Prevention and treatment of synucleinopathic and amyloidogenic disease

A technology of synuclein, disease, applied in the field of prevention and treatment of synucleinopathies and amyloidosis

Inactive Publication Date: 2007-10-10
ELAN PHARM INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the reason for the excess acc

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

Embodiment I

[0331] Immunization of human α-synuclein transgenic mice with human α-synuclein results in high titers of anti-α-synuclein antibodies capable of crossing the blood-brain barrier

[0332]The full-length recombinant human α-SN was resuspended in 1X phosphate buffered saline (PBS) at a concentration of 1 mg / ml. For each injection, 50 μl of α-SN was used; to give a final concentration of 50 μg per injection, an additional 150 μlX PBS was added. Freund's complete adjuvant was then added 1:1 to [alpha]-SN or PBS alone (control), vortexed and sonicated to completely resuspend the emulsion. For the initial injection, eight single-transgenic D-line human α-SN transgenic (tg) mice (Masliah et al., Science 287:1265-1269 (2000)) aged 4-7 months received human α-SN transgenic (tg) mice in CFA. -SN injection, as a control, 4 line D human α-SN tg mice received PBS injection in CFA. Mice received a total of 6 injections. Three injections were given two weeks apart, and three subsequent inj...

Embodiment II

[0335] In vitro screening of antibodies that clear synuclein inclusion bodies

[0336] GT1-7 neuronal cells (Hsue et al. Am.J.Pathol.157:401-410 (2000)) were transfected with pCR3.1-T expression vector expressing murine α-SN (Invitrogen, Carlsbad, CA), and Comparison with cells transfected with the expression vector alone (Figure 3, experimental groups B and A, respectively). Cells transfected with the carrier alone (experimental group A) showed fibrosis, while the cells transfected with α-SN were round, and the inclusion bodies on the cell surface could be observed by optical and confocal scanning microscopes . Then use rabbit pre-immune serum (experimental group C) or 67-10, the rabbit polyclonal antibody (Iwai et al., Neuron 14: 467 (1995) against mouse α-SN C-terminal residue 131-140 of affinity purification ) (experimental group D) treated transfected cells. It can be seen that the levels of synuclein in the cytoplasmic fraction were not significantly changed by treatm...

Embodiment III

[0339] Prophylactic and therapeutic efficacy of immunization with alpha-synuclein

[0340] i. Immunization of human α-synuclein transgenic mice

[0341] For this study, heterozygous human α-SN transgenic (tg) mice (strain D) (Masliah et al, 2000, Science 286: 1265-69) and non-transgenic (nontg) controls were used. Experimental animals were divided into 3 groups. For group I, the preventive effect of early immunization was determined by immunizing mice for 8 months starting from 2 months of age. For group II, young adult mice were immunized starting at 6 months of age for 8 months to determine whether immunization reduced disease progression once the appropriate pathology had been established. For Group III, adult mice were immunized for 4 months at 12 months of age to determine whether immunization reduced the severity of symptoms once stronger pathology had established. For all groups, mice were immunized with recombinant human α-SN plus CFA or CFA only, and 20 transgenic ...

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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

[0001] Cross References to Related Applications [0002] This application is a continuation-in-part of 11 / 185907, filed July 19, 2005, which is a continuation-in-part of 10 / 915,214, filed August 9, 2004, which is a continuation-in-part of 10 / 699,517, filed October 31, 2003 and continuation-in-part of 10 / 698,099, filed October 31, 2003, both of which claim priority under 35 U.S.C. § 119(e) to 60 / 423,012, filed November 1, 2002. The aforementioned application is hereby incorporated by reference for all purposes. Background of the invention [0003] Alpha-synuclein (αSN) brain pathology is the cause of several disorders including Parkinson's disease (PD), dementia with Lewy bodies (DLB), Lewy body variant of Alzheimer's disease (LBVAD), multiple system atrophy (MSA) and neurodegeneration with brain iron accumulation type 1 (NBIA-I) are prominent features of neurodegenerative diseases. A common feature of all these diseases, termed synucleinopathies, are insoluble protein inclus...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61K38/17C12P21/08
Inventor 戴尔・B・申克埃利泽・马斯利亚曼纽尔・J・布蒂尼塔梅・J・奇莱科特爱德华・罗肯施泰因卡特・多拉・盖姆斯
Owner ELAN PHARM INC
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