Treatment of mitochondrial diseases

a technology for mitochondrial diseases and treatment methods, applied in the field of treatment, amelioration, or prevention of mitochondrial diseases, can solve the problems of difficulty in walking, loss of muscle control and strength in hands and arms, and difficulty in breathing, so as to limit or prevent damage to organelles

Inactive Publication Date: 2013-10-10
EDISON PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0012]It has surprisingly been found that certain compounds limit or prevent damage to organelles, cells, and tissues caused by mitochondrial dysfunction, oxidative stress or neuroinflammation, as demonstrated by providing protection in standard experimental models of mitochondrial dysfunction caused by MPP+ / MPTP (1-methyl-4-phenylpyridinium / 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine) or of oxidative stress caused by beta amyloid or high glutamate. These compounds show protection in the experimental model using FRDA fibroplasts and may be used for the treatment of Friedreich's disease and other ataxias, Leber's hereditary optic neuropathy (LHON), mitochondrial myopathy, encephalopathy, lactacidosis, stroke (MELAS), Myoclonic Epilepsy with Ragged Red Fibers (MERFF), macular degeneration, Down's syndrome, Creutzfeldt-Jakob syndrome.

Problems solved by technology

The first symptom is usually difficulty in walking.
Most people with Friedreich's ataxia develop scoliosis (a curving of the spine to one side), which, if severe, may impair breathing.
Symptoms may include tripping, stumbling and falling, loss of muscle control and strength in hands and arms, difficulty speaking, swallowing and / or breathing, chronic fatigue, and muscle twitching and / or cramping.
Symptoms of lower motor neuron damage include muscle weakness and muscle shrinking (atrophy).

Method used

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  • Treatment of mitochondrial diseases

Examples

Experimental program
Comparison scheme
Effect test

example 1

Beta-Amyloid Cell Death Assay

Media Composition

[0193]Neurobasal / B27i: Neurobasal medium plus 1×B27 supplement, 0.5 mM L-glutamine, 25 μM L-glutamic acid, and 0.5× Penicillin / Streptomycin

Neurobasal / B27m: Neurobasal medium plus 1×B27 supplement and 0.5 mM L-glutamine

BSS (Ca / Mg free): HBSS (calcium / magnesium free) plus 10 mM Hepes (pH 7.25), 1×Penicillin / Streptomycin, and 1 mM Sodium Pyruvate

Glucose-free BSSo: 143.6 mM NaCl, 5.4 mM KCl, 1.8 mM CaCl2, 0.8 mM MgSO4, 1 mM NaH2PO4, 26.2 mM NaHCO3, 10 mg / l phenol red, 0.25× Penicillin / Streptomycin, and 10 mM Hepes (pH 7.4)

Papain Quench solution: Neurobasal medium plus 1×B27 supplement, 1× Penicillin / Streptomycin and 0.5 mg / ml DNase1

Assay media: Neurobasal medium plus 1×B27 (minus AO) supplement, 0.5 mM L-glutamine, and 0.25× Penicillin / Streptomycin.

Experimental Procedure

Hippocampal Cell Culture

[0194]Hippocampal neurons were isolated from E18 rat embryos as follows. Embryos were decapitated and the heads immersed in cold BSS (Ca / Mg free). Usi...

example 2

MPP+ Cell Death Assay

Media Composition

[0201]RF media: DMEM-No glucose, glucose (29.1 mM), L-glutamine (1.4 mM), 10% heat-inactivated FBS, and 1× penicillin / streptomycin (P / S)

Wash media: DMEM-No glucose and 1×P / S

Low serum media: DMEM-No glucose, glucose (29.1 mM), L-glutamine (1.4 mM), 0.5% FBS, and 1×P / S

Assay Media: DMEM-No glucose, L-glutamine (1.4 mM), 0.5% FBS, and 1×P / S

Experimental Procedure

[0202]A substantia nigra-derived dopaminergic progenitor cell line was seeded in poly-D-lysine-coated 24-well plates at a density of 4500 cells per well in RF media. The cells were left to attach for 16 hours in a 33° C. incubator (5% CO2) after which time they were washed once with 500 μL wash media and then differentiated into a neuronal phenotype by incubating in low serum media for 24 hours in a 39° C. incubator (5% CO2).

