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Title:  Methods of inducing nervous tissue regeneration

United States Patent:  6,569,423

Issued:  May 27, 2003

Inventors:  Weinstein; David E. (Dobbs Ferry, NY)

Assignee:  Albert Einstein College of Medicine of Yeshiva University (Bronx, NY)

Appl. No.:  294764

Filed:  April 19, 1999

Abstract

This invention relates to a method of regenerating nervous tissue by contacting the tissue with Schwann cells that express .DELTA.SCIP. The inventors have demonstrated herein that Schwann cells expressing .DELTA.SCIP induce regeneration of nervous tissue. Also provided by the present invention is a method for treating a subject in need of nervous tissue regeneration by introducing Schwann cells expressing .DELTA.SCIP into the subject.

SUMMARY OF THE INVENTION

The present invention provides a method for regenerating nervous tissue comprising contacting the tissue with an effective amount of Schwann cells expressing .DELTA.SCIP to regenerate the nervous tissue.

The present invention also provides a method for treating a subject in need of nervous tissue regeneration comprising introducing an effective amount of Schwann cells expressing .DELTA.SCIP into the subject to induce nervous tissue regeneration in the subject. The subject in need of nervous tissue regeneration may have a neurodegenerative disease or damaged neurons.

Further provided by the present invention is a method of inducing nervous tissue regeneration in a subject in need of such treatment comprising administering to the subject an effective amount of .DELTA.SCIP to induce nervous tissue regeneration in the subject. The administration of .DELTA.SCIP may be effected by administration of the .DELTA.SCIP protein or the .DELTA.SCIP nucleic acid.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a method for regenerating nervous tissue comprising contacting said tissue with an effective amount of Schwann cells expressing .DELTA.SCIP to regenerate the nervous tissue.

As defined herein, "nervous tissue" comprises any or all of the following: neuronal cells, Schwann cells, stellate cells, neuroglial cells, granule cells, ganglia cells, grey matter, white matter, myelin, neurolimma, axons, dendrites, motor neurons, fibrils and fibular processes.

As used herein, "neural cells" are any of the cells that constitute nervous tissue and the tissue that supports it including, but not limited to, Schwann cells, stellate cells; neuroglial cells, granule cells and ganglia cells. The granule cells may be cerebellar granule cells or cerebral granule cells.

Inducing "nervous tissue regeneration" is herein defined as inducing one or more of: the myelination of a nerve, the growth of neurons, the growth of the axons or dendrtes of the nerve, the growth of fibrils of neuroglia, the growth of stellate cells, the growth of fibular processes of neuroglia, the remyelination of grey matter, and the remyelination of white matter.

As used herein, "growth" may be defined as an increase in thickness, diameter, and length of the nerve fibers or the myelin or neurolimma coverings, and the supporting fibrils and fibular processes. The definition of "growth" as used herein also includes an increase in the numbers of Schwann cells, stellate cells or neuroglial cells present on or supporting a nerve.

The neuronal regeneration may take place in nerves of both the central nervous system and the peripheral nervous system.

The present invention also provides a method for treating a subject in need of nervous tissue regeneration comprising introducing an effective amount of Schwann cells expressing .DELTA.SCIP into the subject to induce nervous tissue regeneration in the subject. The subject in need of nervous tissue regeneration may have a neurodegenerative disease, damaged neurons and/or damaged myelin.

Non-limiting examples of neurodegenerative diseases which may be treated using the methods described herein are Alzheimer's disease, Pick's disease, Huntington's disease, Parkinsoni's disease, cerebral palsy, amyotrophic lateral sclerosis, muscular dystrophy, multiple sclerosis, myasthenia gravis, and Binswanger's disease.

In addition, damaged neurons or myelin caused by vascular lesions of the brain and spinal cord, trauma to the brain and spinal cord, cerebral hemorrhage, intracranial aneurysms, hypertensive encephalopathy, subarachanoid hemorrhage or developmental disorders may also be treated using the methods provided by the present invention. Examples of developmental disorders include, but are not limited to, a defect of the brain, such as congenital hydrocephalus, or a defect of the spinal cord, such as spina bifida.

Also provided by the present invention is a method of inducing nervous tissue regeneration in a subject in need of such treatment comprising administering to the subject an effective amount of .DELTA.SCIP to induce nervous tissue regeneration in the subject.

The administration of .DELTA.SCIP may be effected by administration of the .DELTA.SCIP protein itself or administration of a nucleic acid encoding .DELTA.SCIP by the use of standard DNA techniques.

The .DELTA.SCIP protein may be administered to a tissue or subject topically or by intravenous, intramuscular, intradermal, subcutaneous or intraperitoneal injection. The .DELTA.SCIP protein is administered in amounts sufficient to promote nervous tissue regeneration in a subject.

The .DELTA.SCIP protein maybe produced synthetically or recombinantly, or may be isolated from native cells, or may be an analogue of the .DELTA.SCIP protein. As used herein, "analogue" means functional variants of the .DELTA.SCIP protein, and includes .DELTA.SCIP protein isolated from mamimalian sources other than human, such as mouse, as well as functional variants thereof.

The nucleic acid sequence encoding .DELTA.SCIP protein administered to a mammal may be genomic DNA or cDNA. The nucleic acid sequence may be administered using a number of procedures known to one skilled in the art, such as electroporation, DEAE Dextran, monocationic liposome fusion, polycationic liposome fusion, proto plast fusion, DNA coated microprojectile bombardment, by creation of an in vivo electrical field, injection with recombinant replication-defective viruses, homologous recombination, and naked DNA transfer. It is to be appreciated by one skilled in the art that any of the above methods of DNA transfer may be combined.

