Alopecia (hair loss) is a common condition that results from diverse causes. For example, adrenergic alopecia (common baldness) is seen in the vast majority of adult males and is considered physiologic and part of the aging process. Besides the loss of hair, the length and diameter of each hair will be reduced in the adjacent areas even though the follicles remain intact.
Telogen effluvium is a transient, reversible, diffuse shedding of hair in which a high percentage of hair follicles enter the telogen phase prematurely as a result of physical or mental illness. Among the most important factors incriminated are childbirth, high fever, hemorrhage, sudden starvation, accidental or surgical trauma, severe emotional stress, and certain drugs.
Alopecia areata is an immunologic alopecia characterized by the abrupt onset of sharply defined areas of hair loss. In the most severe cases, the scalp will develop total hair loss (alopecia totalis) or the hair loss will involve the whole body surface (alopecia universalis). Most of the patients will run an unpredictable and relapsing course with multiple episodes of hair loss and regrowth. Only about 20 to 30 percent will have a single reversible episode. Regrowth of hair is common within several months, but in many instances is not complete, and relapses are common. Alopecia areata may be associated with autoimmune diseases such as vitiligo, pernicious anemia, collagen disease, and endocrinopathies.
Traumatic alopecia is induced by physical trauma, of which the two most important groups, from the therapeutic standpoint are trichotillomania and alopecia resulting from cosmetic procedures or improper hair care. Trichotillomania is a compulsive habit in which the individual repeatedly pulls or breaks off his or her own hair in a partially conscious state similar to thumb sucking or nail biting. Traumatic alopecia from cosmetic procedures is done consciously in ill-advised individuals and is almost exclusively seen among females. Sometimes this type of alopecia is associated with folliculitis induced by the occlusive effect of the oily cosmetics used in the procedure.
Anagen effluvium is a temporary alopecia caused by the inhibition of mitosis in the hair papilla by certain cytotoxic drugs, leading to constriction of the hair shaft or to complete failure of hair formation. In particular, alopecia frequently occurs in cancer patients who are treated with chemotherapeutic drugs such as cyclophosphamide (CY) and/or irradiation. Such agents damage hair follicles which contain mitotically active hair-producing cells. Such damage may cause abnormally slow growth of the hair or may lead to frank loss. While various attempts have been made to protect against alopecia or abnormal rates of hair growth during such treatments, there remains a need for an agent that prevents damage to hair follicles in a safe and effective manner.
Alopecia may also result from nutritional deficiencies and metabolic defects. Caloric deprivation must be very severe to produce hair loss. Increased shedding sometimes occurs after marked weight loss for obesity. Anemia, diabetes, hyper- and hypovitaminosis, and zinc deficiency may also lead to alopecia.
Treatments for androgenetic alopecia have been ineffective in inducing regrowth. The use of cyclic estrogen therapy in females with an estrogen-dominant contraceptive or topical estrogen has been advocated to reduce the rate of hair loss, but results are not impressive. The claim that topical testosterone induces the growth of terminal hairs in bald scalp of males has not been confirmed.
There have been some indications that minoxidil (Rogaine®, Upjohn), a potent vasodilator, has been effective in causing scalp hair regrowth in patients with androgenetic alopecia, but the results have been mixed. Thus, there remains a need in the art for methods of treating and preventing the various types of alopecia.
Transforming growth factor-β (TGF-β) is a family of structurally homologous dimeric proteins; three mammalian isoforms (TGF-β1, TGF-β2, TGF-β3) share 70% sequence identity and exhibit distinct functions in vivo. All three TGF-β isoforms are potent growth inhibitors for most cell types, induce apoptosis in certain cell types and are physiologically important. TGF-β isoforms regulate multiple biological processes, including hair growth. TGF-β has been implicated in promoting the regression phase (catagen) of hair growth cycle by inducing cellular growth inhibition or apoptosis during anagen-catagen transition. Hair follicles are composed primarily of epithelial and dermal components.
The hair growth cycle is coordinated with the interactions of epithelial and dermal components. Dermal papilla cells (DPCs), which are androgen target cells, are believed to mediate androgenetic alopecia by androgen-induced secretion of TGF-β. The secreted TGF-β induces growth inhibition and/or apoptosis of hair follicle epithelial cells, resulting in loss of hair follicles and resultant alopecia. Increasing evidence also indicates that TGF-β is involved in the pathogenesis of alopecia caused by other factors. TGF-β therefore, appears to be the target for innovative treatment of alopecia. The present invention provides TGF-β peptantagonists and derivatives thereof that are effective in promoting hair growth.