In some embodiments, the cytotoxicity (e.g., in human keratinocytes and / or fibroblasts) of the recombinant viral genome (e.g., recombinant herpes simplex virus 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%, at least about 90%, at least about 95 ... The cytotoxicity is reduced by 0%, at least about 85%, at least about 90%, at least about 95%, or at least about 99% (e.g., measuring the relative cytotoxicity of recombinant ΔICP4 (one or both copies) herpes simplex virus genome versus wild-type herpes simplex virus genome in human keratinocytes or fibroblasts (primary cells or cell line), measuring the relative cytotoxicity of recombinant ΔICP4 (one or both copies) / ΔICP22 herpes simplex virus genome versus wild-type herpes simplex virus genome in human keratinocytes or fibroblasts (primary cells or cell line), etc.).In some embodiments, the cytotoxicity (e.g., in human keratinocytes and / or fibroblasts) of the recombinant herpesvirus genome (e.g., recombinant herpes simplex virus genome) is at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 6-fold, at least about 7-fold, at least about 8-fold, at least about 9-fold, at least about 10-fold, at least about 15-fold, at least about 20-fold, at least about 25-fold, at least about 50-fold, at least about 75-fold, at least about 100-fold, at least about 150-fold, at least about 200-fold, at least about 250-fold, at least about 500-fold, at least about 1500-fold, at least about 2000-fold, at least about 2500-fold, at least about 2000-fold, at least about 2500-fold, at least about 2500-fold, at least about 2500-fold, at least about 2500-fold, at least about 2500-fold, at least about 2500-fold, at least about 2500-fold, at least about 2500-fold, at least about 2500-fold, at least about 30 ... Both cytotoxicity and cytotoxicity are reduced by at least about 250-fold, at least about 500-fold, at least about 750-fold, at least about 1000-fold, or more (e.g., measuring the relative cytotoxicity of a recombinant ΔICP4 (one or both copies) herpes simplex virus genome to a wild-type herpes simplex virus genome in human keratinocytes or fibroblasts (primary cells or cell lines), measuring the relative cytotoxicity of a recombinant ΔICP4 (one or both copies) / ΔICP22 herpes simplex virus genome to a 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, including, for example, the use of vital dyes (formazan dyes), protease biomarkers, the MTT assay (or assays using related tetrazolium salts, such as XTT, MTS, water-soluble tetrazolium salts), measuring ATP content, etc.

[0258] In some embodiments, the recombinant herpesvirus genome (e.g., recombinant herpes simplex virus genome) is engineered to reduce its effect on host cell proliferation following exposure of a target cell to the recombinant genome, compared to a corresponding wild-type herpesvirus genome (e.g., a wild-type herpes simplex virus genome). In some embodiments, the target cell is a human cell. In some embodiments, the target cell is an epidermal cell and / or a dermal cell. In some embodiments, the target cell is a keratinocyte and / or a fibroblast. In some embodiments, host cell proliferation (e.g., human keratinocytes and / or fibroblasts) after exposure to the recombinant genome is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least 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%, or at least about 99% faster (e.g., measuring the relative cell growth following exposure to a recombinant ΔICP4 (one or both copies) herpes simplex virus genome relative to the cell growth following exposure to a wild-type herpes simplex virus genome in human keratinocytes or fibroblasts (primary cells or cell line); measuring the relative cell growth following exposure to a recombinant ΔICP4 (one or both copies) / ΔICP22 herpes simplex virus genome relative to the cell growth following exposure to a wild-type herpes simplex virus genome in human keratinocytes or fibroblasts (primary cells or cell line), etc.).In some embodiments, host cell proliferation (e.g., human keratinocytes and / or fibroblasts) after exposure to the recombinant genome is at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 6-fold, at least about 7-fold, at least about 8-fold, at least about 9-fold, at least about 10-fold, at least about 15-fold, at least about 20-fold, at least about 25-fold, at least about 50-fold, at least about 75-fold, at least about 100-fold, at least about 250-fold, or at least about 500-fold greater than host cell proliferation after exposure to the corresponding wild-type herpesvirus genome. , at least about 750-fold, or at least about 1000-fold faster (e.g., measuring the relative cell proliferation following exposure to a recombinant ΔICP4 (one or both copies) herpes simplex virus genome relative to the cell proliferation following exposure to a wild-type herpes simplex virus genome in human keratinocytes or fibroblasts (primary cells or cell lines), measuring the relative cell proliferation following exposure to a recombinant ΔICP4 (one or both copies) / ΔICP22 herpes simplex virus genome relative to the cell proliferation following exposure to a wild-type herpes simplex virus genome in human keratinocytes or fibroblasts (primary cells or cell lines), etc.). Methods for measuring cell proliferation are known to those skilled in the art, including, for example, using a Ki67 cell proliferation assay, a BrdU cell proliferation assay, etc.

