Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2001-03-21
2004-08-10
Nguyen, Dave T. (Department: 1635)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S363000, C435S371000
Reexamination Certificate
active
06773881
ABSTRACT:
BACKGROUND OF THE INVENTION
The hair follicle undergoes a life-long transformation from a resting phase (telogen) to a growth phase (anagen) with rapid proliferation of follicular keratinocytes and elongation and thickening of the hair shaft. Anagen phase is followed by regression phase (catagen) leading to involution of the hair follicle (telogen) which continues until a new hair shaft is generated in the existing follicle during the subsequent anagen phase. Hardy et al. (1992)
Trends in Genetics
8:55-61. These cyclic changes involve rapid remodeling of both epithelial and dermal components of the hair follicle.
SUMMARY OF THE INVENTION
The invention is based, in part, on the discovery that increased perifollicular vascularization promotes hair growth and that expression of VEGF by follicular keratinocytes leads to increased perifollicular vascularization. In addition, it was found that increasing the level of VEGF expression resulted in accelerated hair regrowth and increased hair follicle size, which leads to hair thickening. It was also found that by inhibiting the levels of VEGF, hair growth and hair thickening can be reduced.
Accordingly, in one aspect, the invention features a method of modulating hair growth and/or hair thickness. The method includes modulating VEGF protein, e.g., modulating VEGF gene expression and/or modulating VEGF protein production and/or activity, to thereby modulate hair growth and/or thickness.
In another aspect, the invention features a method of promoting hair growth in a subject. The method includes increasing the VEGF activity, e.g., increasing the level of VEGF protein, e.g., increasing the levels of VEGF gene expression and/or increasing VEGF protein production and/or activity, to thereby promote hair growth.
In a preferred embodiment, VEGF activity is increased by administering an agent which increases the level of VEGF protein. An agent which increases the level of VEGF protein can be one or more of: a VEGF polypeptide or a functional fragment or analog thereof; a nucleotide sequence encoding a VEGF polypeptide or functional fragment or analog thereof; an agent which increases VEGF nucleic acid expression, e.g., a transition metal ion, or a small molecule which binds to the promoter region of VEGF.
In a preferred embodiment, VEGF is increased by administering, e.g., introducing, a nucleotide sequence encoding a VEGF polypeptide or functional fragment or analog thereof, into a particular cell, e.g., a keratinocyte, e.g., a follicular keratinocyte, in the subject. The nucleotide sequence can be a genomic sequence or a cDNA sequence. The nucleotide sequence can include: a VEGF coding region; a promoter sequence, e.g., a promoter sequence from a VEGF gene or from another gene; an enhancer sequence, e.g., 5′ untranslated region (UTR), e.g., a 5′ UTR from a VEGF gene or from another gene, a 3′ UTR, e.g., a 3′ UTR from a VEGF gene or from another gene; a polyadenylation site; an insulator sequence.
In another preferred embodiment, the agent is a compound, e.g., a small molecule, which increases VEGF expression. For example, the molecule can be a transition metal ion, e.g., manganese, cobalt, nickel, or combinations thereof. In another preferred embodiment, the agent is a polypeptide other than VEGF which increases VEGF expression. For example, the agent can be a cytokine, e.g., interleukin-1, or a growth factors, e.g., transforming growth factor-&agr;, epidermal growth factor.
In another preferred embodiment, the level of VEGF protein is increased by increasing the level of expression of an endogenous VEGF coding sequence, e.g., by increasing transcription of the VEGF coding sequence. In a preferred embodiment, transcription of the VEGF gene is increased by: altering the regulatory sequences of the endogenous VEGF gene, e.g., by the addition of a positive regulatory element (such as an enhancer or a DNA-binding site for a transcriptional activator); the deletion of a negative regulatory element (such as a DNA-binding site for a transcriptional repressor) and/or replacement of the endogenous regulatory sequence, or elements therein, with that of another gene, thereby allowing the coding region of the VEGF gene to be transcribed more efficiently.
In another preferred embodiment, the method can include introducing a cell, e.g., a cell which expresses and preferably secretes a VEGF protein, into a subject. In a preferred embodiment, the cell has been genetically modified to express a VEGF protein, a fragment or an analog thereof, or a protein other than VEGF which causes an increase in the levels of VEGF. The cell can be an autologous, allogeneic, or xenogeneic cell, but is preferably autologous. In a preferred embodiment, the cell is encapsulated, e.g., in a gel or biocompatible mesh, which is introduced into the subject. The cell can be any cell type, e.g., a fibroblast, a keratinocyte, an epithelial cell, an endothelial cell. Preferably the cell is a keratinocyte, e.g., a follicular keratinocyte. The cell can be introduced into a subject to increase the level of VEGF protein.
In a preferred embodiment, the agent which increases the level of VEGF protein is administered, e.g., by topically administering the agent; systemically administering the agent; orally administering the agent; or injecting the agent, preferably dermally or subcutaneously. In preferred embodiments, the compound is administered using a suitable delivery vehicle, for example, a surfactant or an agent which increases permeability in the skin, e.g., an SDS or DMSO containing formulation. Preferably, the agent is included in a composition for topical use, e.g., the composition is a gel, cream, or liquid. In a preferred embodiment, the agent is administered: by continuous administration, e.g., the agent is administered with sufficient frequency such that the affect on the VEGF protein level is maintained for a selected period, e.g., 10, 20, 30, 50, 90, 180, 365 days or more. In another preferred embodiment, administration of the agent is repeated, e.g., is repeated at least 1, 2, 3, 5, 10, 20 or more times.
In a preferred embodiment, hair growth is promoted on: the subject's scalp; the subject's face, e.g., beard and/or mustache facial hair growth is promoted.
In a preferred embodiment, the subject has an insufficient amount of hair or an insufficient rate of hair growth. In a preferred embodiment, the subject suffers from genetic pattern baldness; suffers from a hormonal disorder which decreases hair growth; has received a treatment, e.g., radiation, or chemotherapy, or a drug which inhibits hair growth; or has had a surgical procedure, e.g., skin graft, which is in need of hair growth.
In another aspect, the invention features a method of enhancing hair thickness. The method includes increasing the level of VEGF protein, e.g., increasing the levels of VEGF gene expression and/or increasing VEGF protein production and/or activity, to thereby promote thickening of the hair.
In a preferred embodiment, VEGF activity is increased by administering an agent which increases the level of VEGF protein. An agent which increases the level of VEGF protein can be one or more of: a VEGF polypeptide or a functional fragment or analog thereof; a nucleotide sequence encoding a VEGF polypeptide or functional fragment or analog thereof; an agent which increases VEGF nucleic acid expression, e.g., a transition metal ion, or a small molecule which binds to the promoter region of VEGF.
In a preferred embodiment, VEGF is increased by administering, e.g., introducing, a nucleotide sequence encoding a VEGF polypeptide or functional fragment or analog thereof, into a particular cell, e.g., a keratinocyte, e.g., a follicular keratinocyte, in the subject. The nucleotide sequence can be a genomic sequence or a cDNA sequence. The nucleotide sequence can include: a VEGF coding region; a promoter sequence, e.g., a promoter sequence from a VEGF gene or from another gene; an enhancer sequence, e.g., 5′ untranslated region (UTR), e.g., a 5′ UTR from a VEGF gene or
Detmar Michael
Yano Kiichiro
Angell J. Eric
Fish & Richardson P.C.
Nguyen Dave T.
The General Hospital Corporation
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