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Methods for treating neurodegenerative disorders

A technology for disorders and neurasthenia, applied in neurological diseases, biochemical equipment and methods, pharmaceutical formulations, etc., can solve problems such as uncertain pathogenic processes and effort limitations

Pending Publication Date: 2022-07-15
THOMAS JEFFERSON UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Disease-modifying therapies that alter clinical progression are urgently needed, however, efforts to find such therapies are limited in part because of uncertainties about the causative processes that drive DA neuronal degeneration in PD targeted by disease-modifying therapies

Method used

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  • Methods for treating neurodegenerative disorders
  • Methods for treating neurodegenerative disorders
  • Methods for treating neurodegenerative disorders

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0165] Example 1 - Early onset GM1 administration partially protects motor behavior and striatal DA levels

[0166] Spontaneous forelimb use was assessed in AAV-A53Tα-synuclein-transduced animals using the cylinder test, and treatment had a significant main effect, with protection observed in GM1-treated animals (F(5,102)=16.59, P Figure 1A ). In animals that received GM1 administration starting 24 hours after AAV-A53Tα-synuclein injection, limb use asymmetry (percentage of ipsilateral limb use) also increased at 3 and 6 weeks after AAV-A53Tα-synuclein injection increased, but this increase was only significantly different from baseline at 3 weeks (mean ± SEM: baseline: 50.1 ± 1.8%; 3 weeks: 67.1 ± 3.7%, 6 weeks: 56.0 ± 2.5%) ( Figure 1A ). GM1-treated animals had significantly less asymmetric limb use at 6 weeks compared to saline-treated animals at 6 weeks (P Figure 1A ). Animals receiving AAV blank vector injections showed no significant changes in limb use (% ipsilate...

Embodiment 2

[0172] Example 2 - Early initiation GM1 administration partially protects SN neurons from alpha-synuclein-induced toxicity

[0173] To investigate the potential protective role of GM1 in the context of PD-related pathology, the extent to which GM1 administration affects the survival of A53Tα-synuclein-overexpressing substantia nigra DA neurons was examined. Significant reduction in the number of TH+ cells in the SNc on the ipsilateral injected side: AAV-A53T-α-synuclein injection resulted in a 60.0±2.3% loss of TH+ neurons compared to the contra (non-injected) side ( Figures 3A-3B ). Animals receiving early initiation GM1 administration had 43.7±2.7% loss of TH+ neurons compared to the non-injected side (t(28)=4.379, P=0.0002) ( Figures 3A-3B ;Table 2). Similarly, the number of cresyl violet-stained cells in the SNc was significantly affected by AAV-A53T-α-synuclein injection and GM1 treatment. AAV-A53T-α-synuclein injection resulted in a 54.9±1.8% loss of cresyl violet...

Embodiment 3

[0177] Example 3 - Delayed onset GM1 administration partially restores motor behavior and preserves striatal DA levels

[0178] Animals that received AAV-A53Tα-synuclein followed by saline for 8 weeks also developed significant asymmetry in paw use, preferentially using the forepaw on the ipsilateral side of the virus injection to contact the cylinder ( Figure 4A ). When tested 3 weeks after AAV-A53Tα-synuclein injection, saline-treated animals showed a significant increase in the percentage of ipsilateral limb use, similar to that seen in the aforementioned animals, and was consistently observed at 8 weeks after virus injection to (mean ± SEM; baseline: 50.9 ± 2.4%; 3 weeks: 74.5 ± 3.8%, 8 weeks: 81.4 ± 4.5%) ( Figure 4A ). There was a significant treatment effect supporting the GM1 treatment group (F(5,84)=19.14, P Figure 4B ).

[0179] Eight weeks after AAV-A53Tα-synuclein injection, striatal DA levels on the virus-injected side of the brains of saline-treated animals ...

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Abstract

The present invention relates to methods of treating Lewy body dementia, multi-system atrophy, or simple autonomic failure in a subject in need thereof. Also provided are compositions for treating dementia with Lewy bodies, multi-system atrophy, or simple autonomic failure.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS [0002] This application benefits from US Provisional Patent Application No. 62 / 840,235, filed April 29, 2019, under 35 U.S.C. § 119(e), the entirety of which is hereby incorporated by reference. Background technique [0003] Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopamine (DA)-producing neurons, reduced DA levels in the substantia nigra pars compacta (SNc), and decreased levels of DA—primarily in the caudate Accumulation of insoluble alpha-synuclein aggregates (ie, Lewy bodies and Lewy axons) in the nucleus and nucleocapsid and slow progressive worsening of clinical symptoms. Current drug therapies for PD improve various motor signs and symptoms of the disease, but drugs that necessarily slow or stop PD progression have not been identified. Disease-modifying therapies capable of altering clinical progression are urgently needed, however, efforts to find such therapies have been limited...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/70A61P25/28A61P25/00
CPCA61P25/28A61K31/7032A61P25/16A61K38/45A61K38/47C12N15/86C12N2750/14143C12N2750/14171C12Y204/01062C12Y302/01018
Inventor J·S·施耐德
Owner THOMAS JEFFERSON UNIV
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