[0259] A vector (e.g., a herpes virus vector) can contain one or more polynucleotides of the present disclosure in a form suitable for expression of the polynucleotide in a host cell. The vector can include one or more regulatory sequences (e.g., as described above) operably linked to the polynucleotide to be expressed.

[0260] In some embodiments, a recombinant nucleic acid (e.g., a recombinant herpes simplex virus genome) of the present disclosure comprises one or more of the polynucleotides described herein inserted into the recombinant nucleic acid in any orientation. When a recombinant nucleic acid comprises two or more (e.g., two or more, three or more, etc.) polynucleotides described herein, the polynucleotides may be inserted in the same orientation or in opposite orientation to each other. Without wishing to be bound by theory, incorporating two polynucleotides (e.g., two transgenes) into a recombinant nucleic acid (e.g., a vector) in antisense orientation may help avoid read-through and ensure proper expression of each polynucleotide.

[0261] IV. Viruses Certain aspects of the present disclosure relate to viruses comprising any of the polynucleotides and / or recombinant nucleic acids described herein. In some embodiments, the viruses are capable of infecting one or more target cells of a subject (e.g., a human). In some embodiments, the viruses are suitable for delivering polynucleotides and / or recombinant nucleic acids to one or more target cells of a subject (e.g., a human subject). 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 cells are selected from keratinocytes, melanocytes, Langerhans cells, Merkel cells, mast cells, fibroblasts, and / or adipocytes. In some embodiments, the one or more cells are keratinocytes. In some embodiments, the one or more cells are present in the stratum corneum, stratum granulosum, stratum spinosum, stratum basale, and / or basement membrane. In some embodiments, the one or more target cells are one or more epidermal cells.

[0262] Any suitable virus known in the art may be used, including, for example, adenovirus, adeno-associated virus, retrovirus, lentivirus, Sendai virus, herpes virus (e.g., herpes simplex virus), vaccinia virus, and / or any hybrid virus thereof. In some embodiments, the virus is attenuated. In some embodiments, the virus is replication-deficient. In some embodiments, the virus is replication-competent. In some embodiments, the virus has been modified to alter its tissue tropism relative to that of the unmodified wild-type virus. In some embodiments, the virus has reduced cytotoxicity compared to the corresponding wild-type virus. Methods for producing viruses containing recombinant nucleic acids are well known to those of skill in the art.

[0263] 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-competent. In some embodiments, the herpesvirus has reduced cytotoxicity compared to the corresponding wild-type herpesvirus. In some embodiments, the herpesvirus is not oncolytic.

[0264] In some embodiments,...

