Estriol therapy for autoimmune and neurodegenerative disease and disorders

Abstract

The present invention discloses administering steroid hormones to mammals to treat autoimmune related diseases, including post-partum auto immune diseases) and more particularly. Most preferably the invention uses estrogens, estranges, estriol or estrogen receptor active agents to prevent or ameliorate clinical symptoms of these Th1-mediated (cell-mediated) autoimmune diseases known to either have an initial onset following the birth of a child or which are exacerbated in patients in the post-partum period.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. patent application Ser. No. 11 / 992,558, filed Mar. 25, 2008, which claims priority from International Patent Application No. PCT / US2006 / 037259, filed Sep. 26, 2006, which claims priority to U.S. Provisional Application No. 60 / 833,527, filed Jul. 26, 2006, and U.S. Provisional Application No. 60 / 720,971, filed Sep. 26, 2005, which is a continuation-in-part application of U.S. patent application Ser. No. 11 / 151,040, filed on Jun. 13, 2005, and issued as U.S. Pat. No. 8,372,826, which is a continuation of application Ser. No. 10 / 131,834, filed on Apr. 24, 2002, and issued as U.S. Pat. No. 6,936,599, which claims priority to Provisional Application No. 60 / 286,842, filed on Apr. 25, 2001, all of which are incorporated by reference herein.[0002]This invention was made with Government support under Grant No. NS045443 awarded by the National Institute of Neurological Disorders and Stroke, National Instit...

AI Technical Summary

Benefits of technology

The present invention provides a method for treating autoimmune related diseases, particularly Th1-mediated diseases, in mammals by administering steroid hormones, specifically estrogen or estrogen receptor-effective compositions. The treatment may include the use of a primary agent comprising an estrogen receptor alpha ligand or an estrogen receptor beta ligand in combination with a secondary active agent such as progesterone, glucocorticoids, or other drugs used to treat autoimmune diseases. The method may also include the treatment of post-partum patients with a therapeutically effective amount of estriol, a primary agent of estrogen, or a combination of estriol and a secondary active agent. The invention further includes the use of a primary agent comprising an estrogen receptor alpha ligand or an estrogen receptor beta ligand for preventing or ameliorating clinical symptoms of autoimmune and neurodegenerative diseases or disorders, including multiple sclerosis.

Problems solved by technology

This demyelinization can cause weakness, impaired vision, loss of balance, and poor muscle coordination.

In the worst cases the disease can lead to paralysis or blindness.

However, it remains unclear what cellular mechanisms are involved in regulating in vivo amelioration of autoimmune symptomology.

However, there was no investigation as to how estrogens delayed the day of onset of disease, nor as to whether disease severity was effected in these animals once symptomology occurred.

However, the etiology and disease progression of EAE and MS are not identical, thus it is unclear that estrogens alone would be effective in ameliorating autoimmune responses in human patients.

Indeed, not only is it unknown whether pregnancy doses of estrogens might be protective in humans with autoimmune disease, it is unclear even in mice whether low doses of estrogens are protective.

Thus, it is controversial whether low levels of estrogens, as they exist during the menstrual cycle, are protective even in mice.

Data from human studies to date have shown no clear benefit of steroids in treating any autoimmune disease.

For example, there has been no conclusive evidence that women are protected from or have a decrease in symptomology or relapse rates due to sex steroids.

Thus, low dose of the estrogens in oral contraceptives are not of sufficient type or dose to ameliorate the immunopathogenesis of MS even temporarily during intercurrent use.

In contrast, the absence of such an effect on relapses during OCP or HRT indicate that low level sex steroids are not adequate to treat these symptoms.

Further, women having rheumatoid arthritis that were treated with HRT did not show significant improvement in their symptomology.

Thus, the low doses of hormones found naturally during the menstrual cycle or in ORT and HRT have not been shown to be effective at ameliorating the symptomology of autoimmune diseases.

Thus, a challenge has been to identify a hormone and a treatment dose that is therapeutic in treating particular autoimmune diseases, while minimizing undesirable side effects.

Obviously, the dose and method of administration of steroids in humans differs from steroid treatment in laboratory animals due to toxic effects of prolonged exposure by patients to steroid hormones.

However, the relationship between ER alpha and ER beat became complex, with most tissues expressing some detectable level of each of these receptors.

Furthermore, in some issues the two receptors were shown to act synergistically, whereas in the other tissues they act antagonistically.

However, any selective effects by ER alpha and ER beta on MS and other auto-immune and Neurodegerative diseases have yet to be examined

Further, the direct and indirect neuroprotective mechanisms by estrogens in EAE are not necessarily mutually exclusive, and have yet to be fully explored.

Because it is known that up to 5 years of continuous treatment with immunomodulatory treatments are needed to impact disability in MS, a temporary anti-inflammatory effect of the third trimester of pregnancy would not necessarily be expected to improve long-term disability.

Further, neurodegenerative diseases and disorders in addition to MS comprise a substantial clinical problem for which existing treatments have been ineffective at ameliorating the clinical symptomology or preventing the progression of the disease or disorder.

However, the role of estrogen and estrogen receptor subtypes involved neuroprotection has yet to be fully explored.

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