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Inhibitor of trpm-4 ion channel for treating or preventing neurodegeneration

Inactive Publication Date: 2014-12-25
REPRISE PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent is about a compound that can prevent damage to nerve cells in the brain and spinal cord, which is associated with a neurodegenerative disease. The compound works by inhibiting a protein called TRPM4, which regulates the influx of ions into cells. By blocking this protein, the compound reduces the membrane current that occurs when the channel is opened. The compound can be an antisense polynucleotide, a RNA molecule, or a ribozyme that cleaves the gene that encodes TRPM4. The technical effect of this patent is to provide a tool for preventing damage to nerve cells and treating neurodegenerative diseases.

Problems solved by technology

Neurodegenerative diseases of the central nervous system (CNS) which cause progressive loss of neuronal structure and function are particularly devastating diseases for the affected patients and their families.
Due to the complexity of the CNS many of these diseases are only poorly understood to date.
It affects approximately 2.5 million individuals worldwide and currently no curative treatment is available.
While the pathophysiological mechanisms leading to neuro-axonal injury during chronic inflammation of the CNS are still ill defined, it has been suggested that chronic CNS inflammation is associated with an increased oxidative stress and release of glutamate, which results in axonal and neuronal injury by inducing mitochondrial dysfunction and increased metabolic demand.
However, the downstream mechanisms, which are initiated by ATP shortage and Ca2+ overload culminating in a sustained influx of cations and eventually leading to neuro-axonal degeneration, remain elusive (Stirling et al.
Expression of the TRPM4 ion channel was up-regulated in capillary epithelial cells after spinal cord injury, leading to capillary leakiness and failure of capillary integrity.
However, functional neuronal expression and a contribution of TRPM4 to neurodegeneration in diseases like MS have thus far not been shown or otherwise suggested.

Method used

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  • Inhibitor of trpm-4 ion channel for treating or preventing neurodegeneration
  • Inhibitor of trpm-4 ion channel for treating or preventing neurodegeneration
  • Inhibitor of trpm-4 ion channel for treating or preventing neurodegeneration

Examples

Experimental program
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Effect test

example 1

TRPM4 Deficiency Ameliorates Experimental Autoimmune Encephalomyelitis (EAE)

[0062]In order to investigate whether TRPM4 modulates the pathogenesis of EAE, knockout mice with a dysfunctional Trpm4 gene (Trpm4− / −) and wild-type (WT) mice were immunized with the myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55) in order to induce EAE in these animals. The sequence of the MOG35-55 peptide used for immunization is shown in SEQ ID NO:3. Briefly, C57BL / 6 Trpm4− / − mice (Vennekens et al. (2007), Nat Immunol. 8:312-320) and Trpm4+ / + littermates (referred to as WT controls) were immunized subcutaneously with 200 μg / mouse MOG35-55 in complete Freund's adjuvant (Sigma-Aldrich) containing 4 mg / ml Mycobacterium tuberculosis (H37Ra, Difco). In addition, 200 ng pertussis toxin (Calbiochem) was injected intravenously on the day of immunization and 48 h later. The mice were sex and age (6-10 weeks) matched and were scored for clinical signs every day over a period of 60 days by the followin...

example 2

Analysis of Immune Cell Activation by Detecting Incorporation of [methyl-3H]-thymidine

[0065]Since EAE is an autoimmune disease and TRPM4 was previously shown to fulfil functions in immune cell activation and migration, it was first examined whether the protective phenotype in Trpm4− / − could be explained by altered immune cell activation or infiltration. For this purpose, C57BL / 6 Trpm4− / − mice and WT controls were treated as described in Example 1. For assessing T-cell proliferation, single cell suspensions from draining lymph nodes and spleens were prepared 15 days after immunization from WT EAE (n=6) and Trpm4− / − EAE (n=6) mice by homogenizing the tissues through a 40 μm cell strainer (BD Biosciences). Cells were sedimented by centrifugation (300×g, 7 min, 4° C.) and splenic red blood cells were lysed in red blood cell lysis buffer for 7 min at 4° C. Cells were washed once in PBS and resuspended in buffer. The lymph node cells obtained from the immunized animals were cultured in 96...

example 3

Analysis of CNS Infiltrates by Flow Cytometry

[0068]Since the protective phenotype observed in Example 1 could not be explained by altered immune cell activation, CNS (brain and spinal cord) infiltrates were analyzed by flow cytometry. For the isolation of CNS-infiltrating immune cells, WT EAE (n=4) and Trpm4− / − EAE (n=3) mice were sacrificed by CO2 inhalation and immediately transcardially perfused with ice-cold PBS. Brain and spinal cord were removed, minced with blades and digested in collagenase / DNAseI solution (Roche) for 45 min at 37° C. Tissue was triturated through a 40 μm cell strainer. The homogenized tissue was washed in PBS (300× g, 10 min, and 4° C.). Immune cells including microglia were separated from myelin, other glia and neuronal cells by centrifugation over a discontinuous percoll (GE Healthcare) gradient. The homogenized tissue was resuspended in 30% isotonic percoll, transferred into a 15 ml Falcon tube and 78% isotonic percoll was layered underneath. The gradien...

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Abstract

The invention relates to a compound which is effective in inhibiting the function of the TRPM4 ion channel and the use of such compound in treating or preventing a neurodegenerative disease, such as Multiple Sclerosis, Parkinson's disease, Alzheimer's disease, or a myotrophic lateral sclerosis, in a subject. The invention also provides a pharmaceutical composition comprising a TRPM4 inhibitory compound. The invention further relates to in vitro methods for identifying pharmaceutically active compounds that are useful for treating or preventing a neurodegenerative disease.

Description

[0001]The invention relates to a compound which is effective in inhibiting the function of the TRPM4 ion channel and the use of such compound in treating or preventing a neurodegenerative disease, such as Multiple Sclerosis, Parkinson's disease, Alzheimer's disease, or amyotrophic lateral sclerosis, in a subject. The invention also provides a pharmaceutical composition comprising a TRPM4 inhibitory compound. The invention further relates to in vitro methods for identifying pharmaceutically active compounds that are useful for treating or preventing a neurodegenerative disease.BACKGROUND OF THE INVENTION[0002]Neurodegenerative diseases of the central nervous system (CNS) which cause progressive loss of neuronal structure and function are particularly devastating diseases for the affected patients and their families. Among these neurodegenerative diseases are, for example, Multiple Sclerosis (MS), Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS) and stroke...

Claims

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Application Information

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IPC IPC(8): A61K31/18C12Q1/68
CPCA61K31/18C12Q2600/158C12Q2600/136C12Q1/6881A61K45/06A61K31/00A61K31/05A61K31/132A61K31/196A61K31/198A61K31/352A61K31/365A61K31/4402A61K31/4453A61K31/473A61K31/565A61K31/566A61K31/64G01N33/6872G01N2500/04A61P25/00A61P25/28A61K2300/00
Inventor FRIESE, MANUELSCHATTLING, BENJAMINSTEINBACH, KARINFREICHEL, MARCFLOCKERZI, VEITVENNEKENS, RUDIMERKLER, DORON
Owner REPRISE PHARMA INC
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