[0203]After 24 hours the low serum medium was aspirated from the cells and the monolayer was washed once with 500 μL wash media. Test articles were diluted to 2-fold the ...

example 3

MPTP Animal Model

[0216]Male C57 / BL6 mice (Harlan, Ind.), weight 25-30 g, were used in all studies. MPTP-HCl (Sigma) was administered i.p. according to one of the following protocols. The maximum volume which was given per injection is 200 μL. In all studies, animals were euthanized with carbon dioxide and, brains were removed for subsequent determination of dopamine depletion where appropriate.

Subacute Model

[0217]Animals received 25 mg / kg of MPTP once a day for 5 consecutive days. The end point was 2 days after the final dose.

Acute Model

[0218]Animals received 4×20 mg / kg of MPTP at 2 hour intervals. The end point was at either 7 or 14 days.

Subchronic Model

[0219]Animals received 2×40 mg / kg of MPTP with this repeated 16 hours later. The end point was at either 14 or 28 days.

Chronic Model

[0220]Animals received 25 mg / kg of MPTP, given twice weekly for 5 weeks. The end point was either 1, 3 or 24 weeks after the final dose.

Neurobehavioral Outcome Measures

[0221]Compound efficacy was examin...

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Abstract

The invention relates the method of treatment or amelioration of mitochondrial disorders such as Alzheimer's disease, Parkinson's disease, Friedreich's ataxia (FRDA), cerebellar ataxias, Leber's hereditary optic neuropathy (LHON), mitochondrial myopathy, encephalopathy, lactacidosis, stroke (MELAS), Myoclonic Epilepsy with Ragged Red Fibers (MERFF), amyotrophic lateral sclerosis (ALS), motor neuron diseases, Huntington's disease, macular degeneration, and epilepsy, with chroman derivatives of Formula I or Formula II as described herein.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This U.S. patent application claims priority under 35 U.S.C. 119(e) to U.S. Provisional Application Ser. No. 60 / 504,391, filed Sep. 19, 2003, and Ser. No. 60 / 541,737, filed Feb. 4, 2004 incorporated herein by reference in their entirety.BACKGROUND INFORMATION[0002]The present invention relates to a method of treatment, amelioration, or prevention of mitochondrial diseases with certain pharmaceutical formulations containing chroman derivatives.[0003]Mitochondrial dysfunction leads to impaired calcium buffering, generation of free radicals that may participate in intracellular and extracellular processes, changes in mitochondrial permeability and oxidative damage which is observed in several neurodegenerative diseases. Some disorders involved in mitochondrial dysfunction affecting cellular processes include but are not limited to as Alzheimer's disease, Parkinson's disease, Friedreich's ataxia and other ataxias, Leber's hereditary optic neu...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D319/08C07D295/096C07D311/58A61K31/353A61K31/675A61K31/7048C07D311/74C07D311/94C07D405/06C07D405/12C07D405/14C07D409/04C07D417/06C07D417/12
CPCA61K31/353C07D311/70A61K31/7048C07D311/74C07D311/94C07D319/08C07D405/06C07D405/12C07D405/14C07D409/04C07D417/06C07D417/12C07D295/096C07D311/58A61K31/675A61P1/00A61P11/00A61P11/06A61P13/12A61P15/00A61P17/00A61P17/02A61P17/06A61P17/10A61P19/02A61P21/00A61K31/357A61K31/352A61K31/496A61P25/00A61P25/08A61P25/14A61P25/16A61P25/28A61P27/02A61P29/00A61P35/00A61P37/00A61P41/00A61P43/00A61P9/00A61P9/10A61P3/10
Inventor WALKINSHAW, GAILBODDUPALLI, SEKHARWANG, BINGMILLER, GUY M.
Owner EDISON PHARMA
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