Compositions and methods of treatment using modulators of motoneuron diseases

A motor neuron and disease technology, applied in nervous system diseases, neuromuscular system diseases, drug combinations, etc., can solve problems such as lack of understanding of the fundamental mechanism of motor neuron diseases

Inactive Publication Date: 2011-06-15
KINEMED
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Relative paucity of successful drug candidates in SOD1-G93A TGN mice reflects a lack of fundamental understanding of the underlying mechanisms of motor neuron disease

Method used

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  • Compositions and methods of treatment using modulators of motoneuron diseases
  • Compositions and methods of treatment using modulators of motoneuron diseases
  • Compositions and methods of treatment using modulators of motoneuron diseases

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0232] Example 1: Separation of Tubulin Dimers and Aggregates

[0233] By reviewing previously described protocols (Fanara, P., Oback, B., Ashman, K., Podtelejnikov, A., Brandt, R. Identification of MINUS, a small polypeptide that functions as a microtubule nucleation suppressor. EMBO J. 18, 565-577 (1999); Fanara, P. et al., In vivo measurement of microtubule dynamics using stable isotope labeling with heavy water. Effect of taxanes. J. Biol. Chem. 279, 49940-49947 (2004)) slightly Modified to purify tubulin. For ex vivo purification, mice were anesthetized with isoflurane and euthanized by cervical dislocation. The sciatic nerve was cut and isolated as follows. Pull the skin back to expose the muscles of the lower body. The spinal cord was transected with scissors at a location just below the lumbar region and also just above the broad sacral region. Slide the partially opened scissors down the lumbar region of the spine until the scissors touch near the broad ilium port...

example 2

[0234] Example 2: Isolation of cold stable microtubules

[0235] A slight modification of the previously described protocol was used to isolate cold-stable microtubules (Pirollet, F., Derancourt, J., Haiech, J., Job, D., Margolis, R.L. Ca( 2+ )-calmodulin regulated effectors of microtubule stability in bovine brain. Biochemistry 31, 8849-8855 (1992)). Briefly, in the presence of 1.5mM CaCl 2 The ice-cold MSB (Fanara, P., Obaek, B., Ashman, K., Podtelejnikov, A., Brandt, R. Identification of MINUS, a small polypeptide that functions as a microtubule nucleation suppressor. EMBO J.18, 565- 577 (1999)), the ratio of buffer to cell pellet or brain tissue was set at a ratio of 1.4:1 (volume / weight). After 2 minutes on ice, EGTA was added to a final concentration of 3 mM and the mixture was homogenized for an additional 1 minute on ice. The extract was centrifuged at 150,000 x g for 30 min at 4°C and the supernatant collected. Microtubule assembly was initiated by incubating supe...

example 3

[0236] Example 3: GC / MS analysis of tubulin

[0237] Tubulin samples were hydrolyzed by treatment with 6N HCl at 110°C for 16 hours. Derivatization of protein-derived amino acids to pentafluorobenzyl derivatives and measurement by GC / MS 2 Incorporation of H into alanine, as detailed elsewhere (Fanara, P. et al., In vivo measurement of microtubule dynamics using stable isotope labeling with heavy water. Effect of taxanes. J. Biol. Chem. 279, 49940 -49947 (2004)). 2 The enrichment of H was calculated as the percentage increase of the alanine derivative present as the (M+1) mass isotopologue over the natural abundance.

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Abstract

The invention disclosed herein describes a novel therapeutic target for motoneuron diseases (altered dynamics of microtubules in neurons); methods for measuring the state of activity of this therapeutic target in subjects with established, incipient, or potential motoneuron disease; the discovery of drug agents that modulate neuronal microtubule dynamics in living subjects with motoneuron diseases; the discovery that administration of such agents, alone or in combinations, can improve MT-mediated transport of ''cargo'' molecules along and through axons; the discovery that such modulation of altered microtubule dynamics and improvement in MT-transport of molecules along axons can provide marked neuroprotective therapy for living subjects with motoneuron diseases, including delay in symptoms and prolongation of survival; and the discovery that monitoring of neuronal microtubule dynamics in response to therapeutic interventions in subjects with motoneuron diseases,, allows diagnostic monitoring, to optimize therapeutic regimens and treatment strategies in individual subjects or in drug trials.

Description

[0001] Cross References to Related Applications [0002] This invention is based on U.S. Provisional Patent Application No. 61 / 128,522 filed May 21, 2008, required by 35 U.S.C. §119(e) and U.S. Patent Application filed on January 5, 2007, required by 35 U.S.C. §120 Priority of No. 11650,020, which claims U.S. Provisional Patent Application No. 60 / 756,836, filed January 5, 2006, and U.S. Provisional Patent Application No. 60 / 756,836, filed January 5, 2006, under 35 U.S.C. Priority to Provisional Patent Application No. 60 / 756,952, the contents of each of which are hereby incorporated by reference in their entirety. technical field [0003] The present invention relates to new pharmaceutical compounds affecting the activity and dynamics of motor neurons. The present invention also relates to the use of this new pharmaceutical compound in the treatment of motor neuron disorders such as amyotrophic lateral sclerosis. The invention also relates to screening and monitoring test sub...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N33/68A61K31/4741
CPCG01N33/6896G01N2800/2835G01N2500/10G01N33/5058A61P21/00A61P25/00
Inventor M·K·赫勒施泰因P·法纳扎
Owner KINEMED
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