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Title:  Method of treatment for spinal cord injury
United States Patent: 
7,199,110
Issued: 
April 3, 2007

Inventors: 
Borgens; Richard B. (Delphi, IN), Shapiro; Scott A. (Indianapolis, IN)
Assignee: 
Purdue Research Foundation (West Lafayette, IN)
Indiana University Research & Technology Corp. (Indianapolis, IN)

Appl. No.: 
10/748,572
Filed: 
December 30, 2003


 

George Washington University's Healthcare MBA


Abstract

Injuries to the central nervous system, particularly spinal cord injuries, are treated by administering a purine nucleoside or analog to the patient and, optionally, electrically stimulating the site of injury.

SUMMARY OF THE INVENTION

The present invention provides a method for the treatment of injuries to the central nervous system (CNS) in a patient, including injuries to the spinal cord. It has been found that a two-part therapy involving the application of electrical stimulation, such as oscillating field stimulation (OFS), in combination with the administration of a purine nucleoside, or analog thereof, such as inosine, produces nerve regeneration, resulting in at least a partial recovery of nerve functioning and behavior in patients suffering CNS injuries. The methods of the present invention are effective for the treatment of both acute and chronic injuries. Advantageously, the co-administration of a purine nucleoside, or analog thereof, such as inosine, extends the usefulness of OFS as a treatment option to chronic CNS injuries.

In one aspect, the present invention provides a method for treating a patient having a spinal cord injury, the method including electrically stimulating the site of the injury and administering a purine nucleoside or analog thereof to the patient, wherein nerve function through the injured spinal cord is at least partially restored and/or wherein nerve regeneration at the site of the spinal cord injury is stimulated. Electrical stimulation of the injury site may be accomplished by implanting a device into the patient. This device is preferably an oscillating field stimulation (OFS) device.

In another aspect, the present invention provides a method for treating a patient having a spinal cord injury by administering to the patient a purine nucleoside or analog thereof under conditions effective to stimulate nerve regeneration at the site of the injury and/or under conditions effective to at least partially restore nerve function through the injured spinal cord.

The spinal cord injury may be a complete severing of the spinal cord, a partial severing of the spinal cord, or a crushing or compression injury of the spinal cord. The spinal cord injury may have occurred more than three months prior to the treatment, more than three weeks prior to the treatment, or more than two weeks prior to the treatment.

Restoration of nerve function can be evidenced by restoration of nerve impulse conduction, a detectable increase in conduction action potentials, observation of anatomical continuity, restoration of more than one spinal root level, an increase in reflex behavior, or a combination thereof.

The purine nucleoside or analog thereof may be administered to the patient systemically, including orally or subcutaneously. The purine nucleoside or analog thereof may be administered locally to the site of the spinal cord injury. The purine nucleoside or analog thereof may be administered by implanting a device into the patient, which device administers the purine nucleoside or analog thereof. The purine nucleoside or analog thereof may be administered locally in a pharmaceutically acceptable carrier. A preferred purine nucleoside includes inosine.

Also included in the present invention is a kit for the treatment of a central nervous system (CNS) injury, the kit including, as a first component, a means for the application of an electrical stimulation to the injury site and, as a second component, a purine nucleoside or analog thereof. In some embodiments, the means for the application of an electrical stimulation to the injury site is an oscillating field stimulation (OFS) device. In some embodiments, the purine nucleoside or analog thereof includes inosine. In some embodiments, the kit further includes a device for the subcutaneous, intravenous, or intrathecal delivery of the purine nucleoside or analog thereof. In some embodiments, the kit further includes written instructions for the treatment of a CNS injury.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The present invention relates generally to methods for treating injuries to the mammalian central nervous system (CNS), including but not limited to spinal cord injuries, to at least partially restore nerve function. With the present invention, it has been found that a two-part therapy involving the application of electrical stimulation to the injured CNS in combination with the administration of a purine nucleoside or analog thereof produces nerve regeneration and restores nerve function in both acute and chronic CNS injuries. In a preferred embodiment, treatment of spinal cord injuries with the combined therapy of oscillating field stimulation (OFS) and the purine nucleoside inosine is used to produce spinal cord nerve regeneration and recovery of nerve functioning and behavior in spinal cord injuries in both acute and chronic spinal cord injuries.

