Use of CpG oligodeoxynucleotides to induce epithelial cell growth
Inventors
KLINMAN, DENNIS M. • Sato, Takashi
Assignees
US Department of Health and Human Services
Publication Number
US-8466116-B2
Publication Date
2013-06-18
Expiration Date
2022-12-19
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Abstract
This disclosure provides a method of inducing epithelial cell growth. The method includes administering an effective amount of a K-type CpG oligonucleotide, thereby inducing epithelial cell growth. The epithelial cell can be in vivo or in vitro. Methods are also provided for inducing wound healing in a subject. The methods include administering to the subject a therapeutically effective amount of at least one K-type CpG ODN.
Core Innovation
This disclosure provides methods of inducing epithelial cell growth by administering a therapeutically effective amount of a K-type CpG oligodeoxynucleotide (ODN), which induces epithelial cell division. The epithelial cells can be located anywhere in the body and can be in vitro or in vivo, including at wound sites. The method can induce epithelial cell growth with or without angiogenesis and can induce vascular endothelial growth factor (VEGF) production by the contacted cells.
Methods for promoting wound healing are provided, which include administering therapeutically effective amounts of one or more K-type CpG ODNs to a subject with a wound, including both traumatic and surgical wounds. The CpG ODNs can be administered systemically or locally, for instance via topical application using ointments or transdermal patches. Compositions including CpG ODNs combined with basal membrane extracts can be used to facilitate the treatment.
The background describes wound healing as a complex process involving multiple biological phases and cellular interactions, including keratinocyte and fibroblast proliferation and neovascularization, regulated by growth factors and cytokines. Existing therapies with growth factors are acknowledged, but additional methods to accelerate wound healing and tissue repair remain needed, motivating the use of CpG oligodeoxynucleotides for this purpose.
Claims Coverage
The patent contains multiple independent claims focusing on methods of inducing epithelial cell growth and promoting wound healing using CpG oligodeoxynucleotides. The main inventive features cover the specific use and combinations of CpG ODNs with defined nucleic acid sequences, selection of subjects, wound types, and formulations.
Inducing epithelial cell growth with specific CpG oligodeoxynucleotide sequences
A method of inducing epithelial cell growth by contacting an epithelial cell with an effective amount of a CpG oligodeoxynucleotide comprising defined nucleic acid sequences (including sequences set forth in the patent's SEQ ID NOs).
Promoting wound healing by administering multiple CpG oligodeoxynucleotides with distinct sequences
A method of promoting wound healing in a subject by selecting a subject with a wound and administering at least two CpG oligodeoxynucleotides, each having a different nucleic acid sequence as specified, including sequences such as SEQ ID NO: 11 and others.
Promoting healing of surgical wounds with administration of at least one CpG oligodeoxynucleotide
A method of promoting surgical wound healing in a subject, including transplant recipients, by administering a therapeutically effective amount of at least one CpG oligodeoxynucleotide with characterized nucleic acid sequences, optionally including local administration and co-administration with basal membrane extract.
Using defined CpG oligodeoxynucleotide sequences and configurations in epithelial cells including lung epithelium
Methods specifically involving human or lung epithelial cells contacted with at least two distinct CpG oligodeoxynucleotides of defined sequence and structure, with constraints on nucleotide arrangements and spacing between CpG motifs.
The claims cover the use of K-type CpG oligodeoxynucleotides with specific sequences and configurations to induce epithelial cell growth and to promote wound healing in various contexts, including surgical wounds and grafts, with flexible administration routes and co-treatments.
Stated Advantages
CpG oligodeoxynucleotides accelerate wound healing by stimulating epithelial cell proliferation and migration.
The methods promote wound healing both in normal and healing-impaired subjects, including aged individuals.
The approach induces production of vascular endothelial growth factor, contributing to angiogenesis and tissue repair.
CpG oligodeoxynucleotides can be administered locally or systemically, and formulated in various compositions including basal membrane extracts for effective delivery.
The use of K-type CpG ODNs is effective in both in vitro and in vivo models, including enhancing graft adherence and survival.
Documented Applications
Promoting healing of various types of wounds such as traumatic wounds, surgical wounds including anastomotic wounds, excisional wounds, deep dermal and epidermal wounds, burns, blisters, and ulcers (including diabetic, dermal, arterial and venous stasis ulcers).
Enhancing epithelial cell proliferation and repair in lung tissue, including treatment of inhalation injuries, lung damage from chemotherapy, radiation, lung cancer, asthma, and other lung conditions.
Improving skin graft adherence and acceptance by administering CpG ODNs to grafts or subjects receiving grafts.
Treating internal organ injuries such as ovary injury, chemotherapy or radiation-induced cystitis, and intestinal injury resulting from high-dose chemotherapy.
Administering CpG ODNs in conjunction with basal membrane extracts or growth factors to enhance epithelial growth and wound healing.
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