Surgery – Means for introducing or removing material from body for... – Treating material introduced into or removed from body...
Reexamination Certificate
2000-06-30
2003-10-28
Mendez, Manuel (Department: 3763)
Surgery
Means for introducing or removing material from body for...
Treating material introduced into or removed from body...
C604S131000
Reexamination Certificate
active
06638264
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods and apparatus for delivery of pharmaceuticals to target tissues in situ, in vivo, ex vivo, or in vitro.
BACKGROUND OF THE INVENTION
Advances in recombinant-DNA technology have made introduction of therapeutic genes into somatic cells possible (Anderson, Nature 357:455-457, 1992). In recent years, several clinical trials involving human gene therapy have been accepted by regulatory agencies. The initial human gene therapy clinical trials aimed at treating both inherited diseases (such as severe combined immunodeficiency caused by lack of adenosine deaminase in peripheral T-lymphocytes, cystic fibrosis, and familial hypercholesterolemia), as well as noninherited disease such as cancer (Wolfe, Curr. Opinion in Pediatr. 6: 213-219, 1994; Sanda et al., J. Urology 44:617-624, 1994; O'Malley et al., Arch. Otolaryngol. Head Neck Surgery 119:1191-1197, 1993; Engelhardt et al., Nature Genetics 4: 27-34, 1993; Lemarchand et al., PNAS (USA) 89: 6482-6486, 1992; Jaffe et al., Nature Genetics 1:372-378, 1992).
The development of suitable, safe, and effective gene transfer systems is a major goal of research in gene therapy. Thus far, viruses have been extensively used as vectors for gene therapy. (See, for example, Pilewshi et al., Am. J. Physiol. 1995;268(4 pt 1):L657-665; Prince, Pathology 1998;30(4):335-347). For example, retroviruses have been widely used, but they can only target actively dividing cells, and do not readily accommodate large DNA inserts. Adeno-associated viruses are also limited in the ability to accommodate large inserts, yet replication defective adenoviruses have been used successfully to transfer of a variety of genes into cells in culture and in vivo. Adenoviruses can accommodate larger inserts than retroviruses, but extra-chromosomal expression usually lasts only for a few weeks. Herpes viruses have been exploited for specific gene transfer trials into the central nervous system. Herpes viruses can carry large foreign DNA inserts, and may remain latent for long periods of time.
In spite of the availability of replication defective viruses, concerns about the safety and efficiency of such viral vectors have generated interest in the development of non-viral gene transfer systems such as liposome-DNA complexes and receptor mediated endocytosis (Felgner P. L. et al., PNAS (USA) 84: 7413-7417, 1987; Hyde Nature 362: 250-255, 1993; Nu G. Y. J. Biol. Chem. 266: 14338, 1991).
A major hurdle for effective gene therapy is the development of methods for targeting the gene transfer to appropriate target cells and tissues. Ex vivo gene transfer into explanted cultured cells and implantation of the treated cells has been used for the treatment of hematopoietic tissues (U.S. Pat. No. 5,399,346, hereby incorporated by reference), and bronchial epithelial cells in animal model. (Engelhardt et al., Nat Genet 1993;4:27-34) Also, direct injection into brain and lung tumors (Cusack et al., Cancer Gene Ther 1996; 3(4):245-249), intravenous or intra-arterial administration (Schachtner et al., Circ Res 1995; 76:701-708), inhalation (Katkin et al., Hum Gene Ther 1995; 6:985-995), and topical application (Pilewshi et al., Am J Physiol 1995;268(4 pt 1):L657-665) have been used. Major drawbacks to all of these methods are that the transduction is not highly selective, significant amounts of the therapeutic gene containing vector may be needed, and efficiency of the gene transfer is severely limited by the constraints of vector concentration, time of exposure to the target, and effectiveness of the gene transfer vector.