A wide variety of injuries of the CNS may be treated by the methods of the present invention. As used herein, the term "injury" generally denotes a breakdown of the membrane of a nerve cell, such that there is a collapse in the ability of the nerve membrane to separate the salty gel on their insides (cytoplasm) from the salty fluid bathing them (extracellular fluid). The types of salts in these two fluid compartments are very different and the exchange of ions and water caused by injury leads to the inability of the nerve to produce and propagate nerve impulses--and further to the death of the cell. An injury includes damage that directly or indirectly affects the normal functioning of the CNS. The injury may be a structural, physical, or mechanical impairment and may be caused by physical impact, as in the case of a crushing, compression, or stretching of nerve fibers. Alternatively, the cell membrane may be destroyed by or degraded by an illness, a chemical imbalance, or a physiological malfunction such as anoxia (e.g., stroke), aneurysm, or reperfusion. A CNS injury includes, for example and without limitation, damage to retinal ganglion cells, a traumatic brain injury, a stroke-related injury, a cerebral aneurism-related injury, a spinal cord injury, including monoplegia, diplegia, paraplegia, hemiplegia and quadriplegia, a neuroproliferative disorder, or neuropathic pain syndrome.

With injury to the spinal cord of a mammal, connections between nerves in the spinal cord are broken. Such injuries block the flow of nerve impulses for the nerve tracts affected by the injury, with a resulting impairment to both sensory and motor function. Injuries to the spinal cord may arise from compression or other contusion of the spinal cord, or a crushing or severing of the spinal cord. A severing of the spinal cord, also referred to herein as a "transection," may be a complete severing or, may be an incomplete severing of the spinal cord.

The methods of the present invention may be used to treat both acute and chronic injuries of the CNS, including but not limited to acute and chronic spinal cord injuries. In preferred embodiments, the methods of the present invention are used to treat chronic injuries of the spinal cord. As used herein, the term "acute injury" includes injuries that have recently occurred. For example, an acute injury may have very recently occurred, may have occurred within an hour or less, may have occurred within a day or less, may have occurred within a week or less, or may have occurred within two weeks or less. As used herein, the term "chronic injury" is an injury that has persisted for a period of time. For example, a chronic injury may have occurred more than two weeks ago, may have occurred more than three weeks ago, may have occurred more than two months ago, or may have occurred more than three months ago.

One part of the two-part therapy for the treatment of CNS injuries of the present invention is the application of electrical stimulation to the site of the CNS injury. It has been known for two decades that electrical stimulation will enhance regeneration of mammalian spinal cord axons and reduce the retrograde degeneration of axons after an injury. Any of a variety of known methods of delivering electrical stimulation to the site of a CNS injury can be used. The method encompasses the application of a current through, and/or a voltage differential or potential across, the site of injury. The current can be an alternating or a direct current. The current and/or voltage differential can be constant or changing. Electrical stimulation of the CNS injury may be accomplished with the implantation of a bioelectric stimulator device.

A preferred method for electrically stimulating the site of injury is the use of oscillating field stimulation (OFS) wherein the polarity of an electric field is periodically reversed. Oscillating field stimulation has produced positive and beneficial results in the treatment of acute, severe, naturally produced paraplegia in dogs (U.S. Pat. No. 4,919,140), and is currently undergoing clinical trials for the treatment of acute spinal cord injuries in humans. However, all successful uses of such electrical stimulation to date have been limited to the treatment of acute injuries. Any regeneration of injured nerves in the CNS of mammals has been found to occur, if at all, only within a very short time period immediately after the injury occurs. After this short time period expires, nerves have not been found to regenerate. Thus, the present results for the effective treatment of chronic injuries are dramatic and unexpected.

