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Imaging methods and compositions comprising fluorescent dyes associated with viral components for nerve imaging

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Title: Imaging methods and compositions comprising fluorescent dyes associated with viral components for nerve imaging.
Abstract: Disclosed herein are compositions and methods for imaging nerve cells. The composition comprises a fluorescent dye; and a viral component selected from a neurotropic, replication-defective virus, a viral protein of a neurotropic virus, and a capsid of a neurotropic virus. Although the fluorescent dye in itself cannot penetrate nerve cells, the fluorescent dye is bound to the viral component to form a dye/viral component complex that is capable of penetrating nerve cells. ...

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USPTO Applicaton #: #20120078093 - Class: 600431 (USPTO) - 03/29/12 - Class 600 
Surgery > Diagnostic Testing >Detecting Nuclear, Electromagnetic, Or Ultrasonic Radiation >Detectable Material Placed In Body



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The Patent Description & Claims data below is from USPTO Patent Application 20120078093, Imaging methods and compositions comprising fluorescent dyes associated with viral components for nerve imaging.

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RELATED APPLICATION

This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Prov. App. No. 61/127,659, filed May 14, 2008, and U.S. Prov. App. No. 61/082,981, filed Jul. 23, 2008, the disclosures of which are incorporated herein by reference.

FIELD OF THE INVENTION

Disclosed herein are compositions and methods relating to the field of medical imaging.

BACKGROUND OF THE INVENTION

Iatrogenic nerve injury can result in debilitating loss of function in humans. Common causes of iatrogenic nerve injury include surgical failure, traction or pressure lesions, hematoma, or inadequate positioning of the patient (Fercan Komurcu, MD et al., 2005, Annals of Plastic Surgery, 54(2):135-139).

For example, nerves are often imaged during prostatectomy procedures. By way of background, prostate cancer is the most common type of cancer in American men. One common treatment option is removal of cancerous prostate tissue (i.e., prostatectomy) before the cancer spreads locally and before metastasis. Radical prostatectomy complications include incontinence and impotence. A significant percentage of men undergoing radical prostatectomy procedures become impotent due to injury to the cavernous nerves during the surgery.

The risk of iatrogenic nerve injury may be reduced by avoiding injury to the bundles of nerves that run along the surface of the prostate gland and are needed for an erection. Successful nerve sparing surgery, however, is often difficult to achieve because of the difficulty in distinguishing between the prostate tissue and the innervating nerve tissue.

There exists a need for improved imaging methods and compositions for nerve imaging.

SUMMARY

OF THE INVENTION

Disclosed herein are compositions and methods for imaging nerves. The nerves can be located in different areas of a subject.

Also disclosed herein is the discovery that binding a fluorescent dye to a viral component (e.g., virus, viral proteins, capsids) capable of penetrating nerve axons can form a dye/viral component complex that can penetrate nerve axons, thus allowing improved nerve cell imaging. One embodiment provides a composition comprising:

a fluorescent dye; and

a viral component selected from a neurotropic, replication-defective virus, a viral protein of a neurotropic virus, and a capsid of a neurotropic virus,

wherein the fluorescent dye is bound to the viral component to form a dye/viral component complex that is capable of penetrating nerve cells.

In this and other embodiments disclosed herein, neurotropic, replication-defective viruses can be, for example, attenuated or inactivated viral components that are capable of penetrating nerve cells. In another embodiment, the composition can be a vaccine comprising the fluorescent dye and a viral component selected from a neurotropic virus, a viral protein of a neurotropic virus, and a capsid of a neurotropic virus. Accordingly, another embodiment provides a vaccine, comprising:

a fluorescent dye; and

a viral component selected from a neurotropic virus, a viral protein of a neurotropic virus, and a capsid of a neurotropic virus,

wherein the fluorescent dye is bound to the viral component to form a dye/viral component complex that is capable of penetrating nerve cells.

Another embodiment provides a method of making a composition, comprising:

combining a fluorescent dye with a viral component selected from a neurotropic, replication-defective virus, a viral protein of a neurotropic virus, and a capsid of a neurotropic virus,

allowing the fluorescent dye to be bound to the viral component to form a dye/viral component complex that is capable of penetrating nerve cells.

