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Compositions comprising necrosis inhibitors, such as necrostatins, alone or in combination, for promoting axon regeneration and nerve function, thereby treating CNS disorders

a technology of necrosis inhibitors and axons, applied in the field of necrosis inhibitors, can solve the problems of axonal loss, disruption of neuronal function, and inability of the central nervous system to self-repair and regenerate, so as to promote axon growth and nerve function, preserve neuron viability, and reduce or even reverse cognitive loss

Inactive Publication Date: 2014-12-04
MASSACHUSETTS EYE & EAR INFARY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention is based on research showing that a necrosis inhibitor, called RIP kinase inhibitor, can protect neurons and promote the growth of nerves. This could help prevent or reverse the loss of brain function associated with certain disorders such as Alzheimer's disease and spinal cord injuries. The invention provides methods for promoting nerve function and preserving the viability of CNS neurons, which may support axonal regeneration. This could lead to improved treatments for CNS disorders.

Problems solved by technology

While the peripheral nervous system is capable of repair and regeneration, the central nervous system is unable to self-repair and regenerate.
These traumatic and age-related insults to the CNS cause axonal loss, disrupt neuronal connections, and ultimately result in permanent blindness, paralysis, and other losses in cognitive, motor, and sensory functions.
There is currently no effective treatment for recovering human nerve functions after CNS injury.

Method used

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  • Compositions comprising necrosis inhibitors, such as necrostatins, alone or in combination, for promoting axon regeneration and nerve function, thereby treating CNS disorders
  • Compositions comprising necrosis inhibitors, such as necrostatins, alone or in combination, for promoting axon regeneration and nerve function, thereby treating CNS disorders
  • Compositions comprising necrosis inhibitors, such as necrostatins, alone or in combination, for promoting axon regeneration and nerve function, thereby treating CNS disorders

Examples

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example 1

Efficacy of a Necrosis Inhibitor and a Pan-Caspase Inhibitor in Promoting RGC Survival and Axon Regeneration

[0337]Like most pathways in the mature central nervous system, the optic nerve cannot regenerate if injured, leaving victims of traumatic nerve injury or degenerative diseases such as glaucoma with life-long visual losses. This situation can be, at least, partially reversed by enhancing the intrinsic growth state of retinal ganglion cells (RGCs). In this example, the efficacy of necrosis inhibitor and a pan-caspase inhibitor in promoting RGC survival and axon regeneration is investigated using a mouse optic nerve crush model.

A. A Necrosis Inhibitor in Combination with a Caspase Inhibitor Promotes RGC Survival in a Optic Nerve Crush Model

[0338]Mice were subjected to optic nerve crush surgery. Specifically, animals were anesthetized with an intraperitoneal injection of ketamine (60-80 mg / kg: Phoenix Pharmaceutical, St. Joseph, Mo.) and xylazine (10-15 mg / kg: Bayer, Shawnee Missi...

example 2

Efficacy of a Necrosis Inhibitor and a Pan-Caspase Inhibitor in a Rat Model of Motor Neuron Regeneration

[0345]The specificity of motor axon regeneration can be investigated in the rat femoral nerve. Proximally, at the site of nerve transection and suture, axons that contribute to both cutaneous and muscle branches intermingle throughout the nerve. As these axons regenerate, they have equal access to neighboring motor and sensory Schwann cell tubes in the distal nerve stump. This assures an element of “choice” at the axonal level. Distally, where the specificity of regneration is assessed, axons are segregated into terminal cutaneous and muscle branches. Motor axons are normally found only in the muscle branch, so any motor reinnervation of the cutaneous branch represents a pathfinding failure. The specificity of axon regeneration is evaluated by simultaneous application of horseradish peroxidase (HRP) to one distal femoral branch and fluoro-gold (FG) to the other. Motor-axon regener...

example 3

Efficacy of a Necrosis Inhibitor and a Pan-Caspase Inhibitor in a Rat Model of Damaged Vertebra

[0348]Two-month old Sprague-Dawley rats (200-220 g) are used. Starting from 14 days before surgical operations, the animals undergo basic walking training for the Basso, Beattie and Bresnahan (BBB) test and the grid walk test, which measure locomotor functions. At 3 days before surgical operations, the animals are subjected to basic evaluations with respect to their behaviors and movement functions.

[0349]Rats are anesthetized with 2 kg / ml of a mixture of 25 mg / ml of ketamine and 1.3 mg / ml of Rompun and subjected to L2 Ventral Laminectomy. The animals are intramuscularly injected with the antibiotic Cefalexin (5 mg / 100 g bodyweight / day) to prevent infections. Spinal cord injury is induced by opening the second lumbar vertebra of each rat and puncturing a small hole (1 mm2) in the outside of the left arcus vertebra using a microrongeur. The blade of a blade holder is inserted into the hole a...

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Abstract

Provided are methods for promoting axon regeneration of a Central Nervous System (CNS) neuron and promoting nerve function following injury to a CNS neuron, for example, brain and / or spinal cord injury. Axon regeneration in a CNS neuron or nerve function following injury to a CNS neuron can be promoted by administering a necrosis inhibitor either alone or in combination with an apoptosis inhibitor to a subject suffering from a CNS disorder, wherein a symptom of the CNS disorder is axon degeneration.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of and priority to U.S. Provisional Patent Application No. 61 / 550,191, filed Oct. 21, 2011, the contents of which are hereby incorporated by reference in their entirety.GOVERNMENT FUNDING[0002]The work described in this application was sponsored, in part, by the National Eye Institute under Grant No. EY14104. The United States Government has certain rights in the invention.FIELD OF THE INVENTION[0003]The field of the invention relates generally to methods for promoting axon regeneration. More particularly, the invention relates to the use of a necrosis inhibitor, e.g., a RIP kinase inhibitor, e.g., a necrostatin, either alone or in combination with an apoptosis inhibitor, e.g., a pan-caspase inhibitor, for preserving neuron viability, promoting nerve function, and enhancing axon outgrowth.BACKGROUND OF THE INVENTION[0004]The nervous system is divided into two parts: the central nervous system (CNS), whi...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/4178A61K38/05
CPCA61K38/05A61K31/4178A61K45/06A61K31/27A61K38/005A61P25/00A61P25/14A61P25/16A61P25/28A61P43/00A61P9/00A61K2300/00
Inventor VAVVAS, DEMETRIOS G.
Owner MASSACHUSETTS EYE & EAR INFARY
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