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Prevention and treatment of synucleinopathic and amyloidogenic disease

a technology of amyloid and amyloid, which is applied in the field of prevention and treatment of synucleinopathic and amyloidogenic disease, can solve the problems of asymptomatic patients and risk factors for the disease, and achieve the effect of improving patient motor characteristics and preventing deterioration of patient motor characteristics

Inactive Publication Date: 2010-02-04
JANSSEN ALZHEIMER IMMUNOTHERAPY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0014]In one aspect, the invention provides methods of preventing or treating a disease characterized by Lewy bodies or alpha-SN aggregation in the brain. Such methods entail, inducing an immunogenic response against alpha-SN. Such induction may be achieved by active administration of an immunogen or passive by administration of an antibody or a derivative of an antibody to synuclein. In some methods, the patient is asymptomatic. In some methods, the patient has the disease and is asymptomatic. In some methods the patient has a risk factor for the disease and is asymptomatic. In some methods, the disease is Parkinson's disease. In some methods, the disease is Parkinson's disease, and the administering the agent improves motor characteristics of the patient. In some methods, the disease is Parkinson's disease administering the agent prevents deterioration of motor characteristics of the patient. In some methods, the patient is free of Alzheimer's disease.
[0031]Optionally, the immunogenic fragment is linked to a carrier to form a conjugate. Optionally, the polypeptide comprises the immunogenic fragment fused to the carrier. Optionally, the immunogenic fragment is linked to the carrier molecule at the C-terminus of the alpha-synuclein fragment. Optionally, multiple copies of the fragment are interlinked with multiple copies of the carrier. Optionally, the immunogenic fragment is administered with an adjuvant. Optionally, the administering step effects at least partial clearance of Lewy Bodies. Optionally, the administering step disaggregates Lewy Bodies. Optionally, the administering step reduces levels of alpha synuclein oligomers in synapses. Optionally, the administering step clears synuclein by activation of a lysosomal pathway.

Problems solved by technology

In some methods the patient has a risk factor for the disease and is asymptomatic.

Method used

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  • Prevention and treatment of synucleinopathic and amyloidogenic disease
  • Prevention and treatment of synucleinopathic and amyloidogenic disease
  • Prevention and treatment of synucleinopathic and amyloidogenic disease

Examples

Experimental program
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Effect test

example i

Immunization of Human Alpha-Synuclein Transgenic Mice With Human Alpha-Synuclein Results in the Production of High Titer Anti-Alpha-Synuclein Antibodies that Cross the Blood-Brain Barrier

[0247]Full-length recombinant human alpha-SN was resuspended at a concentration of 1 mg / ml in 1× phosphate buffered saline (PBS). For each injection, 50 μl of alpha-SN was used; giving a final concentration of 50 μg per injection to which 150 μl of 1×PBS was added. Complete Freund's adjuvant (CFA) was then added 1:1 to either alpha-SN or PBS alone (control), vortexed and sonicated to completely resuspend the emulsion. For the initial injections, eight D line human alpha-SN transgenic (tg) single transgenic 4-7 months old mice (Masliah, et al. Science 287:1265-1269 (2000) received injections of human alpha-SN in CFA and, as control, four D line human alpha-SN tg mice received injections of PBS in CFA. Mice received a total of 6 injections. Three injections were performed at two weeks intervals and th...

example ii

In Vitro Screen for Antibodies Clearing Synuclein Inclusions

[0248]GT1-7 neuronal cell (Hsue et al. Am. J. Pathol. 157:401-410 (2000)) were transfected with a pCR3.1-T expression vector (Invitrogen, Carlsbad, Calif.) expressing murine alpha-SN and compared with cells transfected with expression vector alone (FIG. 3, panels B and A respectively). Cells transfected with vector alone (panel A) have a fibroblastic appearance while cells transfected with alpha-SN are rounded, with inclusion bodies at the cell surface visible via both light and confocal scanning microscopy. Transfected cells were then treated with rabbit preimmune serum (panel C) or 67-10, an affinity purified rabbit polyclonal antibody against a murine alpha-SN C terminal residues 131-140 (Iwai, et al., Neuron 14:467 (1995) (panel D). It can be seen that the inclusion bodies stain less strongly in panel D than in panel C indicating that the antibody against alpha synuclein was effective in clearing or preventing the devel...

example iii

Prophylactic and Therapeutic Efficacy of Immunization with Alpha-Synuclein

[0250]i. Immunization of Human Alpha-Synuclein tg Mice

[0251]For this study, heterozygous human alpha-SN transgenic (tg) mice (Line D) (Masliah et al., 2000, Science 286:1265-69) and nontransgenic (nontg) controls are used. Experimental animals are divided into 3 groups. For group I, the preventive effects of early immunization by immunizing mice for 8 months beginning at 2 months of age are tested. For group II, young adult mice are vaccinated for 8 months beginning at the age of 6 months to determine whether immunization can reduce disease progression once moderate pathology had been established. For group III, older mice are immunized for 4 months beginning at the age of 12 months to determine whether immunization can reduce the severity of symptoms once robust pathology has been established. For all groups, mice are immunized with either recombinant human alpha-SN plus CFA or CFA alone, and for each experim...

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Abstract

The invention provides improved agents and methods for treatment of diseases associated with synucleinopathic diseases, including Lewy bodies of alpha-synuclein in the brain of a patient. Such methods entail administering agents that induce a beneficial immunogenic response against the Lewy body. The methods are particularly useful for prophylactic and therapeutic treatment of Parkinson's disease.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The present application is a continuation-in-part of application Ser. No. 11 / 185,907, filed Jul. 19, 2005, which is a continuation-in-part of application Ser. No. 10 / 915,214, filed Aug. 9, 2004, which is a continuation-in-part of application Ser. Nos. 10 / 699,517, filed Oct. 31, 2003, and 10 / 698,099 filed Oct. 31, 2003, both of which claim the benefit under 35 U.S.C. §119(e) of Application No. 60 / 423,012, filed Nov. 1, 2002. The foregoing applications are incorporated by reference herein for all purposes.BACKGROUND OF THE INVENTION[0002]Alphα-synuclein (alphaSN) brain pathology is a conspicuous feature of several neurodegenerative diseases, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), the Lewy body variant of Alzheimer's disease (LBVAD), multiple systems atrophy (MSA), and neurodegeneration with brain iron accumulation type-1 (NBIA-1). Common to all of these diseases, termed synucleinopathies, are proteinaceous inso...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K49/00A61K39/395C07K16/18C12N5/16A61K39/00A61P25/28
CPCA61K38/1709A61K39/00A61K2039/505C07K16/18A61P25/16A61P25/28A61K38/17A61K39/395
Inventor SCHENK, DALE BMASLIAH, ELIEZERBUTTINI, MANUEL J.CHILCOTE, TAMIE J.ROCKENSTEIN, EDWARDGAMES, KATE DORA
Owner JANSSEN ALZHEIMER IMMUNOTHERAPY
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