Much research is being conducted to enhance transgene expression in target cells. Gene transfer efficiency has been reported to improve by pretreatment with host barrier properties modificating agents (e.g polidocanol), before vector administration. (Parsons et al., Hum Gen Ther Dec. 10, 1998; 9(18):2661-72). Modification of the host's immune system may enhance the transgene expression in viral mediated gene transfer. (Ghia et al., Transplantation Dec. 15, 1998; 66(11):1545-51) Another method reported to enhance gene transfer efficacy is prolonging the incubation time with the vector and the target cells. (Zabner et al., J. Virol. 1996; 70;6994-7003)
One area of active research is gene therapy into mammalian kidneys, but the results have been disappointing because of poor gene transfer efficiency (Woolf et al., Kidney Int. 43: Suppl. 39: S116-S119, 1993). Moullier et al. showed some adenovirus-mediated transfer of lacZ gene into rat tubular, but not glomerular cells, following a combination of virus infusion into the renal artery and retrograde infusion into the vector (Kidney Int. 45: 1220-1225, 1994). Simple infusion of soluble virus does not appear to be an efficient transfer system. Better results were obtained by Tomita et al., (Biochem. Biophys. Res. Commun. 186: 129-134, 1992), who infused a complex of Sendai virus and liposomes into the rat renal artery in vivo, resulting in marker gene expression in about 15% of the glomerular cells.
Alport syndrome is an inherited kidney disease characterized by progressive hematuria, development of renal failure and frequently also hearing loss (Atkin C L and Gregory M C: Alport syndrome; IN: Schrier W W, Gottschalk C W, eds. Diseases of Kidney, Little Brown, Boston 1993 pp 571-592; Tryggvason K, Heikkilä P: Alport syndrome. In: Jamison L, ed. Principles of molecular medicine, Humana Press Inc.
Totowa N.J. USA 1998 pp 665-668). The only available treatment is hemodialysis and/or kidney transplantation. The underlying cause of the disease is defective structure of the type IV collagen meshwork of the glomerular basement membrane (GBM). This typically results in abnormal thinning and thickening and a basket-weave-like pattern of the GBM. The disease affects about 1:5,000 males (Atkin C L and Gregory M C: Alport syndrome; IN: Schrier W W, Gottschalk C W, eds. Diseases of Kidney, Little Brown, Boston 1993 pp 571-592). About 85% of the cases are caused by mutations in the X chromosomal gene for the type IV collagen &agr;5 chain (Barker, D., Hostikka, S. L., Zhou, J., Chow, L. T., Oliphant, A. R., Gerken, S. C., Gregory, M. C., Skolnick, M. H., Atkin, C. L. and Tryggvason, K.: Identification of mutations in the COL4A5 collagen gene Alport syndrome. Science 248, 1226-1227, 1990, Hostikka S L, Eddy R L, Byers M G, Höyhtyä M. Shows T B. Tryggvason K Identification of a distinct type IV collagen a chain with restricted kidney distribution and assignment of its gene to the locus of X chromosome-linked Alport syndrome. Proc Natl. Acad Sci USA 1990:87:1606-1610, Tryggvason, K Mutations in type IV collagen genes and Alport phenotypes. In: Molecular Pathology and Genetics of Alport Syndrome (Ed. Karl Tryggvason), Karger, Basel, Vol. 117, pp. 154-171, 1996). The less frequent autosomal forms are caused by mutations in the type IV collagen &agr;3 or &agr;4 chain genes located on chromosome 2 (Mochizuki T, Lemmink H H, Mariyama M, Antignac C, Gubler M-C, Pirson Y, Verellen-Dumoulin C, Chan B, Schöder C H, Smeets H J, Reeders S T: Identification of mutations in the
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3(IV) and 4(IV) collagen genes in autosomal recessive Alport syndrome. Nature Genet 1994;8: 77-81, Lemmink K K, Mochizuki T, van den Heuvel L P W J, Schröder C H, Barrientos A, Monnens L A H, van Oost B A, Brunner H G, Reeders S T, Smeets J M mutations in the type IV collagen &agr;3 (COL4A3) gene in autosomal recessive Alport syndrome. Hum Mol Genet 1994;3:1269-1273.
Type IV collagen is a basement membrane specific collagen type which is the main structural component of these extracellular structures (Hudson B G. Reeders S T. Tryggvason K Type IV collagen: Structure, gene organization and role in human diseases. Molecular basis of goodpasture and Alport syndromes and diffuse leiomyomatosis. J Biol chem. 1993:268:26033-26036). Similarly to other collagens type IV collagen is a triple-helical protein consisting of three &agr; chains. The collagen &agr; chains have (Gly-Xaa-Yaa)
n
repeats, glycine being the only ami
Heikkilä Pirkko
Lukkarinen Olavi
Parpala Teija
Tryggvason Karl
Biostratum Incorporation
Fay Sharpe Fagan Minnich & McKee LLP
Mendez Manuel
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