Procedures for the implantation of a device (e.g., a "bioelectric implant") and the application of electrical stimulation to an injury site by OFS are well known in the art. A current is generated in order to produce a voltage differential or potential across the site of injury. A preferred bioelectric implant produces a standing direct current (DC) electrical field around the injury on the order of hundreds of .mu.V/mm (e.g. 100 .mu.V/mm 500 .mu.V/mm). In a small dog, this field can be generated by, for example, an approximately 200 .mu.A current running between two electrodes on either site of the injury. In a human, multiple pairs of electrodes are preferably used, as discussed below. The stimulator device is small and easily implanted surgically beneath the skin of the back. The amount of current needed to generate the weak electric field varies with the cross-sectional area of the injury site and the distance between the electrodes. It has been found that the use of 2 or more pairs of electrodes to deliver the requisite current is preferable as it reduces the amount of current passing through the intervening tissue. As the cross-sectional area increases, the number of electrode pairs used to create the field preferably also increases. For example, a 3-fold increase in cross-sectional area may require tripling of the number of electrodes in order to keep the amount of current passing through any tissue section at a safe level. For example, in one embodiment, six electrodes (3 pairs) are routed to the vertebral column and are affixed above and below the site of injury. The wires (electrodes) remain on the outside of the spine and do not touch the spinal cord itself--however the electrical field produced by them is imposed across the spinal cord. The entire unit is typically surgically removed approximately 14 weeks after implantation. This implantation/explantation has already been determined to be completely safe during Phase One trials in human spinal cord injured patients. See, for example, U.S. Pat. No. 4,919,140, Borgens et al. (1986) J Comp Neurol 250, 168 180; Borgens et al. (1987) Science 238, 366 369; Borgens et al. (1990) J Comp Neurol 296, 634 653; Borgens et al. (1993) Restor Neurol Neurosci 5, 305 322; Borgens et al. (1993) Restor Neurol Neurosci 5, 173 179; Borgens and Bohnert (1997) Exp Neurol 145, 376 89; Borgens et al. (1999) J Neurotrauma 16, 639 57; Borgens (1999) Neuroscience 91, 251 64; and Borgens (2003) Restoring Function to the Injured Human Spinal Cord, (Springer-Verlag, Heidelberg). The complete core circuitry and schematic of a representative bioelectric stimulator are as shown, for example, in Borgens et al. (1999) J Neurotrauma 16, 639 57. In the two part treatment of the invention, the electrical stimulation (administered via the "bioimplant") and the health food additive inosine or other purine nucleoside or analog thereof (administered orally or via subcutaneous injection) can be delivered, preferably concurrently, anytime post-injury.

The length of the time period for the application of electrical stimulation, such as OFS, to the injured site may vary. An electrical stimulation may be administered for several days, for example, for about one day, for about two days, for about three days, for about four days, for about five days, or for any interval thereof. An electrical stimulation may be administered for weeks, for example, for about one week, for about two weeks, for about three weeks, for about four weeks, or for any interval thereof. An electrical stimulation may be administered for several months, for example, for about one month, for about three months, for about four months, for about five months, for about six months, or for any interval thereof. For the treatment of an acute injury, the application of an electrical stimulation to the injured site may begun almost immediately after the injury has occurred, or the application of an electrical stimulation to the injured site may begin several hours or several days after the injury has occurred. For example, treatment may begin about 8 to about 12 hours post injury, several days post injury, or about 14 to about 21 days post injury. For the treatment of a chronic injury, the application of an electrical stimulation may begin at any point in time. For example, application may begin about two weeks after an injury, about three weeks or about one month after an injury, or may begin several months or several years after an injury.

The second part of the two-part therapy for the treatment of CNS injuries according to the present invention is the administration of a purine nucleoside or analog thereof. As used herein, "purine nucleoside" includes any purine base linked to a sugar, or an analog thereof. For example, purine nucleosides include guanine, inosine, or adenine and analogs thereof, include 6-thioguanine (6-TG) and the like. In a preferred embodiment, the purine nucleoside is inosine.

