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A Genetically Modified Dermal Micro-Organ Expressing Erythropoietin

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A Genetically Modified Dermal Micro-Organ Expressing Erythropoietin (19) & (11) EP 2 377 401 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 19.10.2011 Bulletin 2011/42 A01N 63/00 (2006.01) A01N 65/00 (2009.01) C12N 5/00 (2006.01) C12N 5/02 (2006.01) (2010.01) (21) Application number: 11174205.2 C12N 5/071 (22) Date of filing: 29.04.2004 (84) Designated Contracting States: • Bukhman, Mordechay AT BE BG CH CY CZ DE DK EE ES FI FR GB GR 21891 Carmiel (IL) HU IE IT LI LU MC NL PL PT RO SE SI SK TR • Stern, Baruch, S. Designated Extension States: 34366 Haifa (IL) AL HR LT LV MK • Shalhevet, David 36090 Kiryat Tivon (IL) (30) Priority: 01.05.2003 US 466793 P • Shavitt, Menachem, D. 06.08.2003 US 492754 P 20142 D.N. Misgav (IL) • Pearlman, Andrew, L. (62) Document number(s) of the earlier application(s) in 20164 D.N. Miscav (IL) accordance with Art. 76 EPC: • Noam, Shani 04760621.5 / 1 653 807 30900 Zichron Yaakov (IL) • Almon, Einat (71) Applicant: Medgenics, Inc. 23840 Timrat (IL) Palo Alto, CA 94303 (US) (74) Representative: Modiano, Micaela Nadia (72) Inventors: Modiano & Partners • Bellomo, Stephen, F. Thierschstrasse 11 30900 Zichron Yaakov (IL) 80538 München (DE) • Lippin, Itzhak 42920 Moshav Beit Yitzhak (IL) Remarks: • Piva, Guillermo, Alberto This application was filed on 15-07-2011 as a Winston Salem, NC North Carolina 27104 (US) divisional application to the application mentioned • Rosenberg, Lior under INID code 62. 84965 Omer (IL) (54) A genetically modified dermal micro-organ expressing erythropoietin (57) The present invention is directed to a genetically cro-organ and diffusion of cellular waste out of said cells modified dermal micro-organ expressing at least one re- so as to minimize cellular toxicity and concomitant death combinant gene product, wherein said dermal micro-or- due to insufficient nutrition and accumulation of waste in gan consists essentially of a plurality of dermal compo- said dermal micro organ, wherein at least some of said nents and does not include epidermal layers, which main- cells of said genetically modified dermal micro-organ ex- tains the micro- architecture and three dimensional struc- press at least a portion of at least one recombinant gene ture of the dermal tissue from which it is derived, having product, wherein said recombinant gene product is eryth- dimensions selected so as to enable passive diffusion of ropoietin. adequate nutrients and gases to cells of said dermal mi- EP 2 377 401 A1 Printed by Jouve, 75001 PARIS (FR) 1 EP 2 377 401 A1 2 Description augmentation procedures. To operate this device, which is not commonly used, a sharpened cutting tube, which FIELD OF THE INVENTION includes a reusable thick walled tube with an inner diam- eter of approximately 4.5 mm, is manually rotated at a [0001] The invention relates to the field of tissue based 5 very slow speed. Using this type of device generally re- micro organs, therapeutic tissue based micro organs and quires applying pressure to the skin surface directly methods and apparatuses for harvesting, processing, im- above the harvest site and installing sutures with active planting and manipulating dermal tissue. tugging as the cutting tube is pushed forward. Further- more, the resulting harvested dermis is generally not uni- BACKGROUND OF THE INVENTION 10 form in dimensions and includes "plugs" of epidermis at either end of the dermal core. [0002] Various methods for delivering therapeutic agents are known. For example, therapeutic agents can SUMMARY OF THE INVENTION be delivered orally, transdermally, by inhalation, by in- jection and by depot with slow release. In each of these 15 [0007] Embodiments of some aspects of the present cases the method of delivery is limited by the body proc- invention provide a DMO/DTMO with the ability to be esses that the agent is subjected to, by the requirement maintained ex-vivo in a generally viable state, which may for frequent administration, and limitations on the size of allow various manipulations to be performedon the DMO, molecules that can be utilized. For some of the methods, while keeping a high production and secretion level of the amount of therapeutic agent varies between admin- 20 the desired therapeutic agent. In addition, embodiments istrations. of some aspects of the present invention provide a meth- [0003] A dermal micro organ (DMO), which can be sus- od of harvesting a DMO and subsequently implanting a tained outside the body ("ex-vivo" or "in-vitro") in an au- DTMO without forming keratin cysts or keratin micro- tonomously functional state for an extended periods of cysts, e.g., upon implantation of the DTMO subcutane- time, and to which various manipulations can be applied, 25 ously or deeper in the body. Furthermore, it will be ap- may then be implanted subcutaneously or within the body preciated by persons skilled in the art