Source: http://www.google.com/patents/US8178124?dq=Frischling
Timestamp: 2017-07-21 15:12:38
Document Index: 755667920

Matched Legal Cases: ['§371', 'Application No. 05819552', 'Application No. 1', 'Application No. 1094', 'Application No. 2005320014', 'Application No. 05819552', 'Application No. 1094', 'Application No. 1094']

Patent US8178124 - Drug carrier and drug carrier kit for inhibiting fibrosis - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inPatentsAn astrocyte-specific drug carrier containing a retinoid derivative and/or a vitamin A analog as a constituent; a drug delivery method with the use of the same; a drug containing the same; and a therapeutic method with the use of the drug. By binding a drug carrier to a retinoid derivative such as vitamin...http://www.google.com/patents/US8178124?utm_source=gb-gplus-sharePatent US8178124 - Drug carrier and drug carrier kit for inhibiting fibrosisAdvanced Patent SearchTry the new Google Patents, with machine-classified Google Scholar results, and Japanese and South Korean patents.Publication numberUS8178124 B2Publication typeGrantApplication numberUS 13/249,072Publication dateMay 15, 2012Filing dateSep 29, 2011Priority dateDec 22, 2004Fee statusPaidAlso published asCA2595517A1, CA2595517C, CA2820728A1, CA2820728C, CN101102795A, CN101102795B, CN102343092A, EP1842557A1, EP1842557A4, EP1842557B1, EP2727583A2, EP2727583A3, EP2730277A2, EP2730277A3, US8173170, US8652526, US20080193512, US20120076852, US20120189691, US20130011464, WO2006068232A1Publication number13249072, 249072, US 8178124 B2, US 8178124B2, US-B2-8178124, US8178124 B2, US8178124B2InventorsYoshiro Niitsu, Junji Kato, Yasushi SatoOriginal AssigneeNitto Denko CorporationExport CitationBiBTeX, EndNote, RefManPatent Citations (24), Non-Patent Citations (75), Referenced by (13), Classifications (26), Legal Events (3) External Links: USPTO, USPTO Assignment, EspacenetDrug carrier and drug carrier kit for inhibiting fibrosis
US 8178124 B2Abstract
1. A method of treating a stellate cell-related disorder, the method comprising administering an effective amount of a stellate cell-specific preparation to a subject in need thereof, wherein the stellate cell-specific preparation comprises: (i) a stellate cell-specific drug carrier comprising a stellate cell-specific amount of a retinoid and a drug carrier component other than the retinoid, and (ii) a drug in an amount effective for controlling the activity or growth of stellate cells.
2. The method of claim 1, wherein the drug for controlling the activity or growth of stellate cells is selected from the group consisting of a TGF β activity inhibitor, a preparation having HGF activity, an MMP production promoter, a TIMP production inhibitor, a PPARγ ligand, an angiotensin activity inhibitor, a PDGF activity inhibitor, a sodium channel inhibitor, an apoptosis inducer and a growth inhibitor.
3. The method of claim 1, wherein the drug for controlling the activity or growth of stellate cells is selected from the group consisting of an siRNA, ribozyme, antisense nucleic acid and DNA/RNA chimera polynucleotide; or a vector expressing same.
4. The method of claim 3, wherein the drug for controlling the activity or growth of stellate cells targets HSP47.
5. The method of claim 1, wherein the stellate cell-related disorder is selected from the group consisting of fibrosis, hepatitis and pancreatitis.
6. The method of claim 5, wherein the fibrosis is selected from the group consisting of hepatic fibrosis, hepatic cirrhosis, pancreatic fibrosis, vocal cord scarring, vocal cord mucosal fibrosis, and laryngeal fibrosis.
7. The method of claim 1, wherein the preparation is parenterally administered.
8. The method of claim 1, wherein the stellate cell-specific carrier is selected from the group consisting of a polymer micelle, liposome, emulsion, microsphere, and nanosphere.
9. A method of treating a fibrotic disorder, comprising administering an effective amount of a stellate cell-specific preparation to a subject in need thereof, wherein the stellate cell-specific preparation comprises: (i) a stellate cell-specific drug carrier comprising a stellate cell-specific amount of a retinoid and a drug carrier component other than the retinoid, and (ii) a drug in an amount effective for controlling the activity or growth of stellate cells.