It has recently been demonstrated that the purine nucleosides, inosine and guanosine, act as neurotrophic agents, stimulating axonal outgrowth when administered in vitro to retinal ganglion cells (see U.S. Pat. No. 6,440,455 and Benowitz et al. (1999) Proc Natl Acad Sci USA 96, 13486 90). Inosine is a naturally occurring metabolite without known side effects. And, as demonstrated by the present invention, when administered in vivo, inosine acts as a "mild" nerve growth factor, without the serious side effects associated with the administration of more commonly known nerve growth factors, such as NGF. Purine nucleosides, and analogs thereof, for use in the present invention are readily available. For example, inosine is commercially available from chemical supply companies (including, for example, Sigma Chemical Company, St. Louis, Mo.) or health stores that sell health supplements.

It should be understood that the purine nucleoside or analog thereof can, according to the invention, be administered as part of the two-part therapy or, alternatively, as a therapy without concomitant electrical stimulation of the injury site. In the latter application, the CNS injury is preferably a spinal cord injury, which can be either an acute injury or a chronic injury.

The length of the time period for the administration of a purine nucleoside, or analog thereof, such as inosine, may vary. A purine nucleoside, or analog thereof, may be administered for several hours, for example, for about one hour, for about two hours, for about four hours, for about six hours, for about eight hours, or about twelve hours, or for any interval thereof. A purine nucleoside, or analog thereof, may be administered for several days, for example, for about one day, for about two days, for about three days, for about four days, for about five days, or for any interval thereof. A purine nucleoside, or analog thereof, may be administered for several weeks, for example, for about one week, for about two weeks, for about three weeks, for about four weeks, or for any interval thereof. A purine nucleoside, or analog thereof, may be administered for several months, for example, for about one month, for about three months, for about four months, for about five months, for about six months, or for any interval thereof. For the treatment of an acute injury, the administration of a purine nucleoside, or analog thereof, may begin almost immediately after the injury has occurred. Alternatively, the administration of a purine nucleoside, or analog thereof, may begin several hours or several days post injury. For example, treatment may begin about 1 to about 2 hours post injury, about 4 to about 6 hours post injury, about 2 days to about 6 days post injury, or about 14 days to about 21 days post injury. For the treatment of a chronic injury, the administration of a purine nucleoside, or analog thereof, may begin at any point in time. For example, administration may begin about two weeks after an injury, may begin about three weeks or about one month after an injury, or may begin several months or several years after an injury.

In the methods of the present invention, a purine nucleoside, or analog thereof, may be provided in a pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and anti fungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. Such carriers include, for example, water, preferably sterile and including distilled water, and any other pharmaceutically acceptable carrier known to the art that will not have an adverse effect on the treatment. In some embodiments, a preferred carrier for inosine is sterile lactated Ringers.

In another aspect of the invention, the purine nucleoside, or analog thereof, may be administered in a pharmaceutically acceptable formulation. The pharmaceutically acceptable formulation may be a dispersion system, for example, a lipid-based formulation, a liposome formulation, a multivesicular liposome formulation, nanocapsules, microspheres, beads, or a lipid-based formulation, including oil-in-water emulsions, micelles, mixed micelles, synthetic membrane vesicles, and resealed erythrocytes. The pharmaceutically acceptable formulation can also comprise a polymeric matrix, selected, for example, from synthetic polymers such as polyesters (PLA, PLGA), polyethylene glycol, poloxomers, polyanhydrides, and pluronics or selected from naturally derived polymers, such as albumin, alginate, cellulose derivatives, collagen, fibrin, gelatin, and polysaccharides.

In yet another aspect of the invention, the pharmaceutically acceptable formulation provides sustained delivery or "slow release" of the purine nucleoside to a subject for at least one, two, three, or four weeks after the pharmaceutically acceptable formulation is administered to the subject. Sustained delivery of a formulation of the invention may be provided by use of, for example, slow release capsules, or an infusion pump.

