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Method of providing patient specific immune response in amyloidoses and protein aggregation disorders

a technology of which is applied in the field of providing patient specific immune response in amyloidoses and protein aggregation disorders, can solve the problems of no known effective treatment for preventing, delaying, stopping, or reversing the progression of alzheimer's disease, and achieving the effect of enhancing naturally occurring immune responses and favoring selective antibody responses

Inactive Publication Date: 2016-12-08
NEW YORK UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is based on the discovery that TLR agonists, such as CpG, can enhance the immune system's response to pathological protein aggregates in a subject. This method involves administering TLR agonists to a subject to induce a selective antibody response against the pathological variants of proteins. This approach can be beneficial for treating age-related degenerative diseases such as Alzheimer's disease and dementia with lewy body by stimulating the immune system to fight against the pathological forms of proteins. The invention also provides a method for enhancing the immunization process by co-administering TLR agonists with ex vivo primed peripheral blood lymphocytes. Overall, the invention provides a novel method for inducing a therapeutically useful immune response against pathological protein aggregates.

Problems solved by technology

Alzheimer's disease (“AD”) is the most common cause of age-related dementia and is a major cause of disability and death in the elderly.
This disease, for which there is currently no effective cure, is a long-progressing, neurodegenerative disorder of the central nervous system characterized by increasingly debilitating, global cognitive defects including loss of memory, language deficits, and impaired judgment and abstract reasoning.
Presently there are no known effective treatments for preventing, delaying, halting, or reversing the progression of Alzheimer's disease and other conditions associated with amyloidosis.
Acetylcholine esterase inhibitors can ameliorate the symptoms of dementia in some, but not all, patients for a limited amount of time.
They are not considered a cure for Alzheimer's disease.
Even though these symptomatic treatments can temporarily slow disease progression in some patients with Alzheimer's disease, causal treatments targeting the underlying beta-amyloid pathology are unavailable and urgently needed.
Likewise, passive immunotherapy with monoclonal antibodies developed in mice can produce brain hemorrhages resulting in significant safety problems (Pfeifer et al., Science 2002).

Method used

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  • Method of providing patient specific immune response in amyloidoses and protein aggregation disorders
  • Method of providing patient specific immune response in amyloidoses and protein aggregation disorders
  • Method of providing patient specific immune response in amyloidoses and protein aggregation disorders

Examples

Experimental program
Comparison scheme
Effect test

example 1

Induction of Elevated Titers of Anti-Beta-Amyloid-Plaque Antibodies Concomitant with Reduced Plaque Load in APP Transgenic Mice

[0111]The hypothesis underlying the present invention is confirmed by applying CpG-motifs or SIMRA compounds to immunocompetent amyloid precursor protein transgenic mice with low baseline-levels of auto-antibodies against the human Abeta peptide. In a preferred embodiment of the present invention, the transgenic animal is a mouse harboring a transgene encoding amyloid precursor protein (APP) consisting of the arctic mutation (G693G) and the Swedish mutation (KM670 / 671NL), under the control of the prion protein promoter (PrP) named arcAbeta mouse (Knobloch et al., Neurobiol. Aging July 28 (2006). Aged arcAbeta mice are treated with a single or multiple subcutaneous injections of 0.2 to 20 mg / kg body weight of completely phosphorothioate-modified CpG-oligodeoxyribonucleotide 1826 which is assumed to be a kind of equivalent to the human TLR-9 agonist CpG 7909 (...

example 2

CpG Treatment Improves Behavior in Transgenic Mouse Models of Alzheimer's Disease

[0112]In the Y-maze, a reduced number of arm entries was observed for the PBS treated transgenic APPsweArc mice compared to both groups of wild type littermates analyzed (FIG. 1a). Treatment with either 10 or 50 μg of CpG resulted in an increased number of arm entries indicating a higher level of exploratory activity. Similarly, the percentage of alternations was reduced in PBS treated APPsweArc mice compared to both wild type groups indicating impaired working memory (FIG. 1b). In contrast, APPsweArc mice treated with either dose of CpG performed similar to wild type mice, suggesting that the CpG treatment improved cognitive function.

[0113]In the RAWM experiments average time and errors to reach the platform was analyzed for blocks 3-5 of day 4. PBS-treated APPsweArc mice exhibit increased time (FIG. 2a) and error rate (FIG. 2b), respectively, compared to both wt groups. Treatment with either 10 μg or ...

example 3

CpG Treatment Reduces Total Brain Aβ Plaque Load and Compact Congophilic Amyloid Deposits

[0114]Total Aβ immunohistochemistry using a polyclonal anti-Aβ antibody revealed extensive deposition of Aβ plaques in the cortex and hippocampus (FIG. 3a) of PBS treated APPsweArc transgenic mice. Treatment with either 10 μg or 50 μg CpG was associated with a clear trend towards a dose dependent reduction in total Aβ plaque load. A similar reduction was observed for compact congophilic amyloid deposits as revealed by Congo red staining indicating that chronic treatment with CpG desoxynucleotides can ameliorate amyloid plaque pathology.

Example 4

CpG Treatment Reduces Brain Soluble and Insoluble Aβ

[0115]To assess the effects of CpG treatment on soluble and insoluble brain levels of Aβ40 and Aβ42, brains of APPsweArc mice were sequentially extracted in PBS, PBS / Triton X-100 and Guanidine and Aβ levels in each fraction were analyzed by sandwich ELISA. Upon chronic CpG treatment modest reductions in ...

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Abstract

A treatment of Alzheimer's disease and other disorders involving protein misfolding or aggregation is provided by enhancing or sustaining an antibody response against predominantly directed against pathological protein aggregates or neo-epitopes present on pathogenic forms of said protein or protein complex. Furthermore, therapeutic methods are described, wherein ex vivo stimulated antigen-selected peripheral blood lymphocytes are regrafted into the cognate donor.

Description

[0001]The present invention relates to the treatment of diseases characterized by the appearance of neo-epitopes present in endogenous protein aggregates both being characteristic for a pathological status of a disease and to be selectively identified as disease antigen by the adaptive immune system. The present invention relates in particular to the treatment of Alzheimer's disease and disorders involving protein misfolding or aggregation by inducing an antibody response against at least one endogenous protein by the sole administration of at least one immunostimulant without need for co-administration of exogenous immunogen, whereby such antibody response is predominantly directed against neo-epitopes present on pathogenic forms of said protein or protein complex. Furthermore, the present invention concerns the use of immunostimulants to be administered ex vivo to antigen-selected peripheral blood lymphocytes that are subsequently re-grafted into the cognate donor. In addition, th...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/00G01N33/68
CPCA61K39/0007G01N33/6896A61K2039/55511A61K2039/575G01N2333/4709A61K2039/53A61K39/39A61K2039/55561A61K2039/57A61K31/7088A61P13/12A61P21/00A61P25/14A61P25/16A61P25/28A61P27/06A61P29/00A61P3/10A61P37/04A61P43/00A61P9/00A61P9/10Y02A50/30C12N15/117A61K2039/545
Inventor HENCO, KARSTENNITSCH, ROGERGRIMM, JANZELLER, ANJAMAIER, MARCEL
Owner NEW YORK UNIV
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