Claims

1. A cosmetic composition for reducing one or more signs or symptoms of dermatological aging in a subject requiring the reduction of one or more signs or symptoms of dermatological aging, The invention comprises a herpesvirus containing a recombinant herpesvirus genome, wherein the recombinant herpesvirus genome comprises a first polynucleotide encoding a first polypeptide containing a first cosmetic protein, The first cosmetic protein comprises the first collagen alpha-1(I) chain polypeptide (COL1-1), the first collagen alpha-2(I) chain polypeptide (COL1-2), the first collagen alpha-1(II) chain polypeptide (COL2), the first collagen alpha-1(III) chain polypeptide (COL3), the first collagen alpha-1(IV) chain polypeptide (COL4-1), the first collagen alpha-2(IV) chain polypeptide (COL4-2), the first collagen alpha-3(IV) chain polypeptide (COL4-3), and the First collagen alpha-4 (IV) chain polypeptide (COL4-4), first collagen alpha-5 (IV) chain polypeptide (COL4-5), first collagen alpha-6 (IV) chain polypeptide (COL4-6), first collagen alpha-1 (V) chain polypeptide (COL5-1), first collagen alpha-2 (V) chain polypeptide (COL5-2), first collagen alpha-3 (V) chain polypeptide (COL5-3), first collagen alpha-1 (VI) chain polypeptide (COL6-1), first collagen alpha-2 (VI) chain polypeptide (COL6-2), first collagen alpha-3 (VI) chain polypeptide (COL6-3), first collagen alpha-4 (VI) chain polypeptide (COL6-4), first collagen alpha-5 (VI) chain polypeptide (COL6-5), first collagen alpha-6 (VI) chain polypeptide (COL6-6), first collagen alpha-1 (VIII) chain polypeptide (COL8), first collagen alpha-1 (IX) chain polypeptide (COL9-1), first collagen alpha-2 (IX) chain polypeptide Collagen alpha-3 (IX) chain polypeptide (COL9-3), Collagen alpha-1 (X) chain polypeptide (COL10), Collagen alpha-1 (XI) chain polypeptide (COL11-1), Collagen alpha-2 (XI) chain polypeptide (COL11-2), Collagen alpha-1 (XII) chain polypeptide (COL12), Collagen alpha-1 (XIII) chain polypeptide (COL13), Collagen alpha-1 (XIV) chain polypeptide (COL14),First collagen alpha-1 (XV) chain polypeptide (COL15), first collagen alpha-1 (XVI) chain polypeptide (COL16), first collagen alpha-1 (XVII) chain polypeptide (COL17), first collagen alpha-1 (XVIII) chain polypeptide (COL18), first collagen alpha-1 (XIX) chain polypeptide (COL19), first collagen alpha-1 (XX) chain polypeptide (COL20), first collagen alpha-1 (XXI) chain polypeptide (COL21), first collagen alpha-1 (XXII) chain polypeptide (COL22), first collagen alpha-1 (XXIII) chain polypeptide (COL23), first Selected from the group consisting of collagen alpha-1 (XXIV) chain polypeptide (COL24), first collagen alpha-1 (XXV) chain polypeptide (COL25), first collagen alpha-1 (XXVI) chain polypeptide (COL26), first collagen alpha-1 (XXVII) chain polypeptide (COL27), first collagen alpha-1 (XXVIII) chain polypeptide (COL28), first fibronectin protein, first elastin protein, first lumican protein, first vitronectin protein, first vitronectin receptor protein, first laminin protein, first botulinum neurotoxin protein, and first fibrillin protein, The recombinant herpesvirus genome does not contain polynucleotides encoding collagen alpha-1(VII) chain polypeptide, lysyl hydroxylase 3 polypeptide, or keratin type I cytoskeleton 17 polypeptide, and The recombinant herpesvirus genome contains inactivating mutations in both copies of the ICP4 gene. Cosmetic composition.

2. Relief of one or more signs or symptoms of dermatological aging, including (a) treatment, reduction, and / or prevention of fine lines and / or wrinkles, (b) reduction of skin pore diameter, (c) improvement of skin thickness, plumpness, and / or firmness, (d) improvement of skin smoothness, suppleness, and / or softness, (e) improvement of skin tone, radiance, and / or clarity, (f) improvement of procollagen and / or collagen production, and (g) improvement of skin texture and / or retexture. The cosmetic composition according to claim 1, characterized by: (h) promoting rization; (i) improving the appearance of the skin contour; (j) restoring the luster and / or brightness of the skin; (k) improving the appearance of the skin diminished by aging and / or menopause; (l) improving skin hydration; (m) increasing the elasticity and / or resilience of the skin; (n) improving skin firmness; (o) reducing pigment spots, patchy skin, and / or scars; (p) improving the optical properties of the skin by light diffraction or reflection; or (p) any combination thereof.

