Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Genetically modified micro-organism – cell – or virus
Reexamination Certificate
1998-07-22
2001-04-17
Hauda, Karen M. (Department: 1632)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Genetically modified micro-organism, cell, or virus
C424S094600, C424S439000, C424S484000, C424S494000, C424S487000, C424S490000, C514S04400A
Reexamination Certificate
active
06217859
ABSTRACT:
BACKGROUND OF THE INVENTION
(a) Field of the Invention
The invention relates to a novel concept of using microencapsulated genetically engineered microorganisms for clinical application by oral administration.
(b) Description of Prior Art
Recent advancements in molecular biology have furnished a variety of genetically engineered microorganisms with many specialized functions. Unfortunately, it is difficult to use genetically engineered microorganisms for the treatment of patients.
Since parental administration of microorganism into human is too risky and dangerous, even if a very small amount is given.
In accordance with the present invention, this problem was solved by microencapsulating genetically engineered microorganisms and giving them orally. Microencapsulation prevents leakage of microorganism also if a small amount leaks out it is still safe since the gastrointestinal tract can safely contain non-pathogenic microorganism. The present invention describes a model study which can be used for a variety of genetically engineered microorganisms.
More particularly, the present invention demonstrates, as an example, the use of microencapsulated genetically engineered bacteria for the removal of urea and ammonia. Urea and ammonia removal is necessary in cases of kidney failure and liver failure, respectively. Uremia is caused by insufficient kidney function. As kidneys fails, substances normally excreted in the urine are retained in the blood and body tissues. This results in increased concentration of metabolites normally measurable in blood. For example, the blood urea nitrogen (BUN) level increases from 15 mg % to 100-300 mg %, and serum creatinine increases from 1.0 mg % to 10-25 mg %. Similarly, elevated level of ammonia in liver failure is evident. These substances in high concentrations become toxins or poisons and result in severe disturbances of metabolic pathways causing many diseases ranging from organ failure to impaired brain functions. Several attempts, including use of oral feeding of oxystarch and urease zirconium phosphate have been applied to remove these unwanted metabolites from the body fluid compartments without success. The amounts of oxystarch and urease-zirconium-phosphate needed were too large to allow for use in the routine treatment of the patients.
The microencapsulation concept is established to provide specialized environment to the living and non living encapsulated materials (Chang, T. M. S. (1964)
Science,
146:524-525). In previous studies, it was shown that microencapsulated genetically engineered bacteria
E. coli
DH5 has great capacity to remove urea and ammonia from the artificial media and from the plasma in vitro (Prakash, S. and Chang, T. M. S. (1995)
Biotechnology and Bioengineering,
46:621-626).
Surprisingly, and in accordance with the present invention, it is demonstrated for the first time that these microencapsulated genetically engineered microorganisms when given orally in very small amounts can effectively remove systemic urea and ammonia in kidney failure rats (Prakash, S. and Chang, T. M. S. (1996)
Nature Medicine,
2(8):883-887). This capacity is much higher than any system available to date.
SUMMARY OF THE INVENTION
One aim of the present invention is to explore the possibility of using microencapsulated genetically engineered microorganisms for the treatment of various diseases by their oral feeding.
Another aim of the present invention is specific, and was directed to explore the potential of encapsulated genetically engineered bacterial cells for the treatment of kidney failure, liver failure and other diseases, which will serve as example for the application of this invention in clinical practice.
Earlier in vitro studies have shown that alginate-polylysine-alginate (APA) encapsulated genetically engineered
E. coli
DH5 cells is very effective in removing urea, without producing ammonia, and ammonia both from reaction media and plasma. However, at that time there was no way to safely used this in patients by parental injection (Prakash, S. and Chang, T. M. S. (1995)
Biotechnology and Bioengineering,
46:621-626). The details of the process parameters of preparation of microcapsules and the kinetics of the in vitro studies are described in the same article (Prakash, S. and Chang, T. M. S. (1995)
Biotechnology and Bioengineering,
46:621-626).
In accordance with the present invention there is provided a composition for oral administration to a patient for the removal of undesired chemicals and/or amino acids caused by a disease, which comprises a microorganism entrapped or microencapsulated to be capable of removing the undesired chemicals and/or amino acids in association with a pharmaceutically acceptable carrier for oral administration to the patient.
In accordance with one embodiment of the present invention, the composition consists in the microorganism which is microencapsulated using any microcapsule material which can retain the microorganism and allows the undesirable molecules for removal to enter the microcapsules.
The microencapsulating material which may be used in accordance with the present invention include, without limitation, nylon, silicon rubber, nylon-polyethylenimine, polylactic acid, polyglycolic acid, chitosan-alginate, cellulosesulphate-poly(dimethyldiallyl)-ammonium chloride, hydroxy-ethyl methacrylate-methyl methacrylate, chitosan-carboxymethyl-cellulose and alginate-polylysine-alginate.
In accordance with another embodiment of the present invention, the composition consists in the microorganism which is entrapped within a carrier using any entrapment material which can retain the microorganism and allows the undesirable molecules for removal to enter in contact with the entrapped microorganism.
The microorganism may be genetically engineered, such as,
E. coli
DH5 cells, among others.
The undesired chemical may be urea and/or ammonia, phenylalanine or tyrosine.
The diseases to be treated may be a kidney failure-causing disease, a liver failure-causing disease, hyperammonemia with elevated ammonia level, phenylketoneuria or tyrosinemia and melanoma among others.
REFERENCES:
patent: 4391909 (1983-07-01), Lim
patent: 5286495 (1994-02-01), Batich et al.
Chang et al., 1995, Art Cells, Blood Subs, and Immob Biotech, 23:1-21.
Bourget et al., 1984, Applied Biochemistry and Biotechnology, 10:57-9.
Prakash et al., 1995 Biotechnology and Bioengineering, 46:621-6.
Prakash et al., 1993, Biomat, Art Cells & Immob Biotech, 21:629-36.
Enosawa et al., 1995, Dialog Information Services, File 73, EMBASE, Dialog Accession, No: 9615461; Japanese J Artificial Organs(Japan), 24/3(736-9).
Gardner et al (Applied Biochemistry and Biotechnology 10: 27-40, abstract only, 1984.*
Voet and Voet, In Biochemistry, Second edition, Wiley and Sons, Publishers. See pp. 670, 701, 720-722, 740, 756, especially Table 23-2 on p. 720), 1995.*
Wrong, Nature Medicine 3(1):3, 1997; see especially paragraph bridging cols. 2 and 3, Jan. 1997.*
Prakash and Chang (1993). Biomat. Art. Cells & Immob. Biotech 21(5): 629-636. See abstract, and paragraph bridging pp. 630 and 631.*
Prakash and Chang. Nature Medicine 2(8): 883-887, Aug. 1996.
Chang Thomas M. S.
Prakash Satya
Hauda Karen M.
Klauber & Jackson
McGill University
Schnizer Richard
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