Inventors: Holick, Michael F
Publication date: 2008-01-24
Invention summary:
Regulating mammalian skin or hair cell proliferation and differentiation by administering nucleic acids encoding peptides derived from N-terminal region of human parathyroid hormone (hPTH) or hPTH-related protein
Abstract:
Methods are disclosed for the regulation of cell differentiation and proliferation, e.g., for treating hyperproliferative skin disorder, such as psoriasis, and skin cancer for enhancing wound healing, for stimulating hair growth and inhibiting hair growth, by administration of nucleic acid molecules encoding parathyroid hormone (PTI), parathyroid related peptide (PTHrP), or fragment, analog or derivative thereof, and salts thereof, encapsulated by particular liposomes or incorporated into a porous biocompatable matrix
First Claim:
A method of inhibiting proliferation or enhancing differentiation of a mammalian skin or hair cell, said method comprising administering to the mammalian skin or hair cell in need of inhibited proliferation or enhanced differentiation with a proliferation-inhibiting or differentiation-enhancing amount of a nucleic acid molecule, wherein the peptide encoded by the nucleic acid molecule is at least 3 amino acids long, has at least 10% sequence identity with the 34 amino acid N-terminal region of HPTH or hPTHrP, and, when expressed, is capable of inhibiting proliferation or enhancing differentiation in vitro of cultured human keratinocytes, or in vivo in mouse skin by inhibiting skin cell proliferation or hair cycle progression or hair cell growth
Background:
1. Field of the Invention
This invention relates to the regulation of cell differentiation and proliferation, e.g., for treating hyperproliferative skin disorder, such as psoriasis, for enhancing wound healing, for stimulating hair growth, and inhibiting hair growth by topical administration of nucleic acid molecules encoding parathyroid hormone (PTH), parathyroid related peptide (PTHrP), or a fragment or analog thereof.
2. Related Art
U.S. Pat. Nos. 5,527,772, 5,840,690 and 6,066,618 describe methods of inhibiting proliferation and enhancing differentiation of mammalian cells, inducing proliferation of mammalian cells, enhancing wound healing, and stimulating hair growth using a peptide which has a 10% or greater homology to a region of human PTH or human PTHrP. Certain fragments and analogs (e.g. PTH (1-34), PTH (3-34) and PTHrP (1-34)) were found to act as agonists of PTH and PTHrP and inhibit proliferation and enhance differentiation of mammalian cells. Other fragments and analogs (e.g. PTH (7-34) and PTHrP (7-34) are antagonists of PTH and PTHrP were also found to enhance the proliferation of mammalian cells. The agonists are useful for treatment of hyperproliferative skin diseases such a psoriasis, actinic keratoses, and skin cancer and the antagonists are useful for wound healing, particularly wounds of the skin, enhancing or maintaining hair growth, particularly following chemotherapeutic treatment of a mammal, and stimulating epidermal regrowth. Methods of administration include oral, nasal, intravenous, topical, subcutaneous, parenteral and intraperitoneal administration. The peptides may be administered by subcutaneous pumps, patches, tapes, or by liposomal carriers.
A variety of PTH and PTHrP analogs and derivatives thereof have been made. See U.S. Pat. Nos. 4,086,196, 4,423,037, 4,771,124, 4,833,125, 4,968,669, 5,001,223, 5,087,562, 5,093,233, 5,116,952, 5,149,779, 5,171,670, 5,229,489, 5,317,010, 5,382,658, 5,393,869, 5,434,246, 5,527,772, 5,589,452, 5,807,823, 5,821,255, 5,840,690, 5,977,070, 6,025,467, 6,051,868, and 6,066,618; WO94/02510, WO00/23594, and WO00/31137; and EP 477,885. Methods for determining whether a particular analog is an agonist or antagonist of PTH and PTHrP are described in U.S. Pat. Nos. 5,527,772, 5,840,690 and 6,066,618.
Active vitamin D compounds are useful for treating hyperproliferative skin diseases and other conditions. A large number of such active vitamin D compounds are known
Summary:
The invention provides two important therapeutic methods one involving inhibition of cell proliferation and enhancement of skin cell differentiation (the agonist activity), which is useful in the treatment of psoriasis, ichthyosis, actinic keratoses, skin cancer, inhibiting hair growth or preventing hair regrowth. A second method involves enhancement of cell proliferation (the antagonist activity), which is useful in wound healing, stimulating epidermal regrowth and hair growth. In addition, the invention provides methods for enhancing wound healing and hair growth based on in vivo wound healing activity or in vitro or in vivo hair growth activity rather than strict agonist or antagonist activity in vitro.