10. The method of claim 9, wherein the fibrotic disorder is fibrosis.
11. The method of claim 10, wherein the fibrosis is selected from the group consisting of hepatic fibrosis, hepatic cirrhosis, pancreatic fibrosis, vocal cord scarring, vocal cord mucosal fibrosis, and laryngeal fibrosis.
12. The method of claim 9, wherein the fibrotic disorder is hepatic fibrosis, the stellate cell-specific carrier is a liposome, the retinoid is vitamin A, and the drug is an siRNA that targets HSP47.
13. The method of claim 9, wherein the fibrotic disorder is hepatic cirrhosis, the stellate cell-specific carrier is a liposome, the retinoid is vitamin A, and the drug is an siRNA that targets HSP47.
14. The method of claim 9, wherein the fibrotic disorder is pancreatic fibrosis, the stellate cell-specific carrier is a liposome, the retinoid is vitamin A, and the drug is an siRNA that targets HSP47. Description
This application is a divisional of U.S. Ser. No. 11/793,736, filed Apr. 8, 2008, which is a national stage filing under 35 U.S.C. §371 of international application PCT/JP2005/023619, filed Dec. 22, 2005, the disclosures of which are hereby incorporated by reference.
The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled KUZU1_SEQ.TXT, created Sep. 29, 2011, which is 4 KB in size. The information in the electronic format of the Sequence Listing is incorporated herein by reference in its entirety.
Furthermore, in the pancreas, chronic pancreatitis develops as a result of pancreatic fibrosis by the same mechanism as that for hepatic fibrosis (Madro A et al., Med Sci Monit. 2004 July; 10(7): RA166-70.; Jaster R, Mol Cancer. 2004 Oct. 6; 3(1): 26.). However, effective means for inhibiting the progress of pancreatic fibrosis or chronic pancreatitis has not yet been found.
As effective means for inhibiting fibrosis of the liver or the pancreas, there is a possibility that stellate cells are one of the important target candidates (Fallowfield J A, Iredale J P, Expert Opin Ther Targets. 2004 October; 8(5): 423-35; Pinzani M, Rombouts K. Dig Liver Dis. 2004 April; 36(4): 231-42.). In the process of fibrosis, stellate cells are activated by cytokine from Kupffer cells or infiltrating cells and transformed into activated cells, and there is marked production of extracellular matrix (ECM). Stellate cells are known as storage cells for vitamin A, and belong to the myofibroblast family. On the other hand, stellate cells produce matrix metalloproteinase (MMP), its inhibitory factor (TIMP), a cytokine such as TGF-β or PDGF, and a growth factor such as HGF, and play a main role in hepatic fibrosis. Activated stellate cells increase contractile ability and are involved in the regulation of blood flow and, furthermore, they increase the expression of various types of cytokine receptors and become highly sensitive to cytokine.
With regard to therapeutic methods for fibrosis that have been attempted up to the present date, the control of collagen metabolism, promotion of the collagen degradation system, inhibition of activation of stellate cells, etc. can be cited. They include inhibition of TGFβ (known as a factor for activating stellate cells and promoting the production of extracellular matrix (ECM)) using a truncated TGFβ type II receptor (Qi Z et al., Proc Natl Acad Sci USA. 1999 Mar. 2; 96(5): 2345-9.), a soluble TGFβ type II receptor (George J et al., Proc Natl Acad Sci USA. 1999 Oct. 26; 96(22): 12719-24.), HGF (published Japanese translation 5-503076 of a PCT application; Ueki K et al., Nat Med. 1999 February; 5(2): 226-30.), etc., promotion of the production of matrix metalloproteinase (MMP) by means of HGF or an MMP gene-containing vector (Iimuro Y et al., Gastroenterology 2003; 124: 445-458.), inhibition of TIMP, which is an MMP inhibitor, by means of antisense RNA, etc. (Liu W B et al., World J Gastroenterol. 2003 February; 9(2): 316-9), control of the activation of stellate cells by means of a PPARγ ligand (Marra F et al., Gastroenterology. 2000 August; 119(2): 466-78) or an angiotensin-II type I receptor antagonist (Yoshiji H et al., Hepatology. 2001 October; 34 (4 Pt 1): 745-50.), inhibition of the growth of stellate cells via inhibition of PDGF action by means of PDGF tyrosine kinase inhibitor, etc. (Liu X J et al., World J Gastroenterol. 2002 August; 8(4): 739-45.) and inhibition of the sodium channel by means of amiloride (Benedetti A et al., Gastroenterology. 2001 February; 120(2): 545-56), etc., and apoptotic induction of stellate cells by means of Compound 861 (Wang L, et al., World J Gastroenterol 2004 Oct. 1; 10(19): 2831-2835), gliotoxin (Orr J G et al., Hepatology. 2004 July; 40(1): 232-42.), etc. However, in all cases, since the specificity of action and/or the organ specificity are low, there are problems with the effects and with side effects.