The precise amount of a purine nucleoside, or analog thereof, used in any one embodiment of the present invention will vary according to factors known in the art including but not limited to the physical and chemical nature of the purine nucleoside, or analog thereof, the nature of the pharmaceutically acceptable carrier, the intended dosing regimen, the state of the subject's injury, and the method of administering the purine nucleoside, or analog thereof. Accordingly, it is not practical to set forth generally the amount that constitutes an amount of a purine nucleoside, or analog thereof, effective for all possible applications. Those of ordinary skill in the art, however, can readily determine the appropriate amount with due consideration of such factors. A non-limiting range for a therapeutically effective concentration of inosine is about 1 .mu.M to about 100 mM, more preferably about 50 .mu.M to about 50 mM. A non-limiting range for a therapeutically effective concentration of guanosine is about 1 .mu.M to about 100 mM, more preferably about 50 .mu.M to about 50 mM.

With the present invention, a purine nucleoside, or analog thereof, may be administered to a subject by a wide variety of means. A purine nucleoside, or analog thereof, may be administered systemically to a subject in need of treatment for a CNS injury. For example, a purine nucleoside, or analog thereof, may be administered intravenously through the blood supply, subcutaneously, intraperitoneally, transdermally, or orally. For subcutaneous delivery, an infusion pump or minipump may be used. Likewise, a purine nucleoside, or analog thereof, may be administered locally to the site of CNS injury. For example, a purine nucleoside, or analog thereof may be delivered intrathecally, into the sheath of the spinal column. An infusion pump or minipump may be used for such local delivery.

For treatment of a CNS injury, both the electrical stimulation of the injured site and the administration of a purine nucleoside, or analog thereof, may be started at the same point in time. Alternatively, one part of the two part therapy of the present invention may be started before the other. That is, the electrical stimulation of the injured site may be initiated before the administration of a purine nucleoside, or analog thereof, or, the administration of a purine nucleoside, or analog thereof, may be initiated before the electrical stimulation of the injured site. In other words, electrical stimulation of the injured site and the administration of a purine nucleoside or analog thereof may be begun and/or halted at the same or different points in time.

Alternatively, one part of the two part therapy of the present invention may be completed before the other. That is, the electrical stimulation of the injured site may be stopped before the administration of a purine nucleoside, or analog thereof, is stopped, or, the administration of a purine nucleoside, or analog thereof, may be stopped before the electrical stimulation of the injured site is stopped.

Preferably there is a period during the treatment period where both electrical stimulation of the injury site and administration of the purine nucleoside or analog thereof are administered simultaneously or concurrently. However, it should be noted that the invention also encompasses sequential administration of the electrical stimulation of the injured site and the administration of a purine nucleoside, or analog thereof. In a sequential administration, the period in between the two parts of the treatment is preferably short, e.g., less than hours or days. Likewise the invention encompasses alternating or intermittent administration of the electrical stimulation and the purine nucleoside or analog thereof. In other words, the invention is not intended to be limited by the order in which the two therapies are administered or whether they are administered in a strictly simultaneous fashion. While concurrent administration of the electrical stimulation and the purine nucleoside or analog thereof is preferable, it is envisioned at a minimum both therapies are part of a coordinated treatment plan.

The methods of the present invention are effective for at least partial restoration of nerve function and/or nerve regeneration following a CNS injury. The efficacy of the treatment of the present invention may be determined in a variety of ways. For example, the efficacy of the treatment of the present invention may be determined by methods that detect restoration of nerve function. Restoration or increase in conduction of action potentials, such as CAPs, through the injured site may be used as an indicator that nerve function has at least partially been restored. Nerve function is considered to have been at least partially restored if there is an increase in the conduction of action potentials after treatment. Preferably, the treatment will be conducted sufficiently to achieve at least about 10% increase in conduction of CAPs. Moreover, restoration of anatomical continuity may also be observed by examination with high-resolution light microscopy and/or by diffusion of intracellular fluorescent dyes through the repaired nervous tissue, such as repaired axons, or by direct observation of repaired axonal membranes, as described in the examples. Additionally, in human applications, the efficacy of preferred treatments may be observed by the restoration of more than one spinal root level as determined by the American Spinal Injury Association (ASIA) motor score and/or the National Animal Spinal Cord Injury Study (NASCIS) score as know in the art and as described in Wagih et al. (1996) Spine 21, 614 619. Furthermore, in veterinary applications, behavioral analysis of the cutaneous trunci muscle (CTM) reflex, as more fully discussed in the examples, may also be used to determine the efficacy of the treatment, and whether nerve function has at least partially been restored. Using this analysis, nerve function is considered to have been at least partially restored if there is an increased reflex behavior after treatment, but treatments are desirably preferred so as to achieve at least about a 10% increase in the area of CTM behavioral recovery. The efficacy of the method of treatment of the present invention may also be determined by a combination of the above-discussed methods.