The first method of the invention generally involves inhibiting proliferation and enhancing differentiation of mammalian skin cells by contacting the cell with a nucleic acid molecule encoding a peptide which is preferably at least 3, and more preferably at least 8, amino acids long and has 10% or greater (more preferably, 50% or greater, and most preferably 75% or greater) sequence identity with a region (preferably within the amino-terminal 34 amino acid region) of human PTH or human PTHrP and, when expressed, is capable of inhibiting proliferation or enhancing the differentiation in vitro of cultured human keratinocytes; or in vivo in mouse skin by inhibiting skin cell proliferation or hair cycle progression or hair growth. In preferred embodiments of this method, the peptide encoded by the nucleic acid molecule is HPTH (1-84), hPTH (1-34), hPTHrP (1-31), hPTHrP (1-40), HPTH (1-44), hPTH (1-36), hPTH (1-38), hPTH (1-31), HPTH (3-34), hPTHrP (1-34), hPTHrP (1-141), hPTHrP (1-139) or hPTHrP (1-173). This method has particular application in the treatment of hyperproliferative skin disorders such as psoriasis. The method may also be useful in the treatment of certain preskin cancers and skin cancers, by the inhibition of cancer cell proliferation and by the induction of differentiation and inhibition of hair growth or preventing hair growth and acne.
The second method of the invention generally involves enhancing proliferation of mammalian skin cells by contacting the skin cells with a nucleic acid molecule encoding a peptide which is preferably at least 3, and more preferably at least 8, amino acids long and has 10% or greater (more preferably, 50% or greater, and most preferably 75% or greater) sequence identity with a region (preferably within the amino-terminal 34 amino acid region) of HPTH or hPTHrP and, when expressed, is capable of blocking the differentiation or the inhibition of proliferation in vitro of cultured human keratinocytes by PTH (1-34) or 1,25(OH)2D3 or PTHrP (1-34); or in vivo in mouse skin by stimulating skin cell proliferation or accelerating hair cycle progression or stimulating hair growth. In a preferred embodiment of this method, the peptide encoded by the nucleic acid molecule is PTH (7-34), PTH (7-84), hPTH (5-34), hPTHrP (7-34), hPTHrP (5-34), hPTHrP (7-141), hPTHrP (7-134), or hPTHrP (7-173). In a related method of the invention, proliferation of mammalian skin cells, e.g., during wound healing, is enhanced by contacting the cell or wound with nucleic acid molecule encoding a peptide which is preferably at least 3, and more preferably at least 8, amino acids long and has 10% or greater (more preferably, 50% or greater, and most preferably, 75% or greater) sequence identity with a region (preferably, within the amino-terminal 34 amino acid region) of hPTH or hPTHrP, and, when expressed, is capable of enhancing wound healing in an in vivo skin punch assay. In preferred embodiments of this method, the peptide encoded by the nucleic acid molecule is hPTH (1-84), HPTH (1-34), HPTH (7-34), HPTH (5-34), hPTH (5-36), hPTH (1-31), hPTHrP (1-34), hPTHrP (1-135), hPTHrP (1-141), hPTHrP (1-173) or hPTHrP (7-34). These related methods have particular application in the enhancement of wound healing and also have applications in the promotion of skin growth in patients with burns or skin ulcerations as well as in the stimulation of epidermal regrowth in people who have decreased epidermal cell proliferation due to aging.
Hair growth is stimulated by administering to a mammal a nucleic acid molecule encoding a peptide which is preferably at least 3, and more preferably at least 8, amino acids long and has 10% or greater (more preferably, 50% or greater, and most preferably, 75% or greater) sequence identity with a region (preferably, within the amino-terminal 34 amino acid region) of hPTH or hPTHrP, and, when expressed, is capable of stimulating hair growth in vitro or in vivo. In preferred embodiments of this method, the peptide encoded by the nucleic acid molecule is hPTH (7-34), hPTH (7-84), hPTHrP (7-134), hPTHrP (7-141), hPTHrP (7-173), hPTH (5-34), hPTHrP (7-34) or hPTH (5-36).
The nucleic acid molecules are administered as part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier. In a preferred embodiment, the carrier is a liposome or gel. In another preferred embodiment the nucleic acid molecules are contained within a porous biocompatable matrix.
The invention also relates to a method of inhibiting proliferation or enhancing differentiation of a skin or hair cell of a mammal, comprising administering to the mammal in need thereof a proliferation-inhibiting or differentiation-enhancing amount of a nucleic acid molecule of the invention and an active vitamin D compound, wherein the peptide encoded by the nucleic acid molecule is at least 3 amino acids long, has at least 10% sequence identity with the 34 amino acid N-terminal region of hPTH or hPTHrP, and, when expressed, is capable of inhibiting proliferation or enhancing differentiation in vitro of cultured human keratinocytes, or in vivo in mouse skin by inhibiting skin cell proliferation or hair cycle progression or hair cell growth. The invention also relates to a composition comprising a nucleic acid molecule of the invention encapsulated within a liposome.
The invention also relates to a composition comprising a proliferation-inhibiting or differentiation-enhancing amount of a nucleic acid molecule of the invention and an active vitamin D compound, optionally encapsulated within a liposome.
Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof, and from the claims
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