3. A cosmetic composition for improving the condition, quality, and / or appearance of the skin in a subject that requires improvement of the condition, quality, and / or appearance of the skin, The invention comprises a herpesvirus containing a recombinant herpesvirus genome, wherein the recombinant herpesvirus genome comprises a first polynucleotide encoding a first polypeptide containing a first cosmetic protein, The first cosmetic protein comprises the first collagen alpha-1(I) chain polypeptide (COL1-1), the first collagen alpha-2(I) chain polypeptide (COL1-2), the first collagen alpha-1(II) chain polypeptide (COL2), the first collagen alpha-1(III) chain polypeptide (COL3), the first collagen alpha-1(IV) chain polypeptide (COL4-1), the first collagen alpha-2(IV) chain polypeptide (COL4-2), the first collagen alpha-3(IV) chain polypeptide (COL4-3), and the First collagen alpha-4 (IV) chain polypeptide (COL4-4), first collagen alpha-5 (IV) chain polypeptide (COL4-5), first collagen alpha-6 (IV) chain polypeptide (COL4-6), first collagen alpha-1 (V) chain polypeptide (COL5-1), first collagen alpha-2 (V) chain polypeptide (COL5-2), first collagen alpha-3 (V) chain polypeptide (COL5-3), first collagen alpha-1 (VI) chain polypeptide (COL6-1), first collagen alpha-2 (VI) chain polypeptide (COL6-2), first collagen alpha-3 (VI) chain polypeptide (COL6-3), first collagen alpha-4 (VI) chain polypeptide (COL6-4), first collagen alpha-5 (VI) chain polypeptide (COL6-5), first collagen alpha-6 (VI) chain polypeptide (COL6-6), first collagen alpha-1 (VIII) chain polypeptide (COL8), first collagen alpha-1 (IX) chain polypeptide (COL9-1), first collagen alpha-2 (IX) chain polypeptide Collagen alpha-3 (IX) chain polypeptide (COL9-3), Collagen alpha-1 (X) chain polypeptide (COL10), Collagen alpha-1 (XI) chain polypeptide (COL11-1), Collagen alpha-2 (XI) chain polypeptide (COL11-2), Collagen alpha-1 (XII) chain polypeptide (COL12), Collagen alpha-1 (XIII) chain polypeptide (COL13), Collagen alpha-1 (XIV) chain polypeptide (COL14),First collagen alpha-1 (XV) chain polypeptide (COL15), first collagen alpha-1 (XVI) chain polypeptide (COL16), first collagen alpha-1 (XVII) chain polypeptide (COL17), first collagen alpha-1 (XVIII) chain polypeptide (COL18), first collagen alpha-1 (XIX) chain polypeptide (COL19), first collagen alpha-1 (XX) chain polypeptide (COL20), first collagen alpha-1 (XXI) chain polypeptide (COL21), first collagen alpha-1 (XXII) chain polypeptide (COL22), first collagen alpha-1 (XXIII) chain polypeptide (COL23), first Selected from the group consisting of collagen alpha-1 (XXIV) chain polypeptide (COL24), first collagen alpha-1 (XXV) chain polypeptide (COL25), first collagen alpha-1 (XXVI) chain polypeptide (COL26), first collagen alpha-1 (XXVII) chain polypeptide (COL27), first collagen alpha-1 (XXVIII) chain polypeptide (COL28), first fibronectin protein, first elastin protein, first lumican protein, first vitronectin protein, first vitronectin receptor protein, first laminin protein, first botulinum neurotoxin protein, and first fibrillin protein, The recombinant herpesvirus genome does not contain polynucleotides encoding collagen alpha-1(VII) chain polypeptide, lysyl hydroxylase 3 polypeptide, or keratin type I cytoskeleton 17 polypeptide, and The recombinant herpesvirus genome contains inactivating mutations in both copies of the ICP4 gene. Cosmetic composition.