With regard to collagen protein synthesis, there are many unclear points with respect to the metabolic route, and a therapeutic method using a drug that inhibits this has not been established as a therapeutic method that is efficient and safe toward a living body in terms of side effects. That is, in a method in which molecules involved in the production of collagen are targeted, the specificity for the target cannot be enhanced because of the diversity of function of the molecules, and the possibility of causing side effects is high. If collagen, which is the final product, could be inhibited directly, this would be reasonable as a common therapeutic method for fibrosis processes, and in order to do this it would be necessary to control all the various types of collagen represented by Types Ito IV at the same time.
The present inventors prepared a ribozyme that specifically controls the function of HSP47 in a cellular system, and showed that the production and secretion of collagens can be controlled by the ribozyme at the same time (Sasaki H, et al. Journal of Immunology, 2002, 168: 5178-83; Hagiwara S, et al. J Gene Med. 2003, 5: 784-94). In order to specifically control the synthesis of HSP47, siRNA, which is easier to optimize than ribozyme, can be employed. The siRNA (small interfering RNAs) used in the present specification is a general term for double-strand RNA used in RNAi (RNA interference). RNAi is a phenomenon in which double-strand RNA (double-strand RNA; dsRNA), which is formed from sense RNA and antisense RNA and is homologous with a given gene, destroys a homologous segment of a transcript (mRNA) of the gene. It was originally exhibited in an experiment using a nematode (Fire A, et al: Nature (1998) 391: 806-811), and it has been shown that a similar induction mechanism is present in mammalian cells (Ui-Tei K, et al: FEBS Lett (2000) 479: 79-82). Furthermore, Elbashir et al. have shown that a short dsRNA having a length of on the order of 21 to 23 by can induce RNAi in a mammalian cell system without exhibiting cytotoxicity (Elbashir S M, et al: Nature (2001) 411: 494-498). However, in order for the effects of these molecules to be exhibited effectively, it is necessary to employ a method that is specific to a target organ.
