Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1995-06-30
1999-01-19
Fox, David T.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
4351723, 435325, C07H 2104, C12N 1585
Patent
active
058615024
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Over 100 different mutations in genes for fibrillar collagens have been shown to cause genetic diseases. Byers, P. H., Trends Genet. 1990, 6, 293-300; Sykes, B., Nature 1990, 348, 18-20; Prockop, D. J., J. Biol. Chem. 1990, 265, 15349-15352; Kuivaniemi, H. et al., FASEB J. 1991, 5, 2052-2060. Moreover, the sequence of certain human collagen genes are known. Myers et al., Proc. Natl. Acad. Sci. USA 1988, 78, 3516, reported structure of a cDNA for the pro.alpha.2 of human type I procollagen and, subsequently, the structures of a series of collagen genes have been defined (see Vuorio, E. and de Crombrugghe, B., An. Rev. Biochem. 1990, 58, 837-875; Chu, M.- L. and Prockop, D. J., Extracellular Matrix and Inherited Disorders of Connective Tissue, Royce and Steinmann, Eds., Alan R. Liss, New York, 1992). Mutations in either of the two genes for type I procollagen (COL1A1 and COL1A2) cause osteogenesis imperfecta and a subset of osteoporosis; mutations in the gene for type II procollagen (COL2A1) cause chondrodysplasias and some forms of osteoarthritis; and mutations in the gene for type III procollagen (COL3A1) cause Ehlers-Danlos syndrome type IV and aneurysms. Most of the mutations of procollagen genes produce disease phenotypes by directing synthesis of structurally abnormal but partially functional pro.alpha. chains of type I, type II or type III procollagen. The partially functional pro.alpha. chains associate with and become disulfide-linked to normal proa chains. As a result, the mutant chains can have one of several major effects. Kuivaniemi, H. et al., FASEB J. 1991, 5, 2052-2060. One effect is to prevent folding of the three chains into a collagen triple helix and thereby cause degradation of both the abnormal and normal pro.alpha. chains through a process referred to as procollagen suicide. The second effect is to produce minor changes in the conformation of the collagen triple helix and thereby generate mutated monomers that interfere with self-assembly of normal monomers synthesized by the same cells.
A third effect of mutations in collagen genes is to decrease the amounts of collagen synthesized by fibroblasts and related cells. Mutations that decrease collagen synthesis, however, cause the relatively mild disease known as type I osteogenesis imperfecta. Deleterious effects of mutant collagen gene expression have been demonstrated in transgenic mice expressing mutated genes for type I procollagen. These transgenic mice developed phenotypes resembling human osteogenesis imperfecta, Stacey, A. et al., Nature 1988, 332, 131-136; Khillan, J. S. et al., J. Biol. Chem. 1991, 266, 23373-23379. Further, it has been demonstrated that transgenic mice expressing mutated genes of type II procollagen developed phenotypes resembling human chondrodysplasia. Vandenberg et al., Proc. Natl. Acad. Sci. 1991, 88, 7640-7644.
Since many heritable diseases of collagen are caused by the protein products from the mutated genes, it is believed that selective inhibition of expression of the mutated genes will be useful as a therapy for such diseases. Clinical observations have demonstrated that many patients with severe diseases caused by mutations in a collagen gene would benefit from selective inactivation of the mutant allele which directs the synthesis of mutant pro.alpha. chains. The diseases in which selective inhibition may be useful include osteogenesis imperfecta, chondrodysplasia, certain forms of osteoporosis, certain forms of aneurysms, and certain forms of osteoarthritis.
In addition, it has been recognized for many decades that many pathological conditions are caused by overproduction of collagen fibers in the forms of scars and excess fibrous tissues. For example, liver cirrhosis is a two-step process in which normal liver tissue is first destroyed by a virus or by alcohol and other toxins, and then excessive amounts of collagen fibers replace the damaged cells before normal liver cell regeneration. Idiopathic pulmonary fibrosis is a lethal condition in which, for largely unknown r
REFERENCES:
patent: 5585479 (1996-12-01), Hoke et al.
Rojanasakul Y. "Antisense oligonucleotide therapeutics: Drug delivery and targeting." Adv. Drug Delivery Rev. 18: 115-131, 1996.
Kuivaniemi H, et al. "Mutations in collagen genes: Causes of rare and some common diseases in humans." FASEB 5: 2052-2060, Apr. 1991.
Uhlmann E, et al. "Antisense oligonucleotides: A new therapeutic principle." Chemical Reviews 90 (4): 543-584, Jun. 1990.