4. A cosmetic composition for reducing the appearance of one or more surface depressions on the skin of a subject whose appearance needs to be reduced, The invention comprises a herpesvirus containing a recombinant herpesvirus genome, wherein the recombinant herpesvirus genome comprises a first polynucleotide encoding a first polypeptide containing a first cosmetic protein, The first cosmetic protein comprises the first collagen alpha-1(I) chain polypeptide (COL1-1), the first collagen alpha-2(I) chain polypeptide (COL1-2), the first collagen alpha-1(II) chain polypeptide (COL2), the first collagen alpha-1(III) chain polypeptide (COL3), the first collagen alpha-1(IV) chain polypeptide (COL4-1), the first collagen alpha-2(IV) chain polypeptide (COL4-2), the first collagen alpha-3(IV) chain polypeptide (COL4-3), and the First collagen alpha-4 (IV) chain polypeptide (COL4-4), first collagen alpha-5 (IV) chain polypeptide (COL4-5), first collagen alpha-6 (IV) chain polypeptide (COL4-6), first collagen alpha-1 (V) chain polypeptide (COL5-1), first collagen alpha-2 (V) chain polypeptide (COL5-2), first collagen alpha-3 (V) chain polypeptide (COL5-3), first collagen alpha-1 (VI) chain polypeptide (COL6-1), first collagen alpha-2 (VI) chain polypeptide (COL6-2), first collagen alpha-3 (VI) chain polypeptide (COL6-3), first collagen alpha-4 (VI) chain polypeptide (COL6-4), first collagen alpha-5 (VI) chain polypeptide (COL6-5), first collagen alpha-6 (VI) chain polypeptide (COL6-6), first collagen alpha-1 (VIII) chain polypeptide (COL8), first collagen alpha-1 (IX) chain polypeptide (COL9-1), first collagen alpha-2 (IX) chain polypeptide Collagen alpha-3 (IX) chain polypeptide (COL9-3), Collagen alpha-1 (X) chain polypeptide (COL10), Collagen alpha-1 (XI) chain polypeptide (COL11-1), Collagen alpha-2 (XI) chain polypeptide (COL11-2), Collagen alpha-1 (XII) chain polypeptide (COL12), Collagen alpha-1 (XIII) chain polypeptide (COL13), Collagen alpha-1 (XIV) chain polypeptide (COL14),First collagen alpha-1 (XV) chain polypeptide (COL15), first collagen alpha-1 (XVI) chain polypeptide (COL16), first collagen alpha-1 (XVII) chain polypeptide (COL17), first collagen alpha-1 (XVIII) chain polypeptide (COL18), first collagen alpha-1 (XIX) chain polypeptide (COL19), first collagen alpha-1 (XX) chain polypeptide (COL20), first collagen alpha-1 (XXI) chain polypeptide (COL21), first collagen alpha-1 (XXII) chain polypeptide (COL22), first collagen alpha-1 (XXIII) chain polypeptide (COL23), first Selected from the group consisting of collagen alpha-1 (XXIV) chain polypeptide (COL24), first collagen alpha-1 (XXV) chain polypeptide (COL25), first collagen alpha-1 (XXVI) chain polypeptide (COL26), first collagen alpha-1 (XXVII) chain polypeptide (COL27), first collagen alpha-1 (XXVIII) chain polypeptide (COL28), first fibronectin protein, first elastin protein, first lumican protein, first vitronectin protein, first vitronectin receptor protein, first laminin protein, first botulinum neurotoxin protein, and first fibrillin protein, The recombinant herpesvirus genome does not contain polynucleotides encoding collagen alpha-1(VII) chain polypeptide, lysyl hydroxylase 3 polypeptide, or keratin type I cytoskeleton 17 polypeptide, and The recombinant herpesvirus genome contains inactivating mutations in both copies of the ICP4 gene. Cosmetic composition.

5. The cosmetic composition according to claim 4, wherein one or more surface depressions in the skin are selected from the group consisting of nasolabial folds, crow's feet, frown lines, forehead wrinkles, scars, frown lines, ptosis, tear troughs, nasojugal lines, bunny lines, cheek / middle face ptosis, marionette lines, poppy dimple formation, laugh lines, chin folds, neck wrinkles, platysma girdle, and any combination thereof.

