Estriol therapy for autoimmune and neurodegenerative diseases and disorders

Abstract

The present invention discloses administering steroid hormones to mammals to treat autoimmune related diseases, including post-partum auto immune diseases. 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. 13 / 722,672, filed Dec. 20, 2012, which 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, all of which are incorporated by reference herein.[0002]U.S. patent application Ser. No. 11 / 992,558, to which this application claims priority, 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 on Feb. 12, 2013, 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 on Aug. 30, 2005, which claims priority to U.S. Provisiona...

AI Technical Summary

Benefits of technology

The present invention is about a method for treating autoimmune diseases, particularly Th1-mediated ones, such as multiple sclerosis and rheumatoid arthritis, by administering steroid hormones to mammals. The method involves using a primary agent, such as estrogen or estrogen receptor-effective compositions, either alone or in combination with other secondary active agents like progesterone and glucocorticoids. The invention also includes the use of specific estrogen receptor alpha or beta ligands that have anti-inflammatory, neuroprotective, or other beneficial effects for preventing or ameliorating symptoms of autoimmune and neurodegenerative diseases.

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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