Prophylactic normalization of cutaneous wound repair

Abstract

The present invention relates to methods of inhibiting scar formation in a skin wound as well as methods of promoting tissue regeneration in a skin wound in a subject in need thereof comprising administering in or near said wound an effective amount of one or more neurotoxins.

1 . A method of decreasing scar formation in a skin wound in a subject in need thereof comprising administering to said subject in or near said wound an effective amount of one or more neurotoxins, wherein said amount is sufficient to decrease formation of scar tissue and insufficient to produce muscular paralysis in said wound. 
     
     
         2 . A method of promoting tissue regeneration in a skin wound in a subject in need thereof comprising administering to said subject in or near said wound an effective amount of one or more neurotoxins, wherein said amount is sufficient to promote regeneration of skin morphology in said wound characteristic of dermis in uninjured skin. 
     
     
         3 . The method of  claim 1  or  claim 2  wherein said neurotoxin is botulinum neurotoxin or a derivative thereof. 
     
     
         4 . The method of  claim 3  wherein the botulinum neurotoxin is selected from the group consisting of botulinum neurotoxin A, B, C, D, E, F, and G. 
     
     
         5 . The method of  claim 4 , wherein said botulinum neurotoxin is botulinum neurotoxin A or a derivative thereof. 
     
     
         6 . The method of  claim 5  wherein the botulinum neurotoxin A is selected from the group consisting of incobotulinumtoxinA, onabotulinumtoxinA, and abobotulinumtoxinA or a derivative thereof. 
     
     
         7 . The method of  claim 4 , wherein said botulinum neurotoxin is botulinum neurotoxin B or a derivative thereof. 
     
     
         8 . The method of  claim 7  wherein the botulinum neurotoxin B is rimabotulinumtoxinB or a derivative thereof. 
     
     
         9 . The method of  claim 1  or  claim 2  wherein said method further comprises administering one or more agents in addition to the neurotoxin in or near said wound. 
     
     
         10 . The method of  claim 9  wherein said agent is administered prior to administration of said neurotoxin, after administration of said neurotoxin, and/or concurrently with the administration of said neurotoxin. 
     
     
         11 . The method of any one of  claim 1 ,  2 , or  9  wherein the neurotoxin and/or the agent is administered in or near the wound in a manner selected from the group consisting of intradermal injection, superficial intradermal injection, jet neubulizer injection, topical application, or a combination thereof. 
     
     
         12 . The method of  claim 11  wherein said topical application is administered in the form of a cream, ointment, or a transdermal patch or transdermal disc. 
     
     
         13 . The method of  claim 11  wherein said neurotoxin and/or the agent is administered by superficial intradermal injection in or near the wound site to form a bleb of neurotoxin and/or agent superficially intradermally in or near the wound site. 
     
     
         14 . The method of  claim 11  or  claim 13  wherein the neurotoxin is diluted prior to injection. 
     
     
         15 . The method of  claim 14  wherein aliquots of the diluted neurotoxin are injected into the superficial dermis or epidermal/dermal junction near the wound site creating one or more bleb reservoirs of neurotoxin. 
     
     
         16 . The method of  claim 15  wherein said aliquots are from about 0.02 ml per cm 2  to about 0.2 ml per cm 2  per injection. 
     
     
         17 . The method of any one of  claim 1 ,  2  or  9  wherein the neurotoxin is incobotulinumtoxinA and said incobotulinumtoxinA is superficially injected in an amount from about 2.5 units/cm 2  to about 7.5 units/cm 2  per injection. 
     
     
         18 . The method of  claim 17  wherein the incobotulinumtoxinA is administered at a dose of about 7.5 units/cm 2  per injection. 
     
     
         19 . The method of  claim 17  wherein the incobotulinumtoxinA is administered at a dose of about 5.0 units/cm 2  per injection. 
     
     
         20 . The method of  claim 17  wherein the incobotulinumtoxinA is administered at a dose of about 2.5 units/cm 2  per injection. 
     
     
         21 . The method of any one of  claim 11 ,  13  or  14  wherein one or more superficial intradermal injections are performed in the wound itself and/or in or near the wound site. 
     
     
         22 . The method of  claim 21  wherein the injections are made in the wound margin from about 0 cm to about 5 cm from the wound. 
     
     
         23 . The method of  claim 22  wherein the injections are made in the wound margin within about 3 cm from the wound. 
     
     
         24 . The method of  claim 21  wherein the injections are made around the entire wound site, or in one or more sections thereof. 
     
     
         25 . The method of  claim 9  wherein said agent is selected from the group consisting of anesthetics, antimicrobials, and vasoconstrictive agents. 
     
     
         26 . The method of  claim 25  wherein the vasoconstrictive agent is selected from the group consisting of amphetamines, antihistamines, decongestants, and other agents capable of enhancing norepinephrine, epinephrine, or adrenergic activity by stimulating α-adrenergic receptors. 
     
     
         27 . The method of  claim 25 , wherein said anesthetic is selected from the group consisting of lidocaine, bupivacaine, and mepivacaine. 
     
     
         28 . The method of  claim 9  wherein said agent is an agent capable of enhancing skin repair, skin regeneration and/or wound healing. 
     
     
         29 . The method of  claim 28  wherein said agent is selected from the group consisting of a growth factor, a cytokine, an integrin, a canonical Wnt protein, connexin 43, an inhibitor or activator of a growth factor, a cytokine, an integrin, a canonical Wnt protein, or connexin 43; an antagonist or agonist of a growth factor receptor or cytokine receptor, or an integrin, a canonical Wnt protein, or connexin 43; or a combination thereof. 
     
     
         30 . The method of  claim 28  wherein the agent can inhibit expression and/or activity of a growth factor or a cytokine. 
     
     
         31 . The method of  claim 30  wherein the agent can inhibit the expression and/or activity of one or more proteins selected from the group consisting of homeobox proteins, early growth protein 1, vascular endothelial growth factor, insulin-like growth factor, integrins, canonical Wnt proteins, connexin 43, and TGFβ. 
     
     
         32 . The method of  claim 28  wherein said agent is one or more autologous blood product. 
     
     
         33 . The method of  claim 32  wherein said autologous blood product is a minimally altered autologous blood product. 
     
     
         34 . The method of  claim 33  wherein said minimally altered autologous blood product is selected from the group consisting of interleukins, platelet derived growth factors, and connective tissue growth factor. 
     
     
         35 . The method of  claim 28  wherein said agent is platelet-rich plasma. 
     
     
         36 . The method of any one of  claim 1 ,  2  or  9  wherein the neurotoxin and/or the agent are modified, formulated, and/or administered to optimize the activity of the neurotoxin and/or the agent in the superficial layers of the skin in or near the site of the wound, including at the wound margins. 
     
     
         37 . The method of any one of  claim 1 ,  2 , or  9  wherein the neurotoxin and/or the agent are modified, formulated and/or administered in a manner designed to minimize diffusion and/or dispersion of the neurotoxin or additional agent away from the site of administration. 
     
     
         38 . The method of  claim 2  wherein said skin morphology is characterized by the formation of rete-ridges and/or collagen deposition in the wound which more closely resembles that seen in uninjured tissue.