Rossouw C, et al. DNA sequences in the first intron of the human pro-alpha1(I) collagen gene enhance transcription. JBC 262 (31): 15151-15157, Nov. 5, 1987.
Gura T. "Antisense has growing pains." Science 270: 575-577, Oct. 27, 1995.
Orkin S, et al. "Report and Recommendations of the Panel to Assess the NIH Investment in Research on Gene Therapy." Dec. 7, 1995.
Helen e C, et al. "Specific regulation of gene expression by antisense, sense and antigene nucleic acids." Biochimica et Biophysica Acta 1049: 99-125, 1990.
Ala-Kokko, L. et al., 1991, "Hepatic fibrosis in rats produced by carbon tetrchloride and dimethylnitrosamine: observations suggestin immunoassays of serum for the 7S fragment of type IV collagen are a more sensitive index of liver damage than immunoassays for the NH2-terminal propeptide of type III procollagen," Hepatology 16(1):167-172.
Byers, P.H., 1990, "Brittle bones-fragile molecules: disorders of collagen gene structure and expressio n," Trends Genet 6(9):293-300.
Chang,E.H. et al., 1991, "Antisense inhibition of ras p21 expresion that is sensitive to a point mutation," Biochemistry 30(34):8283-8286.
Chiang, M.Y. et al., 1991, "Antisense of oligonucleotides inhibit intercellular adhesion moecule 1 expression by two distinct mechanisms," J. Biol. Chem. 266(27):18162-18171.
Chomczynski, P. et al., 1987, "Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction," Anal Biochem 162(1):156-159.
Chu, M.L. and Prockop, D.J., Extracellular Matrix Inherited Disorders of Connective Tissue, Royce and Steinmann, Eds., Alan R. Liss, New York, 1992.
Erickson, R.P. and Izant, J.G., Gene Regulation: Biology of Antisense RNA and DNA, vol. 1, Raven Press, New York, 1992.
Horton et al., "Antisense regulation of human type II collagen synthesis," The American Journal of Human Genetics 51(4), Abstract 1505, 1992.
Khillan, J.S. et al., 1991, "Transgenic mice that express a mini-gene version of the human gene for type I procollagen (COL1A1) develop a phenotype resembling a lethal form of osteogenesis imperfecta," J. Biol. Chem. 266(34):23373-23379.
Kole, R. et al., 1991, Adv. Drug Delivery Rev. 6;271-286.
Kuivaniemi, H. et al., 1991, "Mutations in collagen genes: causes of rare and some common diseases in humans," FASEB J 5(7):2052-2060.
Marmur, J. and Doty, P., 1962, J. Mol. Biol. 5:113.
Mooslehner, K. and Harbers, K., 1988, "Two mRNAs of mouse pro .alpha.-I collagen gene differ in teh size of the 3'-untranslated region", Nucleic Acids Research 16(2):773.
Munroe, S.H., 1988, "Antisense RNA inhibits splicing of pre-mRNA in vitro," EMBO J 7(8):2523-2532.
Myers et al., 1988, Proc. Natl. Acad. Sci. USA 78:3516.
Olsen et al., 1991, J. Biol. Chem. 266:1117-1121.
Orkin, S., The Molecular Basis of Blood Diseases, G. Stamatoyannopoulos et al., Eds., W.B. Saunders, Philadelphia, 1987, pp. 106-126.
Prockop, D.J., 1990, "Mutations that later the primary structur of type I collagen. The perils of a system for generating large structures by the principles of nucleated growth," J. Biol. Chem. 265(26):15349-15352.
Stacey, A. et al., 1988, "Perinatal lethal osteogenesis imperfecta in transgenic mice bearing an engineered mutant pro-.alpha. I collagen", Nature 332:131-136.
Stein, C.A. and Cohen, J.S. et al., Oligodeoxynucleotides as inhibitors of gene expression: a review, Cancer Research 48:2659-2668, 1988.
Sykes, B., 1990, "Human genetics. Bone disease cracks genetics," Nature 348:18-20.
Uhlmann et al., 1990, "Antisense Oligonucleotides: a new therapeutic principle," Chemical Reviews 90(4):544-579.
Vandenber
Baserga Renato
Colige Alain
Nugent Paul
Prockop Darwin
Fox David T.
Nelson Amy J.
Thomas Jefferson University
LandOfFree
Antisense oligonucleotides to inhibit expression of mutated and does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Antisense oligonucleotides to inhibit expression of mutated and , we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Antisense oligonucleotides to inhibit expression of mutated and will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1247669