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Method for treating amyloid disease

Inactive Publication Date: 2007-01-11
NEW YORK UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0011] The present invention is based, in part, on the discovery that amyloid diseases can be treated by removing Aβ peptides from a patient's bodily fluids. This can be accomplished by the administration of compounds that associate with Aβ in order to bind to free Aβ. Free Aβ can also be removed from a patient's bloodstream by dialysis. Both methods lead to an efflux of Aβ from the affected organs, resulting in the reduction of a patient's amyloid burden.
[0012] In one aspect the present invention provides a method for treating a patient suffering from an amyloid disease comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound that is capable of associating with Aβ. In one embodiment, the compound binds to free Aβ present in the blood. In another embodiment, the compound binds to free Aβ present in the blood and in the brain. For example, the compound can be administered intravenously, and the transport of the compound into the brain enhanced by treating the patient in a manner so as to permeabilize the blood-brain-barrier. In a preferred embodiment, the blood-brain barrier is selectively permeabilized to compounds capable of associating with Aβ, including large protein ligands to Aβ and their complexes with Aβ.

Problems solved by technology

Amyloidosis is also a common and serious complication of long-term heamodialysis for end-stage renal failure.
Thus, despite these advances in the art, to date, there is no cure or effective therapy for reducing a patient's amyloid burden or preventing amyloid deposition in AD.
Moreover, even the unequivocal diagnosis of AD can only be made after postmortem examination of brain tissues for the hallmark neurofibrillary tangles (NFT) and neuritic plaques.

Method used

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  • Method for treating amyloid disease
  • Method for treating amyloid disease
  • Method for treating amyloid disease

Examples

Experimental program
Comparison scheme
Effect test

example 1

Binding of ApoE Preparations to Aβ Peptide

[0095] In the present Example, the binding of apoE, derived from various sources and in various forms, to Aβ1-40 and Aβ1-42 peptides is evaluated.

Materials and Methods

[0096] Synthetic Peptides and Proteins. The following peptides, DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVV (SEQ ID NO:1), and DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA (SEQ ID NO:2) corresponding to Aβ40 and Aβ42, and identical to residues 672-711 and 672-713 of Aβ-precursor protein 770, respectively, were synthesized at the W. M. Keck Facility at Yale University (New Haven, Conn., U.S.A.) using N-t-butyloxycarbonyl chemistry and purified by HPLC. Aliquots of the final products were lyophilized and stored at −20° C. until use. For preparation of aggregated peptides, 50 μg of either Aβ40 or Aβ42 were dissolved in 100 μl of PBS (0.02 M phosphate buffer, pH 7.4, containing 0.15 M NaCl) and incubated at 37° C. for 72 h. ApoE3 and apoE4 produced in Sf9 insect cells by the baculovi...

example 2

Elicitation of Anti-Aβ-Antibodies Removing Aβ from Blood

[0109] This Example describes immunization of animals with synthetic Aβ-derivatives, with subsequent analysis of Aβ content in brain and blood after in vivo formation of anti-Aβ-antibodies. According to the invention, similar results could be obtained by administering externally produced antibodies against Aβ.

[0110] Briefly, mice received their first immunization with K6Aβ1-30-NH2(E18E19) at 10.5-13 months of age (peptide: n=23; vehicle: n=24). The animals were bled prior to vaccination, 3 months following the first injection and at the time of sacrifice at 18 to 21 months. The mice were tested in the radial arm maze, subsequently perfused and their brains processed as described (Sigurdsson et al., Am. J. Pathol. 2001; 159:439-4471) (peptide: n=18; vehicle: n=18).

Materials and Methods

[0111] Peptide. K6Aβ1-30-NH2(E18E19) was synthesized at the Keck Foundation (Yale University, New Haven, Conn.). It consists of the first 30 a...

example 3

Apolipoprotein E3 (ApoE3) Treatment of Patients with Alzheimer's Disease

[0122] The present example evaluates the pharmacokinetics and treatment effects of administered ApoE3 versus placebo adjunctive treatment in patients with Alzheimer's disease. Either free, recombinantly produced apoE protein, or apoE protein incorporated into HDL particles can be used in this method. In some cases, apoE incorporated into HDL particles may be preferable, as this is the form apoE is generally found in vivo.

Materials and Methods

[0123] The study is a randomized, double blind, placebo controlled parallel group study, and includes patients meeting the following inclusion criteria. Participants must either have genetic mutations that will result in Alzheimer's disease or be diagnosed with the disease, and may be male or female. Parents or guardians will give informed consent for those under the age of 18 years. Exclusion criteria include females who are pregnant or nursing; life-threatening infectio...

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Abstract

Disclosed herein are methods for treating amyloid disease in humans by clearing amyloid peptides from one or more bodily fluids such as, e.g., blood, of a patient. In particular, the methods are based on the administration capable of binding to amyloid-beta (Aβ) or on dialysis of blood or plasma exchange in order to remove Aβ peptides from the blood circulation, and / or brain or other affected organs.

Description

[0001] This application claims the benefit of U.S. provisional application No. 60 / 434,736, filed Dec. 19, 2002, which is incorporated by reference in its entirety.FIELD OF THE INVENTION [0002] The present invention relates to methods for treating human amyloid disease. Specifically, this invention relates to methods of reducing the levels of amyloid-beta (Aβ) peptides in bodily fluids by, e.g., the administration of compounds capable of associating with Aβ, or the dialyzation of blood through a column or membrane to remove free Aβ. BACKGROUND OF THE INVENTION [0003] Amyloid disease (disorders of protein folding), or amyloidosis, is characterized by the accumulation of a peptide, including the Aβ peptide, existing as abnormal insoluble cross-β sheet fibrils or amytoid deposits in the affected organs. Amyloid diseases include, but are not limited to, Alzheimer's disease, type 2 diabetes, Huntington's disease, Parkinson's disease, and chronic inflammation. Amyloidosis is also a common ...

Claims

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Application Information

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IPC IPC(8): A61K38/17A61K48/00A61K31/739A61KA61K38/38A61K38/39A61K38/57A61M1/34B01J20/28B01J20/32
CPCA61K31/739B01J2220/58A61K38/30A61K38/38A61K38/39A61K38/55A61M1/34B01J20/28033B01J20/3206B01J20/3208B01J20/3217B01J20/3219B01J20/3246B01J20/3248B01J20/3274B01J20/345B01J20/3475B01J20/3425B01J2220/66A61K38/1709A61P25/28
Inventor FRANGIONE, BLASSIGURDSSON, EINAR M.WISNIEWSKI, THOMASGHISO, JORGE
Owner NEW YORK UNIVERSITY
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