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WO2018157011A1 - Produits et méthodes pour le traitement de brûlures - Google Patents

Produits et méthodes pour le traitement de brûlures Download PDF

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Publication number
WO2018157011A1
WO2018157011A1 PCT/US2018/019599 US2018019599W WO2018157011A1 WO 2018157011 A1 WO2018157011 A1 WO 2018157011A1 US 2018019599 W US2018019599 W US 2018019599W WO 2018157011 A1 WO2018157011 A1 WO 2018157011A1
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WO
WIPO (PCT)
Prior art keywords
skin
skin substitute
wound
genetically
products
Prior art date
Application number
PCT/US2018/019599
Other languages
English (en)
Inventor
Paul Holzer
Bo OVERSCHMIDT
Jeremy GOVERMAN
Original Assignee
Xenotherapeutics, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Xenotherapeutics, Inc. filed Critical Xenotherapeutics, Inc.
Publication of WO2018157011A1 publication Critical patent/WO2018157011A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/36—Skin; Hair; Nails; Sebaceous glands; Cerumen; Epidermis; Epithelial cells; Keratinocytes; Langerhans cells; Ectodermal cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/54—Mixtures of enzymes or proenzymes covered by more than a single one of groups A61K38/44 - A61K38/46 or A61K38/51 - A61K38/53
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy

Definitions

  • the present invention relates to the treatment of burn wounds with a debriding agent and a genetically-modified xenogeneic skin substitute.
  • the skin performs many vital functions, allowing the human body to maintain homeostasis. These functions include preventing dessication via fluid loss, preventing electrolyte loss, and insulating the body against unchecked temperature loss. Following severe burn injury these functions are often interrupted, either due to gross skin loss or due to formation of eschar, a layer of nonviable burned skin.
  • tangential excision which involves removal of thin layers of dermis until healthy tissue is visualized
  • fascial excision which involves removal of the full thickness of dermis down to the underlying fascia.
  • Tangential excision allows less viable tissue to be removed with the necrotic tissue, but typically results in higher blood loss, is a larger physiologic stressor than fascial excision, and is more likely to result in "incomplete" debridement, with some devitalized tissue remaining in place.
  • fascial excision blood loss and operative time are minimized, but often a large amount of healthy tissue is removed with the burned tissue.
  • the wound may be covered with autologous skin grafts (autografts), or if autografting is contraindicated or unnecessary, temporary coverage is obtained using one of several wound coverage products.
  • autografts autologous skin grafts
  • These wound coverage products provide differing levels of wound protection and restoration of the skin barrier during healing.
  • Common commercially available products include synthetic and biologic products.
  • synthetic products include, bandages, topical antimicrobial preparations, and other synthetic (such as nylon or similar polymer) products with or without nonviable cellular or protein components.
  • Biologic products can be human or animal derived.
  • human derived products include human acellular dermal matrices, various powdered lyophilized cell preparations, and split thickness cadaver allografts which may be cryopreserved or glycerol preserved.
  • Cryopreserved allograft is the only product that contains viable cells, however its availability is limited. All currently commercially available animal products contain either no cellular components or nonviable cells.
  • biologic or synthetic products are both acceptable.
  • biologic products include human cadaver allograft and nonviable xenograft.
  • Human cadaver allograft is commonly used for recreating the skin's barrier. It adheres to the burn wound and, by virtue of containing viable cells, is able to survive at that site until it is rejected by the recipient's immune system, which typically takes about 1-3 weeks. Because it adheres well and survives, it is able to create a good barrier against fluid and electrolyte loss and prevent wound infection. Additionally, it is thought that the presence of non-crosslinked extracellular matrix proteins in the allograft functions to promote healing of the underlying wound. As a living tissue, its viability is tied to its access to nutrients, and thus, is dependent on maintaining good contact with the wound bed and that the wound bed contains viable tissue.
  • live-cell xenogeneic products provide the highest level of barrier restoration
  • the use of live-cell xenogeneic products was halted by the FDA due to concerns surrounding zoonotic endogenous retroviruses.
  • the available xenogeneic products for the treatment of burns are aldehyde-fixed, so they contain no viable cells, which alleviates the concern for retrovirus transmission.
  • aldehyde cross-linking of cell surface molecules limits the potential efficacy of these products and renders them stiffer and less conformable. They function as a biologic wound coverage but do not adhere, restore the skin's barrier, or prevent infection to the same degree as live-cell products. Similar to allograft, these xenogeneic products are rejected by the recipient's immune system and typically require changing every several days.
  • BIOBRA E Smith & Nephew
  • BIOBRA E is a product consisting of a pliable nylon mesh impregnated with xenogeneic collagen. The manufacturer claims that this product effectively covers wounds and that the collagen peptides promote healing; however it does not restore the skin's barrier function to the same degree as biologies.
  • antimicrobial creams and non-adherent gauzes are available for the treatment of small burns.
  • the present invention is directed to a method of treating a burn wound in a subject in need of such treatment, which comprises:
  • the present invention is directed to a system for treating a burn wound which comprises:
  • Described herein is (1) a method of treatment of burn wounds comprised of burn wound preparation with a debriding agent followed by wound coverage with a viable genetically modified xenogeneic skin substitute; and (2) a combination product comprising a debriding agent and a viable genetically modified xenogeneic skin substitute.
  • the debriding agent of the present invention comprises any agent that is capable of cleaning a burn wound by removing foreign material and dead tissue. Many such agents are known.
  • an enzymatic debridement agent is used. In enzymatic debridement, collagenases or other proteolytic enzymes are employed that break down proteins of the extracellular matrix, allowing devitalized tissue to be wiped away without the need for surgery while preferably leaving healthy tissue substantially intact.
  • the enzymatic debridement agent may be a bromelain enriched enzyme product, but may also be another collagenase or other enzyme product that is capable of clearing devitalized tissue or wound debris.
  • NexoBridTM MediWound Ltd.
  • Such products and methods are described in U.S. Patent Nos. 8,540,983; 8, 119,124; 7,128,719; and 7,794,709, each of which is incorporated by reference herein, and U.S. Patent Application No. 11/571,880 (Publication No. US2009/0010910A1), which is incorporation by reference herein.
  • the enzymatic agent is commonly provided in a dry powder form that is reconstituted prior to use, but it may also be provided in other forms, such as an ointment or cream.
  • Suitable preservation techniques include cryopreservation, glycerol preservation, etc.
  • the skin substitute comprises skin harvested from alpha- 1, 3 -galactosyltransf erase knockout swine, such as those described in U.S. Patent No. 7,547,816, the contents of which are incorporated herein by reference.
  • Such Gal- knockout swine lack the epitope or marker responsible for eliciting the hyperacute rejection response. Instead, the recipient's immune system reacts to products from these swine in the same manner as it would react to allogeneic products.
  • Skin harvested from these swine possesses all of the advantages of live-cell allograft products (such as cadaver allograft) in terms of clinical efficacy and duration of adherence prior to rejection, but avoid the logistical and ethical concerns surrounding the use of human tissues. While there are glutaraldehyde fixed xenogeneic products on the market today, they generally do not meet the clinical efficacy of live-cell and glycerol preserved cadaver allograft at restoring the skin's barrier function.
