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Improvement in locomotor activity and increase in longevity of late infantile neuronal ceriod lipofuscinosis subjects by gemfibrozil

A technology of gemfibrozil and neurons, applied in the field of treatment of neurodegenerative diseases

Pending Publication Date: 2019-08-23
RUSH UNIV MEDICAL CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, despite years of investigation, there is only one treatment for this disease (LINCL in particular); all are only supportive or symptomatic, suggesting an urgent need for new treatments (Chang et al., 2008)

Method used

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  • Improvement in locomotor activity and increase in longevity of late infantile neuronal ceriod lipofuscinosis subjects by gemfibrozil
  • Improvement in locomotor activity and increase in longevity of late infantile neuronal ceriod lipofuscinosis subjects by gemfibrozil
  • Improvement in locomotor activity and increase in longevity of late infantile neuronal ceriod lipofuscinosis subjects by gemfibrozil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Example 1: Materials and methods:

[0050] Reagents and antibodies: Reagents for the TUNEL assay on frozen brain sections were purchased from EMDMillipore (Billerica, MA) and experiments were performed according to the manufacturer's instructions. Blocking buffer and secondary antibodies (IRDye 700 or IRDye 800 labeled) for western blotting (IB) were purchased from Licor (Lincoln, Nebraska). Secondary antibodies (FITC or Cy5-labeled) for immunohistochemistry (IHC) were purchased from Jackson ImmunoResearch (West Grove, PA). The sources of the primary antibodies used in this study and their applications and dilutions are listed in Table 1.

[0051] Animals: Animal maintenance and experimentation were in accordance with the requirements of the National Institutes of Health and were approved by the Institutional Animal Care and Use Committee (IACUC) of Rush University Medical Center, Chicago, IL. Animals exhibiting mild seizures and tremors were fed and watered by animal...

Embodiment 2

[0058] Example 2: Gem treatment prolongs Cln2 (- / -) Mouse lifespan: Cln2 (- / -) Mice are an important animal model for testing new therapeutic approaches against LINCL (Cabrera-Salazar et al., 2007; Sleat et al., 2008; Chang et al., 2008; Sleat et al., 2004). Typically, LINCL progresses rapidly, ending in death between 8 and 10 years of age (Sohar et al., 1999; Sleat et al., 1997). Similarly, Cln2 (- / -) Mice also died within 140 days (Sleat et al., 2004). Therefore, we first examined whether oral gem treatment could increase Cln2 (- / -) mouse lifespan. Earlier we have shown that gem enters the CNS after oral administration (Dasgupta et al., 2007). From 4 weeks of age, mice were treated daily with gem (7.5 mg / kg body weight / day) by gavage. Since the gem is dissolved in 0.1% methylcellulose, a set of Cln2 (- / -) Mice also received 0.1% methylcellulose as a vehicle. Untreated Cln2 (- / -) Male and female mice died from 95 days, and within 137 days, all Cln2 (- / -) Mice died (...

Embodiment 3

[0059] Example 3: gem treatment improves Cln2 (- / -) Locomotor behavior in mice: In addition to increased lifespan, another therapeutic goal for neuroprotection in LINCL patients is to reduce dysfunction. So to check if the gem not only increases lifespan but also improves Cln2 (- / -) For the locomotor behavior of mice, we monitored locomotor activity. Locomotor activity was monitored 8 weeks after gem treatment. Compared with WT mice, Cln2 (- / -) The horizontal activity of mice ( Figure 2A ),sport time( Figure 2B ), exercise times ( Figure 2C ), the total distance traveled ( Figure 2D ) and stereotype counts ( Figure 2E ) was significantly reduced. On the other hand, Cln2 (- / -) The resting time of mice was longer than that of WT mice ( Figure 2F ). However, oral administration of the gem significantly improved Cln2 (- / -) The locomotor activity of mice ( Figure 2A -F).

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Abstract

Provided herein are methods for treatment of a neurodegenerative disease, such as Late Infantile Neuronal Ceroid Lipofuscinosis, including administering to a subject in need of such treatment a composition comprising a therapeutically effective amount of an agent comprising a fibrate.

Description

[0001] related application [0002] This application claims the benefit of US Provisional Application 62 / 440,305, filed December 29, 2016, which is incorporated by reference in its entirety. technical field [0003] The present invention relates to a method for the treatment of neurodegenerative diseases such as advanced infantile neuronal ceroid lipofuscinosis. Background technique [0004] Lysosomes are membrane-enclosed organelles that contain several acid hydrolases responsible for the degradation of lipids, proteins, carbohydrates and nucleic acids (De Duve & Wattiaux, 1966). Defects / deficiencies in almost any of these acid hydrolases lead to accumulation of undigested / partially digested material in lysosomes and form the basis of numerous lysosomal storage disorders (LSDs) (DeDuve & Wattiaux, 1966; Perez-Sala et al., 2009). Late infantile neuronal ceroid lipofuscinosis (Jansky-Bielschowsky disease, LINCL, type 2) is a form of NCL that is caused by excessive mutation...

Claims

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Application Information

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IPC IPC(8): A61K31/192A61K31/216
CPCA61K45/00A61K31/192A61K31/445A61K31/216A61P25/14A61P25/28A61P25/16A61P25/00A61K31/195
Inventor 卡利帕达·帕汉
Owner RUSH UNIV MEDICAL CENT
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