Another embodiment provides methods for imaging nerves and/or diagnosing nerve abnormalities and/or conditions. The methods include the steps of (a) administering a composition, as disclosed herein, to the subject, (b) allowing the dye/viral component complex to penetrate nerve cells, (c) applying a sufficient amount of radiant energy to the subject such that the dye fluoresces, (d) intra-operatively obtaining a fluorescence image of the subject. The method can include the step of observing the fluorescence image to view one or more nerves in the subject, or observing the fluorescence image to determine whether one or more nerves is transected.

Accordingly, another embodiment provides a method for reducing the risk of iatrogenic injury to a subject during a surgical procedure, comprising:

(a) administering a composition to the subject, the composition comprising: a fluorescent dye; and a viral component selected from a neurotropic, replication-defective virus, a viral protein of a neurotropic virus, and a capsid of a neurotropic virus, wherein the fluorescent dye is bound to the viral component to form a dye/viral component complex;

(b) allowing the dye/viral component complex to penetrate nerve cells;

(c) applying a sufficient amount of radiant energy to the subject such that the dye fluoresces;

(d) intraoperatively obtaining a fluorescence image of the subject; and

(e) observing the fluorescence image to view one or more nerves in the subject.

Another embodiment provides a method for diagnosing a nerve condition, comprising:

(a) administering a composition to the subject, the composition comprising: a fluorescent dye; and a viral component selected from a neurotropic, replication-defective virus, a viral protein of a neurotropic virus, and a capsid of a neurotropic virus, wherein the fluorescent dye is bound to the viral component to form a dye/viral component complex;

(b) allowing the dye/viral component complex to penetrate nerve cells;

(c) applying a sufficient amount of radiant energy to the subject such that the dye fluoresces;

(d) intraoperatively obtaining a fluorescence image of the subject; and

(e) observing the fluorescence image to determine whether the nerve is transected.

Other embodiments provide a kit containing the compositions disclosed herein along with instructions to use the composition according to one or more of the methods described herein. In other embodiments, the kit includes one or more ingredients, reagents, dyes, viruses, precursors, or other tools that can be used to make the compositions disclosed herein, along with instructions to use the composition according to one or more of the methods described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 schematically depicts a system for medical imaging;

FIG. 2 is a flowchart depicting algorithms for medical imaging that can be performed by software installed on a computer processor;

FIG. 3A shows a fluorescence image of the back of the mouse of Example 3;

FIG. 3B is a visible (white) light image of the same back of the mouse of FIG. 3A but without fluorescence imaging;

FIG. 3C is a fluorescence image with some visible light illumination of the exposed spinal cord of the mouse of Example 3;

FIG. 3D is a fluorescence image of the same spinal cord closer to the head of the mouse with nerves meeting the spinal cord not labeled with ICG/PBS/HSV-2 ΔRR;

FIG. 4A shows the ICG/PBS/HSV-2 ΔRR (a dye/viral component complex) fluorescence in a ventral view of the whole mouse (lying on its back) of Example 4;

FIG. 4B is an image showing the back (dorsal view) of the mouse of Example 4 dissected to show the spine and the fluorescent nerve from the left foot, using fluorescent and white light imaging;

FIG. 4C is a fluorescence image of the same mouse of FIG. 4B;

FIG. 4D are fluorescence images of (i) the dissected fluorescent dorsal root ganglion from the left side of the spine of the mouse of Example 4 in white light only, with a short segment of its axons on the right side of the ganglion, and (ii) the corresponding ganglion from the right side of the spine, whose right footpad axons were not injected;

FIG. 4E are fluorescence images of (i) the ganglion of FIG. 4D(i) and (ii) the ganglion of FIG. 4D(ii);

FIG. 4F is a magnified fluorescence image of the ganglion from FIG. 4E(i);

FIG. 5A shows an anatomical drawing of a rabbit left limb for comparison with the fluorescence image;

FIG. 5B is a fluorescence image showing that the ICG/HSV-2ΔRR complex traveled from the toe pad injection site up into the upper plantar nerve;

FIG. 5C shows an anatomical drawing of a rabbit right limb for comparison with the fluorescence image;

FIG. 5D is an image of an isolated segment of the saphenous nerve, in visible white light;