The efficacy of the treatment of the present invention may be determined by methods that detect nerve regeneration. For example, nerve regeneration may be observed by examination with high-resolution light microscopy and/or by diffusion of intracellular fluorescent dyes through the repaired nervous tissue, such as repaired axons, or by direct observation of repaired axonal membranes, as described in the examples.

In some embodiments, electrically stimulating the site of the CNS injury and administering a purine nucleoside, or analog thereof, to the patient may result in an increase in the restoration of nerve function that is greater than that obtained with electrically stimulating the site of the CNS injury alone or administering a purine nucleoside, or analog thereof, alone. In some embodiments, electrically stimulating the site of the CNS injury and administering a purine nucleoside, or analog thereof, to the patient may result in a synergistic increase in the restoration of nerve function. That is, the restoration in nerve function obtained with the two part therapy is greater than the sum of the restoration in nerve functions obtained with electrically stimulating the site of the CNS injury alone and administering a purine nucleoside, or analog thereof, alone.

In some embodiments, the present invention may include, in addition to the treatment of an injury with the application of an electrical stimulation and the administration of a purine nucleoside, or analog thereof, the treatment of the injury with other conventional management compounds and/or compositions. For example, the injury may also be treated with a polyalkylene glycol or a steroid, such as methylprednisolone. For example, a polyalkylene glycol may be administered as described in WO 02/092,107 and U.S. patent application Ser. No. 09/438,206, filed Nov. 12, 1999.

Also contemplated within the scope of the present invention is the treatment of a CNS injury by the administration of a purine nucleoside, or analog thereof, without the application of electrical stimulation to the injury site. For example, a spinal cord injury, including, but not limited to a chronic spinal cord injury, may be treated by the administration of inosine, without the application of an electrical stimulation.

The present invention provides a kit for treating a CNS injury, including, but not limited to a spinal cord injury. The kit will typically include a first component and a second component in a suitable packaging material. The first component is a means of administering an electrical stimulation to the site of injury, such as, for example, an OFS device. The second component is a purine nucleoside, or analog thereof, in an amount sufficient for treatment. The purine nucleoside, or analog thereof, may be in a pharmaceutical formulation appropriate for subcutaneous, intravenous, intrathecal, local delivery, or the like. The purine nucleoside, or analog thereof, may be inosine. Additionally, the kit may include other reagents, such as buffers and solutions, needed to practice the invention. Instructions for administering an electrical stimulation and/or administering a purine nucleoside, or analog thereof, for the treatment of a CNS injury are also typically included. The kit may further include additional devices or reagents necessary, for example, for the subcutaneous, intrathecal, or intravenous delivery of a purine nucleoside, or analog thereof. Such devices or reagents may include, for example, minipumps, syringes, needles, local anesthetics, and the like. As used herein, the term "packaging material" refers to one or more physical structures used to house the contents of the kit. The packaging material is constructed by well-known methods, preferably to provide a sterile, contaminant-free environment. The packaging material has a label that indicates that the first component and second component can be used for the treatment of a CNS injury. As used herein, the term "package" refers to a solid matrix or material such as glass, plastic, paper, foil, and the like. "Instructions for use" typically includes a tangible expression describing the preparation and administration of the first and/or second components of the kit for the treatment of a CNS injury.
 


Claim 1 of 19 Claims

1. A method for treating a patient having a spinal cord injury, this method comprising: electrically stimulating the site of the spinal cord injury through the use of oscillating field stimulation; and administering a purine nucleoside to the patient; wherein nerve function through said injured spinal cord is at least partially restored; wherein the spinal cord injury occurred at least 100 hours prior to the combination treatment.

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