  • the xenogeneic skin substitute described herein is a product derived from the skin of GalT-knockout genetically modified swine, which is has not undergone aldehyde fixation or crosslinking.
  • Skin substitute products derived from swine possessing this modification have been studied extensively in a pig-to- baboon model. See, e.g., U.S. Patent No. 9,883,939, the contents of which are incorporated herein by reference.
  • porcine skin substitute is able to vascularize in a manner similar to allograft, remain viable and adherent to the wound bed for a time comparable to allograft, and restore the skin's barrier function similarly to allograft when compared on the basis of preventing infection and minimizing fluid loss.
  • skin substitutes may be obtained, stored and prepared as known in the art, or otherwise utilized as described in U.S. Patent No. 9,883,939 and Weiner et al., Xenotransplantation 2010, 17: 147- 152, the contents of which are incorporated by reference herein.
  • This product most often is a split thickness skin graft composed of the entire epidermis and superficial portion of the dermis, but may also be a full thickness skin graft composed of the entire epidermis and entire dermis, or a product composed of the dermis alone.
  • the product most often is cryopreserved, but may also be preserved in a glycerol solution.
  • the dimensions of the product will vary depending on the specific needs present in each individual case.
  • the thickness of the product is dependent on the composition of the skin substitute (split thickness, full thickness, or dermis alone).
  • Split thickness grafts are most commonly harvested at a thickness of 0.022 inches but may be thinner or thicker.
  • the thickness of dermal and full thickness skin products is dependent on the dermal thickness of the individual swine donor.
  • the resulting wound bed is also different from a wound bed following surgical debridement.
  • the wound bed typically has a relatively uniform contour as tissue is removed along a single plane.
  • the tissue is more uneven, as every pocket of devitalized tissue is removed while leaving intervening healthy tissue. This results in a non-uniform wound bed with increased overall surface area, of which a higher proportion consists of exposed, healthy tissue.
  • cryopreserved, live-cell or glycerol- preserved xenogeneic skin grafts as coverage following enzymatic debridement is a novel method of treatment that is distinct from the use of cadaver allograft and results in better results than other non-allograft products.
  • Cryopreserved and glycerol preserved xenografts maintain their pliability and conformability after storage, and are able to conform to the uneven contour of the enzymatically debrided wound bed more effectively than stiffer, aldehyde cross-linked products.
  • Live-cell xenograft exerts efficacy by adhering to the wound bed, vascularizing, and providing a living-tissue barrier against infection and fluid loss. All of these aspects are primarily dependent on being in contact with a healthy viable wound bed. Therefore, the wound bed provided by enzymatic debridement, in which necrotic tissue is removed more thoroughly and healthy, viable tissue is more effectively spared, provides a special advantage to live-cell xenografts that is not realized with the use of non-live-cell products - including terminally sterilized and/or aldehyde crosslinked xenografts - allowing them to be more effective at restoring the skin's barrier function.
  • nonbiologic products such as gauzes, antimicrobial creams, and nylon meshes, do not exert their efficacy by the mechanisms described above, they do not benefit from the unique wound bed provided by enzymatic debridement to the same degree as a live-cell product.
  • glutaraldehyde fixed products Because the efficacy of glutaraldehyde fixed products is not dependent on being in contact with a healthy, viable wound bed (i.e. they do not exert their effect through readily vascularizing and instead act only by providing a biologic coverage, akin to a bandage) to the same degree as live-cell products, they do not benefit from the unique wound bed provided by enzymatic debridement to the same degree as a cryopreserved or glycerol preserved product.
  • the method of treatment described herein may be referred to as a "clean and cover" technique for the treatment of burn wounds.
  • the enzymatic debriding agent is prepared, mixed, or reconstituted as is appropriate, and its application is carried out in any suitable manner, e.g., according to the manufacturer's recommendations for that product. Such may include application of the debriding agent, followed by a period during which the product exerts its effect. That period may vary depending on the specific product and the nature of the wound to be treated.
  • Treatment times using the enzymatic debridement agent may range from minutes to several days depending on the exact debridement product used and number of serial applications required in order to achieve adequate wound debridement. Most commonly, Nexobrid, a bromelain based product, requires four hours per treatment, and multiple treatments are typically not necessary. After this period the wound may preferably be wiped, scraped, or otherwise cleaned in order to remove the residual product and any enzymatically digested tissue. Treatment in such manner results in a wound, which may be either partial thickness or full thickness, but is commonly a mixture of the two, which requires further management.
  • a skin substitute as described above.
  • the skin substitute is placed on the wound bed and secured in place using appropriate means, such as sutures, staples, bandages, or other similar methods.
  • the skin substitute is left in place until such time as it either is rejected by the recipient's immune system, or is removed intentionally to allow further treatment.
  • This further treatment may include placement of cadaver allograft or another burn care product, placement of autologous skin grafts for definitive closure, etc.
  • the combination product described herein is a product comprising a debridement agent and a skin substitute for the purpose of executing the method of treatment described above.
  • Both the debridement agent and skin substitute may be supplied in various quantities and sizes for use on burn wounds of various sizes, so that a managing physician may make a determination regarding quantity required.
  • the products may be packaged together and sold together, packaged separately and sold together, or packaged separately and sold separately for the purpose of use together.
  • the exact packaging for each will vary, depending on the specific product.
  • the packaging is appropriate for the preservation method.
  • cryopreserved grafts are preserved in cryopreservation medium in a polypropylene (or similar) vial, tube, or other container that is specifically intended for cryopreservation purposes.
  • Cryopreservation media contains a DMSO or glycerol protectant and may be mixed with human or porcine serum with or without antibiotics and other additives.
  • Glycerol preserved grafts may be packaged in an appropriate sterile pouch, vial, tube, or other container with or without residual glycerol containing medium.
  • packaging may optionally include suitable instructional material for use of the combination product (e.g., package insert, printed instructions on container material, etc.).