[Nonpatent Publication 1] Madro A et al., Med Sci Monit. 2004 July; 10(7): RA166-70
[Nonpatent Publication 2] Jaster R, Mol Cancer. 2004 Oct. 6; 3(1): 26
[Nonpatent Publication 3] Fallowfield J A, Iredale J P, Expert Opin Ther Targets. 2004 October; 8(5): 423-35
[Nonpatent Publication 4] Pinzani M, Rombouts K. Dig Liver Dis. 2004 April; 36(4): 231-42
[Nonpatent Publication 5] Qi Z et al., Proc Natl Acad Sci USA. 1999 Mar. 2; 96(5): 2345-9
[Nonpatent Publication 6] George J et al., Proc Natl Acad Sci USA. 1999 Oct. 26; 96(22): 12719-24
[Nonpatent Publication 7] Ueki K et al., Nat Med. 1999 February; 5(2): 226-30
[Nonpatent Publication 9] Liu W B et al., World J Gastroenterol. 2003 February; 9(2): 316-9
[Nonpatent Publication 10] Marra F et al., Gastroenterology. 2000 August; 119(2): 466-78
[Nonpatent Publication 11] Yoshiji H et al., Hepatology. 2001 October; 34(4 Pt 1): 745-50
[Nonpatent Publication 12] Liu X J et al., World J Gastroenterol. 2002 August; 8(4):
[Nonpatent Publication 13] Benedetti A et al., Gastroenterology. 2001 February; 120(2):
[Nonpatent Publication 14] Wang L et al., World J Gastroenterol 2004 Oct. 1; 10(19): 2831-2835
[Nonpatent Publication 15] Orr J G et al., Hepatology. 2004 July; 40(1): 232-42
Moreover, the present invention relates to the medicine wherein the drug and the drug carrier are mixed at a place of medical treatment or in the vicinity thereof
Moreover, the present invention relates to a method for treating a stellate cell-related disorder, the method including administering an effective amount of the medicine to a subject in need thereof
Among optimal sequences for siRNA recognition in targeting a base sequence of HSP47, which is a common molecular chaperone for collagens (types I to IV), Sequences A and B were prepared in accordance with an siRNA oligo design program by iGENE Therapeutics, Inc. Sequence C was prepared by searching on the Internet using the siRNA Target Finder (http://www.ambion.com/techlib/misc/siRNA13finder.html) from Ambion, Inc. and selecting 19 base sequences that would become a target for rat gp46 (human HSP47 homologue, GenBank Accession No. M69246). When carrying out the design, care was taken in 1) starting at 75 to 100 bases downstream from the initiation codon, 2) positioning the first AA dimer, and 3) making sure that the GC content was 30% to 70%. In this example, siRNAs having the sequences below were prepared.
(25 base forward direction strand siRNA starting
at 757th in the sequence, SEQ ID NO: 1)
A: GUUCCACCAUAAGAUGGUAGACAAC
at 1626th in the sequence, SEQ ID NO: 2)
B: CCACAAGUUUUAUAUCCAAUCUAGC
(19 base forward direction strand siRNA starting
at 64th in the sequence, SEQ ID NO: 3)
C: GAAACCUGUAGAGGCCGCA
In order to examine the amount of collagen synthesized, 3H-proline was added to the culture supernatant of rat fibroblasts (NRK cells) under the above-mentioned conditions (siRNA concentration 50 nM, time 48 hours), and after transfection the amount of 3H in secreted protein was examined (FIG. 5). The amount of collagen synthesized was calculated from the ratio of protein secreted in the supernatant to protein degraded by collagenase when culturing gp46siRNA-transfected fibroblasts in the presence of 3H-proline in accordance with a report by Peterkofsky et al. (Peterkofsky et al., Biochemistry. 1971 Mar 16; 10(6): 988-94).
sensttive
An emulsion (VA-Lip-GFP) was prepared by mixing GFP expression plasmid and liposome-encapsulated VA formed by mixing 10% VA and liposome, and after it was intraportally administered to a rat, hepatic tissue was collected and fixed. The emulsion was prepared by supposing that the amount of plasma for a 200 g rat was about 10 mL, and setting the concentrations of VA and GFP in portal blood at 10 μM. Specifically, 25 mg of all-trans-retinol (VA) was first dissolved in 87 μL of DMSO thus to give a 100 mM stock solution. 1 μL of this VA stock solution was mixed with 10 μL of lipofectamine and 179 μL of PBS, 10 μg of GFP expression plasmid was further added thereto to give a total of 200 and the mixture was vortexed for 3 minutes to give VA-Lip-GFP. The abdomen of an SD rat was opened, and the VA-Lip-GFP was slowly injected into a peripheral portal vein. 48 hours after the injection, hepatic tissue was harvested. Since compared with other hepatic cells intermediate filament desmin is specifically expressed in hepatic stellate cells (HSC), when fixed hepatic tissue was stained with Alexa Fluor 568-labeled anti-desmin antibody, and a fluorescence double image with GFP was examined, it was confirmed that GFP was expressed within the hepatic stellate cells (HSC) (FIG. 7). For untreated controls and a group to which the GFP expression plasmid vector alone was administered, expression in rat hepatic stellate cells was not observed, but in a group to which VA-Lip-GFP was administered, expression of GFP was observed specifically in stellate cells.
