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Title:  Nerve regeneration

United States Patent:  6,506,727

Issued:  January 14, 2003

Inventors:  Hansson; Hans-Arne (Hovas, SE); Lynch; Samuel E. (Beverly, MA); Antoniades; Harry N. (Newton, MA)

Assignee:  Institute of Molecular Biology, Inc. (Boston, MA)

Appl. No.:  198542

Filed:  February 18, 1994

Abstract

It has been found that the growth factor PDGF, when used in combination with another growth factor such as IGF-I, acts synergistically with the other factor to promote neuronal regeneration.

SUMMARY OF THE INVENTION

The invention features a method of promoting growth of a mammalian nerve by contacting the nerve with purified PDGF. Preferably, the PDGF is contacted with a nerve process, preferably of a peripheral nerve. As used herein, "growth" refers, most preferably, to increase in length of a functional nerve process, e.g., an axon. Growth can also include inducement of proliferation of nerve cells or Schwann cells. Preferably, PDGF is mixed with another factor, most preferably IGF-I, prior to administration or at the site of desired nerve growth.

The second factor can also be another growth factor such as NGF, fibronectin, fibrin, laminin, acidic or basic FGF, EGF, a TGF, or another of the IGF's, i.e., IGF-II or IGF-III. (Active fragments or analogs of any of the active molecules which bind specifically to the appropriate receptors are included in the invention.)

In particular, it has been found that the synergistic action of PDGF and IGF-I can stimulate the in vivo regeneration of injured peripheral nerves. The effects of the combination of PDGF and IGF-I on nerve regeneration in vivo have been found to be superior to those induced by the administration of purified PDGF alone or purified IGF-I alone. As described below, the synergistic effects of the combination of PDGF and IGF-I stimulated about a 7.0 fold increase in the length of regenerated myelinated axons. The combination of PDGF and IGF aids the regeneration of the injured nerve, at least in part, by promoting both the directional regeneration of myelinated axons and the growth of the Schwann cells. Schwann cell proliferation is crucial for supporting axonal myelinated growth. Thus, the synergistic action of PDGF and IGF-I results in axonal growth, proliferation of Schwann cells, and myelin sheath formation, contributing to the formation of myelinated nerve growth. As described below, the regenerated nerve induced by the synergistic action of PDGF and IGF-I retains in vivo functional activity, as judged by the reflexes of lightly anesthetized animals in response to an induced fine pincett-pain test. Regeneration using the composition of the invention is more effective than that achieved in the absence of treatment (i.e. without administration of exogenous agents) or by treatment with purified PDGF alone or purified IGF-I alone.

In preferred embodiments, nerve process regenerating compositions are prepared by mixing PDGF and any other active components with a pharmaceutically acceptable carrier substance, e.g. saline supplemented with albumin or methyl cellulose gel. Most preferably, purified PDGF and IGF-I are combined in a weight-to-weight ratio of between 1:500 and 100;1, preferably between 1:250 and 50:1 and more preferably between 1:100 and 25:1. The purified PDGF may be obtained from human platelets and the purified IGF-I from human blood, or both may be obtained by recombinant DNA technology. Thus, by the terms "PDGF" and "IGF" we mean both platelet and plasma derived and recombinant materials of mammalian, preferably primate origin; most preferably, the primate is a human, but can also be a chimpanzee or other primate. The terms "PDGF" and "IGF" include analogs which elicit biological activities by binding to the PDGF or IGF receptors, respectively. Recombinant PDGF can be recombinant heterodimer, made by inserting into culture prokaryotic or eukaryotic cells DNA sequences encoding both A and B subunits, and then allowing the translated subunits to be processed by the cells to form heterodimer. Alternatively, DNA encoding just one of the subunits can be inserted into cells, which then are cultured to produce homodimeric PDGF (PDGF-1 (AA) or PDGF-2 (BB) homodimer.

The term "purified" as used herein refers to PDGF, IGF-I, or other factor which, prior to use or combination with the other, is 90% or greater, by weight, i.e., the component is substantially free of other proteins, lipids, and carbohydrates with which it is naturally associated.

A purified protein preparation will generally yield a single major band on a polyacrylamide gel. Most preferably, the purified factors used in the compositions of the invention are pure as judged by amino-terminal amino acid sequence analysis.

The compositions of the invention provides a fast, effective method for the in vivo regeneration of injured nerves. In particular, the PDGF/IGF-I combination enhances the growth of nerves compared to natural healing (i.e. no exogenous agent added) or pure PDGF or IGF-I alone. The synergistic effect of the composition promotes about a 7.0 fold increase in new functional nerve regeneration.

Claim 1 of 5 Claims

What is claimed is:

1. A method of promoting regeneration of a peripheral nerve in a mammal comprising contacting said nerve with purified platelet-derived growth factor (PDGF) and a second purified growth factor selected from the group consisting of insulin-like growth factor-I (IGF-I) and acidic fibroblast growth factor (aFGF).
 


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If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.

 

 

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