FIG. 5E is a fluorescence image showing an isolated segment of the saphenous nerve with ICG/HSV-2ΔRR complex fluorescence;

FIGS. 5F and 5H are fluorescence images showing, respectively, an excised segment of the saphenous nerve of the previous two frames (FIG. 5F) and the nerve in situ (FIG. 5H);

FIGS. 5G and 5I are fluorescence images showing the excised segment of the saphenous nerve of FIG. 5F but stained for the LacZ gene of the UV-inactivated ICG/PBS/HSV-2 ΔRR virus;

FIG. 5J is an anatomical drawing of the rabbit left limb for comparison with the fluorescence image; and

FIG. 5K is a fluorescence image of the dorsal aspect of the left leg of the rabbit of Example 5.

DETAILED DESCRIPTION

One embodiment provides compositions for nerve imaging.

In one embodiment, the composition includes a dye, such as a fluorescent dye used for medical imaging. Many dyes, however, are not suitable for imaging certain portions of the body, such as nerves, as the dyes are typically incapable of penetrating nerve cells. Disclosed herein is the discovery that a neurotropic viral component, i.e., a viral component capable of penetrating nerve cells, can be used to axonally transport a dye through parts or all of a network of nerves. This can be achieved by forming a complex of a dye bound to the viral component.

Dyes

As used herein, the term “fluorescent dye” or “dye” means a small molecule or a protein or other polymer or macromolecule that fluoresces by emitting light in the visible or near-infrared wavelength range upon excitation by radiant light energy of an appropriate wavelength.

Suitable fluorescent dyes include any non-toxic dye that fluoresces when exposed to radiant energy, e.g. light. In certain embodiments the dye is a fluorescent dye that emits light in the near-infrared spectrum. In some embodiments, the dye may not be lipid soluble, while in other embodiments, it may be lipid soluble. In certain embodiments the dye is a tricarbocyanine dye such as indocyanine green (ICG), is sold by Akorn, Inc. (Buffalo Grove, Ill.). ICG dye is FDA approved for human use. In other embodiments, the dye is infracyanine green. In other embodiments the dye is selected from fluorescein isothiocyanate, rhodamine, phycoerythrin, phycocyanin, allophycocyanin, o-phthaldehyde, fluorescamine, Rose Bengal, trypan blue, fluoro-gold, 3-indocyanine-green-acyl-1,3-thiazolidine-thione, green fluorescent protein, red fluorescent protein, yellow fluorescent protein, blue fluorescent protein and other fluorescent proteins. The dyes may be mixed or combined. In some embodiments, dye analogs may be used. A “dye analog” is a dye that has been chemically modified, but still retains its ability to fluoresce when exposed to radiant energy of an appropriate wavelength.

In one embodiment the dye is a fluorescent protein such as green fluorescent protein covalently bound to a protein in a viral capsid, constructed by replacing the viral protein gene with the same viral protein gene but fused to the green fluorescent protein gene. In one embodiment green fluorescent protein is covalently bound to a neutropic virus protein that penetrates nerve cells.

Viral Components

In one embodiment, the viral component is selected from a virus, viral proteins, and capsids. In one embodiment, the viral protein is the capsid or capsid protein. In one embodiment, the viral protein is a viral protein analog. In one embodiment the viral proteins and analogs are capable of penetrating a nerve cell on their own, without being part of a viral capsid or whole virus. In another embodiment the viral proteins and analogs may be part of a viral capsid or whole virus that itself penetrates a nerve cell. Analogs have a different nucleic acid structure resulting in conservative amino acid changes, which although they alter the primary sequence of the protein or peptide, do not normally alter its function. Conservative amino acid substitutions typically include substitutions within the following groups: glycine, alanine;

valine, isoleucine, leucine;

aspartic acid, glutamic acid;

asparagine, glutamine;



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stats Patent Info
Application #
US 20120078093 A1
Publish Date
03/29/2012
Document #
13314418
File Date
12/08/2011
USPTO Class
600431
Other USPTO Classes
4352351
International Class
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Drawings
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Surgery   Diagnostic Testing   Detecting Nuclear, Electromagnetic, Or Ultrasonic Radiation   Detectable Material Placed In Body