A nucleic acid encoding .DELTA.SCIP protein may also be administered to a mammal using gene therapy, i.e. by the administration of a recombinant vector containing a nucleic acid sequence encoding .DELTA.SCIP protein. The nucleic acid sequence may be, for example, genomic DNA or cDNA. The recombinant vector containing nucleic acid encoding .DELTA.SCIP protein may be administered to a mammal using any number of procedures, known to one skilled in the art, including, but not limited to, electroporation, DEAE Dextran transfection, calcium phosphate transfection, cationic liposome fusion, protoplast fusion, by creation of an in vivo electrical field, DNA coated microprojectile bombardment, injection with recombinant replication-defective viruses, homologous recombinantion; gene therapy, and naked DNA transfer. It is to be appreciated by one skilled in the art that any of the above methods of nucleic acid transfer may be combined. Accordingly, a cell, such as a Schwann cell or a glial cell which expresses .DELTA.SCIP protein introduced therein through viral transduction, homologous recombination, or transfection is also provided by the present invention. This cell may then be administered to a subject to promote nervous tissue regeneration.

The recombinant vector may comprise a nucleic acid of or corresponding to at least a portion of the genome of a virus, where this portion is capable of directing the expression of a nucleic sequence encoding .DELTA.SCIP protein, operably linked to the viral nucleic acid and capable of being expressed as a functional gene product in the subject mammal.

The recombinant vectors may also contain a nucleotide sequence encoding suitable regulatory elements so as to effect expression of the vector construct in a suitable host cell. As used herein, "expression" refers to the ability of the vector to transcribe the inserted DNA sequence into mRNA so that synthesis of the protein encoded by the inserted nucleic acid can occur. Those skilled in the art will appreciate that a variety of enhancers and promoters are suitable for use in the constructs of the invention, and that the constructs will contain the necessary start, termination, and control sequences for proper transcription and processing of the nucleic acid sequence encoding .DELTA.SCIP protein when the recombinant vector construct is introduced into a mammal. Vectors suitable for the expression of the nucleic sequence encoding .DELTA.SCIP protein are well known to one skilled in the art.

It is within the confines of the invention that .DELTA.SCIP protein may be administered in combination with a growth factor to promote nervous tissue regeneration. .DELTA.SCIP, in the form of a protein, nucleic acid, or a recombinant vector containing nucleic acid encoding .DELTA.SCIP, may be administered to a subject prior to, simultaneously with or subsequent to administration of a growth factor.

For the purposes of gene transfer into a tissue or subject, a recombinant vector containing nucleic acid encoding .DELTA.SCIP may be combined with a sterile aqueous solution which is preferably isotonic with the blood of the recipient. Such formulations may be prepared by suspending the recombinant vector in water containing physiologically compatible substances such as sodium chloride, glycine, and the like, and having buffered pH compatible with physiological conditions to produce an aqueous solution, and rendering such solution sterile. In a preferred embodiment of the invention, the recombinant vector is combined with a 20-25% sucrose in saline solution in preparation for introduction into a mammal.

The amounts of nucleic acid encoding .DELTA.SCIP, or nucleic acid encoding .DELTA.SCIP contained in a vector are administered in amounts sufficient to induce nervous tissue regeneration in a subject. However, the exact dosage will depend on such factors as the purpose of administration, the mode of administration, and the efficacy of the composition, as well as the individual pharmacokinetic parameters of the subject. Such therapies may be administered as often as necessary and for the period of time as judged necessary by one of skill in the art.

Non-limiting examples, of tissues into which nucleic acid encoding .DELTA.SCIP may be introduced to induce nervous tissue regeneration include fibrous, vesicular, cardiac, cerebrovascular, muscular, vascular, transplanted, and wounded tissues. Transplanted tissues are for example, heart, kidney, lung, liver and ocular tissues.

The tissues into which nucleic acid encoding .DELTA.SCIP may be introduced to induce nervous tissue regeneration include those associated with neurodegenerative disease or damaged neurons.

Non-limiting examples of neurodegenerative diseases which may be treated using the methods described herein are Alzheimer's disease, Pick's disease, Huntington's disease, Parkinson's disease, cerebral palsy, amyotrophic lateral sclerosis, muscular dystrophy, multiple sclerosis, myasthenia gravis, and Binswanger's disease.

In addition, damaged neurons caused by vascular lesions of the brain and spinal cord, trauma to the brain and spinal cord, cerebral hemorrhage, intracranial aneurysms, hypertensive encephalopathy, subarachanoid hemorrhage or developmental disorders may also be treated using the methods provided by the present invention. Examples of developmental disorders include, but are not limited to, a defect of the brain, such as congenital hydrocephalus, or a defect of the spinal cord, such as spina bifida.

In further embodiments of the invention, .DELTA.SCIP is used to enhance wound healing, organ regeneration and organ transplantation, including the transplantation of artificial organs. In addition .DELTA.SCIP can be used to accelerate and enhance nervous tissue coverage of grafts.

Claim 1 of 1 Claim

What is claimed is:

1. A method of culturing nervous tissue that comprises axons, the method comprising contacting said tissue in culture with an effective amount of Schwann cells expressing .DELTA.SCIP under the control of a Schwann cell-specific P0, promoter to induce axonal growth in said nervous tissue, wherein the .DELTA.SCIP is a mammalian SCIP with a deleted amino terminus, an intact POU domain, and is able to induce overexpression of myelin structural genes.


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