Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-02-01
2002-12-31
Crouch, Deborah (Department: 1632)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S054000, C536S023100
Reexamination Certificate
active
06500807
ABSTRACT:
TECHNICAL FIELD
The present invention generally relates to gene therapy. More particularly, the present invention relates to a gene therapy material which includes a nucleic acid material and a carbohydrate as a delivery vehicle.
BACKGROUND OF THE INVENTION
Gene therapy involves the use of genetic material as a therapeutic agent. More specifically, in gene therapy a natural or synthetic gene or an analog thereof is introduced into a patient's tissue, where activation of the gene produces a therapeutic effect. Gene therapy shows great promise for curing various metabolic diseases resulting from a deficiency of, or malformation of, enzymes, proteins, neurotransmitters and other biological molecules. Gene therapy also shows significant promise for treating diseases such as cancer, wherein the introduced gene acts to induce apoptosis, which is programmed cell death, or to otherwise shrink tumors.
The most significant problem heretofore encountered in the practical implementation of gene therapies, has been in delivering therapeutically effective amounts of genetic material into a target tissue. A number of approaches to the delivery problem have been implemented in the prior art. In one approach, a DNA plasmid including the therapeutic gene is injected into the patient. Some limited success has been achieved when this naked DNA is directly injected into a tumor; however, problems arise in obtaining access to the tumor and providing a continued delivery of the therapeutic material to the tumor site. Attempts have been made to inject the naked DNA intravenously; however, such attempts have not been very successful. In other instances, the therapeutic material is incorporated into a virus, typically in the form of a plasmid, and this virus is utilized to infect the target tissue. This approach is occasionally successful; however, the virus is often inactivated by the immune system or fails to infect the target tissue. Furthermore, the delivery of genes using viral vectors raises concerns regarding efficacy, efficiency, viral infection, toxicity, and delivery which limit the broader use of gene therapy delivered through viral vectors. Another approach has been to utilize mutated viruses specifically adapted to avoid immune system inactivation and/or better infect the target tissue. Another approach has been to utilize a mixture of a high molecular weight synthetic polymer with the DNA. Limited success has been achieved with such materials.
Thus, it will be appreciated that there is a need for a delivery system and method for providing gene therapy materials to target tissues. The system and methods should preferably be highly effective, simple to implement, the compounds should be highly stable in vivo, and reduce the need for repeated administration.
SUMMARY OF THE INVENTION
According to the present invention, there is provided a gene therapy material which includes a nucleic acid material and a carbohydrate wherein the carbohydrate preferably is a modified pectin.
Also in accordance with the present invention, there is provided a gene therapy material including a nucleic acid material, a carbohydrate material associated with the nucleic acid material, and a protective coating disposed about the carbohydrate material.
Also in accordance with the present invention, there is provided a method for treating a tumor of the type which has carbohydrate binding sites expressed on the surface thereof by providing a therapeutic material, incorporating the therapeutic material into a body of a modified pectin material so as to produce a therapeutic composition, and administering the therapeutic composition to a patient.
DETAILED DESCRIPTION OF THE INVENTION
In accord with the present invention, it has been found that carbohydrates can provide a very effective delivery vehicle for DNA and other such nucleic acid materials used in gene therapy. That is, a therapeutically effective amount of a therapeutic composition of the carbohydrate and the nucleic acid material can be administered to a patient or subject having a tumor to treat the tumor by causing a reduction and/or an elimination of the tumor from the patient. In the context of this disclosure, nucleic acid materials are meant to comprise genes, plasmids containing genes, other strands of DNA, RNA, and like materials. It has been found that when nucleic acid materials are mixed with, and preferably encapsulated by, carbohydrates, these materials are protected and efficiently delivered to target cells. Multiple genes can be delivered at one time and can be delivered in a single vector or in multiple vectors encapsulated by the carbohydrates of the present invention. The carbohydrate based gene therapy materials of the present invention have been found to be effective even when administered orally, although such materials could also be delivered intravenously or by direct injection to a target tissue (i.e. a tumor).
In the context of this disclosure, carbohydrates shall refer to any hexose or pentose structure and shall specifically include complex carbohydrates as well as simple carbohydrates. One particularly preferred carbohydrate which can be employed in the present invention is a modified citrus pectin material, and such materials are disclosed in U.S. patent application Ser. No. 08/024,487 filed Mar. 1, 1993 and U.S. patent application Ser. No. 08/819,356 filed Mar. 18, 1997 and is referred to herein as GBC-590. The modified citrus pectin material is non-toxic, stable for oral administration, has good uptake characteristics, stable in the circulation for days vs. hours, specifically targeted to tumors, and can be packaged for efficient uptake by tumor cells. The main chains of the modified citrus pectin have the structure
[-4)-&agr;-D-GalpA-(1-4)-&agr;-D-GalpA-(1-]
n
-4)-&agr;-D-GalpA-(1-2)-&bgr;-L-Rhap-(1-[-4)-&agr;-D-GalpA-(1-4))-&agr;-D-Galp-(1-] with minor structural features including
(a) interrupted regions in rhamnogalacturonan chains (configurations and linkage types as above)
—GalA-Rha-GalA-Rha-GalA-GalA-Rha-Rha-GalA-,
(b) short side chains
&bgr;-D-xylp-(1-3)-&bgr;-D-Galp-(1-2)-D-Xylp-(1-&agr;-L-fucp-(1-2)-D-Xylp-(1-L-araf-(1-3)-D-Apif-(103)-D-Apif-(1-, and
(c) extended side chains
-4-&bgr;-D-Galp-(1-4)-&bgr;-D-Galp-(1-&agr;-L-Araf-(1-5)-&agr;-L-Araf-(1—
3
↑
1
&agr;-L-Araf.
The terms “patient” or “subject” as used herein mean all animals including humans. Examples of patients or subjects include humans, rodents, and monkeys.
Those skilled in the art are easily able to identify patients with cancer. For example, patients having malignant tumors in their bodies.
A “therapeutically effective amount” is an amount of a compound and/or composition of the present invention, that when administered to a patient or subject, causes the reduction and/or the elimination of a tumor in the patient or subject.
In accord with another embodiment of the invention, viral vectors such as modified or unmodified adenovirus, viral proteins or other portions of virus which carry gene therapy materials, can be encapsulated in carbohydrate materials in accord with the present invention. In this manner, the viral vectors are protected from inactivation and delivered more directly to target cells.
Vectors are known or can be constructed by those skilled in the art and should contain all expression elements necessary to achieve the desired transcription of the sequences. Other beneficial characteristics can also be contained within the vectors such as mechanisms for recovery of the nucleic acids in a different form. Phagemids are a specific example of such beneficial vectors because they can be used either as plasmids or as bacteriophage vectors. Examples of other vectors include viruses such as bacteriophages, baculoviruses and retroviruses, DNA viruses such as adenoviruses or adeno-associated viruses (AAV), cosmids, plasmids, liposomes and other recombination vectors. The vectors can also contain elements for use in either prokaryotic or eukaryotic host systems. One of ordinary skill in the art will know which host systems a
Chang Yan
Platt David
Crouch Deborah
Gifford, Krass, Groh Sprinkle, Anderson & Citkowski, P.C.
Safescience, Inc.
Woitach Joseph
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