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Cell Biology (AREA)
  • Immunology (AREA)
  • Dermatology (AREA)
  • Biotechnology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biomedical Technology (AREA)
  • Developmental Biology & Embryology (AREA)
  • Virology (AREA)
  • Zoology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Materials For Medical Uses (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne des méthodes de traitement de brûlures dans lesquelles on utilise un agent de débridement et un substitut de peau xénogénique génétiquement modifié viable, et des produits de combinaison utilisant ces agents de traitement.
PCT/US2018/019599 2017-02-24 2018-02-24 Produits et méthodes pour le traitement de brûlures WO2018157011A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201762463275P 2017-02-24 2017-02-24
US62/463,275 2017-02-24

Publications (1)

Publication Number Publication Date
WO2018157011A1 true WO2018157011A1 (fr) 2018-08-30

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999046368A2 (fr) * 1998-03-13 1999-09-16 Biomarin Pharmaceuticals Enzymes de modification des hydrates de carbones utilisees pour le parage de plaies et de brulures et methodes de traitement associees
US20110275972A1 (en) * 2008-10-02 2011-11-10 L.R.R.& D. Ltd. Interface layer wound dressing
US20150164634A1 (en) * 2012-05-08 2015-06-18 The General Hospital Corporation Reducing immunogenicity of xenogeneic transplant tissues
US20150182664A1 (en) * 2002-08-21 2015-07-02 Revivicor, Inc. Tissue Products Derived from Animals Lacking any Expression of Functional Alpha 1, 3 Galactosyltransferase
WO2016065046A1 (fr) * 2014-10-22 2016-04-28 Indiana University Research & Technology Corporation Porcs triples transgéniques appropriés pour la xénogreffe

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999046368A2 (fr) * 1998-03-13 1999-09-16 Biomarin Pharmaceuticals Enzymes de modification des hydrates de carbones utilisees pour le parage de plaies et de brulures et methodes de traitement associees
US20150182664A1 (en) * 2002-08-21 2015-07-02 Revivicor, Inc. Tissue Products Derived from Animals Lacking any Expression of Functional Alpha 1, 3 Galactosyltransferase
US20110275972A1 (en) * 2008-10-02 2011-11-10 L.R.R.& D. Ltd. Interface layer wound dressing
US20150164634A1 (en) * 2012-05-08 2015-06-18 The General Hospital Corporation Reducing immunogenicity of xenogeneic transplant tissues
WO2016065046A1 (fr) * 2014-10-22 2016-04-28 Indiana University Research & Technology Corporation Porcs triples transgéniques appropriés pour la xénogreffe

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BARONE ET AL.: "Genetically modified porcine split-thickness skin grafts as an alternative to . allograft for provision of temporary wound coverage: preliminary characterization", BURNS, vol. 41, no. 3, May 2015 (2015-05-01), pages 565 - 574, XP055535530 *

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