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4-aminopyridine as a therapeutic agent for spinal muscular atrophy

A spinal muscular atrophy, pyridine technology, applied in the direction of muscular system diseases, organic active ingredients, neuromuscular system diseases, etc., can solve problems such as no SMA drug treatment

Inactive Publication Date: 2015-02-04
THE TRUSTEES OF COLUMBIA UNIV IN THE CITY OF NEW YORK
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] There is no effective medical treatment for SMA, and such treatment is greatly needed

Method used

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  • 4-aminopyridine as a therapeutic agent for spinal muscular atrophy
  • 4-aminopyridine as a therapeutic agent for spinal muscular atrophy
  • 4-aminopyridine as a therapeutic agent for spinal muscular atrophy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] The results in Example 1 confirm the Drosophila model and also show that Drosophila smn mutants have increased NMJ-evoked neurotransmitter release with concomitant defects in muscle growth, movement and motor rhythmicity (Figures 1 and 2) .

Embodiment 3

[0035] The results in Example 3 show that, in contrast to muscle recovery of SMN, pan-neuronal recovery of SMN fully rescues the muscle surface area of ​​smn mutants to control levels ( Figure 2B , D, E), and also completely recovered their locomotion velocity, rhythmic motor output, and NMJ eEPSP amplitude ( Figure 2F -H). These results show that the defect in muscle growth in smn mutant larvae is due to an involuntary requirement for normal SMN levels in the nervous system rather than to the muscle fibers themselves.

[0036] The results in Example 3 show that SMN is required in cholinergic neurons but not in glutamatergic motor neurons, and that SMN is required in both proprioceptive and central cholinergic neurons. Transgenic SMN expression levels in central cholinergic neurons completely rescued the muscle growth, locomotor, and rhythmic activity defects of smn mutants ( Figure 3E -G). Furthermore, SMN expression in cholinergic neurons also completely rescued the eE...

Embodiment 4

[0037] Example 4 Based on the hypothesis that motor circuits are functionally defective in smn mutants, experiments were designed to test whether increasing the excitability of central cholinergic neurons in these animals could increase motor network activity and alter smn mutant phenotypes. The results of various experiments showed that pharmacological inhibition of K+ channels (using the FDA-approved broad-spectrum K+ channel antagonist 4-AP) satisfactorily benefited the smn mutant phenotype, results consistent with important results for SMN depletion. Motor circuits are consistent with defective excitability generated by their interneuron or sensory neuron input.

[0038] Discussion of results

[0039] The results presented here show that restoration of the SMN in at least two groups of motor circuit neurons (bd and type I md sensory neurons) resulted in a complete rescue of the larval phenotype. The bd and type I md sensory neurons are important components of the propri...

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Abstract

It has been discovered that pharmacological inhibition of K+ channels (using the FDA-approved broad-spectrum K+ channel antagonist 4-AP) positively benefitted smn mutant phenotypes, a result that is consistent with the defective excitability of motor circuits by their interneuron or sensory neuron inputs being a critical consequence of SMN depletion. Based on these observations, certain embodiments of the invention are directed to methods of treatment of SMA by administering therapeutically effective amounts of one or more potassium channel antagonists, including 4-aminopyridine, 4-(dimethylamino)pyridine, 4-(methylamino)pyridine, and 4-(aminomethyl)pyridine. Other embodiments are directed to new pharmaceutical formulations comprising two or more potassium channel antagonists.

Description

[0001] Cross References to Related Applications [0002] Pursuant to Section 119(e) of the U.S. Patent Act, this application claims priority to U.S. Provisional Application No. 61 / 615,466, filed March 15, 2008, and U.S. Provisional Application No. 61 / 057,190, filed March 26, 2012, as The entire contents of which are hereby incorporated by reference as if fully set forth herein. [0003] Statement of Government Interests [0004] This invention was made with Government support under Contract No. W81XWH-08-1-0009 of the Department of Defense. Background technique [0005] Spinal muscular atrophy (SMA) is a fatal human disease characterized by motor neuron dysfunction and muscle degeneration due to depletion of the ubiquitous Survival Motor Neuron (SMN) protein. SMA is an autosomal recessive disease characterized by degeneration of motor neurons in the anterior horn of the spinal cord, leading to muscle paralysis and atrophy. SMA is conventionally divided into three categories...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4409
CPCA61K31/4409A61P21/00A61P21/02A61P43/00
Inventor B·麦凯布
Owner THE TRUSTEES OF COLUMBIA UNIV IN THE CITY OF NEW YORK
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