6. A cosmetic composition for increasing and / or improving at least one of the texture, smoothness, elasticity, or firmness of the skin of a subject that requires an increase and / or improvement of at least one of the texture, smoothness, elasticity, or firmness of the skin, The invention comprises a herpesvirus containing a recombinant herpesvirus genome, wherein the recombinant herpesvirus genome comprises a first polynucleotide encoding a first polypeptide containing a first cosmetic protein, The first cosmetic protein comprises the first collagen alpha-1(I) chain polypeptide (COL1-1), the first collagen alpha-2(I) chain polypeptide (COL1-2), the first collagen alpha-1(II) chain polypeptide (COL2), the first collagen alpha-1(III) chain polypeptide (COL3), the first collagen alpha-1(IV) chain polypeptide (COL4-1), the first collagen alpha-2(IV) chain polypeptide (COL4-2), the first collagen alpha-3(IV) chain polypeptide (COL4-3), and the First collagen alpha-4 (IV) chain polypeptide (COL4-4), first collagen alpha-5 (IV) chain polypeptide (COL4-5), first collagen alpha-6 (IV) chain polypeptide (COL4-6), first collagen alpha-1 (V) chain polypeptide (COL5-1), first collagen alpha-2 (V) chain polypeptide (COL5-2), first collagen alpha-3 (V) chain polypeptide (COL5-3), first collagen alpha-1 (VI) chain polypeptide (COL6-1), first collagen alpha-2 (VI) chain polypeptide (COL6-2), first collagen alpha-3 (VI) chain polypeptide (COL6-3), first collagen alpha-4 (VI) chain polypeptide (COL6-4), first collagen alpha-5 (VI) chain polypeptide (COL6-5), first collagen alpha-6 (VI) chain polypeptide (COL6-6), first collagen alpha-1 (VIII) chain polypeptide (COL8), first collagen alpha-1 (IX) chain polypeptide (COL9-1), first collagen alpha-2 (IX) chain polypeptide Collagen alpha-3 (IX) chain polypeptide (COL9-3), Collagen alpha-1 (X) chain polypeptide (COL10), Collagen alpha-1 (XI) chain polypeptide (COL11-1), Collagen alpha-2 (XI) chain polypeptide (COL11-2), Collagen alpha-1 (XII) chain polypeptide (COL12), Collagen alpha-1 (XIII) chain polypeptide (COL13), Collagen alpha-1 (XIV) chain polypeptide (COL14),First collagen alpha-1 (XV) chain polypeptide (COL15), first collagen alpha-1 (XVI) chain polypeptide (COL16), first collagen alpha-1 (XVII) chain polypeptide (COL17), first collagen alpha-1 (XVIII) chain polypeptide (COL18), first collagen alpha-1 (XIX) chain polypeptide (COL19), first collagen alpha-1 (XX) chain polypeptide (COL20), first collagen alpha-1 (XXI) chain polypeptide (COL21), first collagen alpha-1 (XXII) chain polypeptide (COL22), first collagen alpha-1 (XXIII) chain polypeptide (COL23), first Selected from the group consisting of collagen alpha-1 (XXIV) chain polypeptide (COL24), first collagen alpha-1 (XXV) chain polypeptide (COL25), first collagen alpha-1 (XXVI) chain polypeptide (COL26), first collagen alpha-1 (XXVII) chain polypeptide (COL27), first collagen alpha-1 (XXVIII) chain polypeptide (COL28), first fibronectin protein, first elastin protein, first lumican protein, first vitronectin protein, first vitronectin receptor protein, first laminin protein, first botulinum neurotoxin protein, and first fibrillin protein, The recombinant herpesvirus genome does not contain polynucleotides encoding collagen alpha-1(VII) chain polypeptide, lysyl hydroxylase 3 polypeptide, or keratin type I cytoskeleton 17 polypeptide, and The recombinant herpesvirus genome contains inactivating mutations in both copies of the ICP4 gene. Cosmetic composition.

7. The cosmetic composition according to any one of claims 1 to 6, wherein the recombinant herpesvirus genome is a recombinant herpes simplex virus genome.

8. The cosmetic composition according to claim 7, wherein the recombinant herpes simplex virus genome is a recombinant herpes simplex virus type 1 (HSV-1) genome.

9. The cosmetic composition according to any one of claims 1 to 8, wherein the first polynucleotide encoding the first polypeptide is located within one or both of the ICP4 virus loci.

10. The cosmetic composition according to any one of claims 1 to 9, wherein the first cosmetic protein comprises a sequence having at least 95% or 100% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NO: 15, SEQ ID NO: 17, and SEQ ID NOs: 53 to 64.

11. The cosmetic composition according to any one of claims 1 to 10, wherein the recombinant herpesvirus genome further comprises a second polynucleotide encoding a second polypeptide containing a second cosmetic protein, the second cosmetic protein being selected from the group consisting of collagen protein, fibronectin protein, elastin protein, lumican protein, vitronectin protein, vitronectin receptor protein, laminin protein, botulinum neurotoxin protein, and fibrillin protein.

12. The cosmetic composition according to claim 11, wherein the first cosmetic protein and the second cosmetic protein are different.

13. The cosmetic composition according to claim 11, wherein the first cosmetic protein and the second cosmetic protein are the same.

14. The cosmetic composition according to any one of claims 1 to 13, wherein the herpes virus is replication-deficient.

15. The cosmetic composition according to any one of claims 1 to 14, wherein the herpes virus is herpes simplex virus.

16. A cosmetic composition according to any one of claims 1 to 15, which is suitable for local, transdermal, subcutaneous, intradermal, oral, intranasal, intratracheal, sublingual, oral cavity, rectal, vaginal, urethral, ​​inhalation, intravenous, intraarterial, intramuscular, intracardiac, intraosseous, intraperitoneal, transmucosal, intravitreous, subretinal, intra-articular, periarticular, local, or cutaneous administration.

17. The cosmetic composition according to any one of claims 1 to 16, which is suitable for intradermal administration.

18. The cosmetic composition according to any one of claims 1 to 17, which is suitable for surface injection.

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