that the methods for the purpose of treating diseases, or disorders, or for and devices according to some embodiments of the plastic surgical purposes. The DMO can be modified to present invention may be relatively uncomplicated and, express a gene product of interest. These modified der- therefore, the level of skill required from a professional mal micro organs are generally referred to as Dermal 30 to carry out the methods and/or to use the devices of the Therapeutic Micro Organs (DTMOs). present invention may not be as demanding as those [0004] Skin micro organs, including layers of epider- required in conventional procedures. mal and dermal tissues, for example; as outlined in [0008] Some exemplary embodiments of the invention PCT/IL02/0880, have been observed to be associated provide a dermal micro organ (DMO) having a plurality with a number of clinical challenges. Harvesting of a skin 35 of dermal components, which may include cells of the sample leaves a superficial wound on the patient that dermal tissue and a surrounding matrix. The DMO ac- may last several weeks and may leave scars. The har- cording to embodiments of the invention may generally vested skin sample requires significant processing to retain a micro-architecture and three dimensional struc- generate micro organs from this sample. Also, implanta- ture of the dermal organ from which it is obtained and tion of skin micro organs subcutaneously or deeper in 40 the dimensions of the DMO may allow passive diffusion the body have been found to result in the development of adequate nutrients and gases to the cells and diffusion of keratin cysts or keratin micro-cysts. Additionally, im- of cellular waste out of the cells so as to minimize cellular plantation of skin micro organs as a graft onto the skin toxicity and concomitant death-due to insufficient nutri- surface in "slits" requires significant technical expertise tion and accumulation of waste. in order to handle the MO while maintaining its proper 45 [0009] In some exemplary embodiments of the inven- orientation. tion, the dermal micro organ of the invention does not [0005] Harvesting of dermis, e.g., to be used as a "filler produce keratin or produces negligible amounts of ker- material" in a plastic surgical or cosmetic procedure, is atin. known in the art. Conventional harvesting techniques in- [0010] In some embodiments of the invention, the der- clude using a dermatome or scalpel to peel away a layer 50 mal micro organ does not produce keratin and/or keratin of epidermis in order to expose a section of dermis. The cysts following subcutaneous or deeper implantation in dermatome or scalpel may then be used again to man- a body. ually harvest the exposed section of dermis. [0011] Inanother embodimentof the invention, the der- [0006] Another conventional apparatus for harvesting mal micro organ of the invention produces micro keratin dermis, albeit not commonly used, is the Martin Dermal 55 cysts following that will atrophy within a relatively short Harvester marketed by Padgett (Part No. P-225) for the period of time, e.g., days or weeks after subcutaneous indication of harvesting dermal cores from the back for implantation. subsequent implantation into the lips during cosmetic lip [0012] Inanother embodimentof the invention, the der- 2 3 EP 2 377 401 A1 4 mal micro organ of the invention contains hair follicles netically modified dermal micro organ of the invention and sebaceous glands, which will atrophy after a short produces substantially no keratin. period of time, e.g., days or weeks. [0018] In some embodiments, the invention provides [0013] Inanother embodiment of the invention, the der- a method of delivering to a recipient a recombinant gene mal micro organ of the invention contains glands that will 5 product produced by the dermal micro organ. connect to the skin surface after a short period of time, [0019] In some embodiments, the invention provides e,g., days or weeks. a method of inducing a local or systemic physiological [0014] Further exemplary embodiments of the inven- effect by implanting a dermal micro organ in a recipient. tion provide a method and apparatus of harvesting a der- [0020] In another embodiment the invention provides mal micro organ. The method may include stabilizing 10 a method of delivering a protein of interest to a subject. and/or supporting a skin-related tissue structure from The method includes implanting the genetically modified which a dermal micro organ is to be harvested, e.g., such dermal micro organ into the skin, under the skin or at that the skin-related tissue structure is maintained at a other locations in the body. desired shape and/or position, separating at least a por- [0021] In another embodiment, the invention provides tion of the dermal micro organ from the skin- related tissue 15 a method of implanting a dermal micro organ so as to structure, and isolating the separated dermal micro organ avoid or to reduce keratin cyst formation.
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