In the same manner as in Example 4, except that FITC-labeled gp46siRNA was used instead of the GFP expression plasmid, an emulsion (VA-Lip-gp46siRNA (FITC)) containing VA-encapsulated liposome and FITC-labeled gp46siRNA was prepared, and intraportally administered to an SD rat (10 μg as the amount of siRNA/200 μL). 48 hours after administration hepatic tissue was harvested, aSMA (smooth muscle actin), which compared with other hepatic cells is expressed specifically in HSC, was stained with Alexa Fluor 568-labeled anti-aSMA antibody, cell nuclei were stained with DAPI, and a fluorescence image was examined by a confocal laser scanning microscope (LSM). As shown on the left-hand side of FIG. 8, in a group to which VA-Lip-gp46siRNA (FITC) was administered, a large number of cells emitting both green fluorescence due to FITC and red fluorescence due to Alexa Fluor 568 were observed, and when a quantitative analysis was carried out by NIH Image (the number of cells was counted by selecting any 10 fields from a ×1000 fluorescence microscope photograph), the transfection efficiency was 77.6% (average of 10 fields). On the other hand, in a group to which Lip-gp46siRNA (FITC) containing no VA was administered, the transfection efficiency was a low value of 14.0% and, moreover, transfection into cells other than stellate cells was observed at 3.0% (right-hand side of FIG. 8). It has been found from the results above that the transfection efficiency into stellate cells is increased remarkably by including VA.
In accordance with a report by Jezequel et al. (Jezequel A M et al., J Hepatol. 1987 October; 5(2): 174-81), an LC model rat was prepared using Dimethylnitrosamine (DMN) (FIG. 10). Specifically, a 1 mL/kg dose of 1% Dimethylnitrosamine (DMN) (intraperitoneal administration) was administered to a 5 week-old SD rat (male) 3 straight days per week. As already reported, an increase in fiber was observed from the 2nd week, and in the 4th week this was accompanied by the findings of marked fibrosis, destruction of hepatic lobule structure, and formation of regenerative nodules being observed (FIG. 11). Then, by the same method as in Example 4, an emulsion (VA-Lip-gp46siRNA) was prepared by formulating gp46siRNA as a liposome and mixing with 10% VA, and was administered. Administration of VA-Lip-gp46siRNA was started in the 3rd week, by which time sufficient fibrosis was observed, and evaluation was carried out in the 4th and 5th weeks. Since it was confirmed by Example 2 that the effects were observed for up to 48 hours in vitro, administration was carried out twice a week (FIG. 11). The amount administered was determined in accordance with a report in which siRNA was directly injected (McCaffery et al., Nature. 2002 Jul. 4; 418(6893): 38-9), and was 40 μg as the total amount of siRNA. From azan staining of the liver after administration of siRNA, in the 4th week there was no apparent difference between a group to which saline had been administered, a group to which siRNA (random) had been administered, and a group to which siRNA (gp46) had been administered, but in the 5th week a decrease in the amount of fiber was observed for the group to which gp46siRNA had been administered (FIG. 12). In order to quantitatively analyze the amount of fiber, an unstained portion was extracted using NIH Image, its area was measured (FIG. 13), and a significant decrease in the area of collagen was observed for the group to which gp46siRNA had been administered (FIG. 14). Furthermore, in order to evaluate the degree of fibrosis using another measure, the amount of hydroxyproline, which is an indicator for fibrosis, was quantitatively measured by a standard method. Specifically, after 20 mg of freeze-dried hepatic tissue was hydrolyzed with HCl for 24 hours, the reaction liquid was centrifuged, and the supernatant was treated with a reagent such as Ehrlich's solution and centrifuged. The supernatant was recovered, and the amount of hydroxyproline in the hepatic tissue was measured by measuring the absorbance at 560 nm (Hepatology 1998 November; vol. 28: 1247-1252). As shown in FIG. 15, in the group to which gp46siRNA had been administered, the amount of hydroxyproline became very small.
Furthermore, in order to examine a change in the survival rate by administration of the medicine of the present invention, in accordance with a method by Qi Z et al. (Proc Natl Acad Sci USA. 1999 Mar. 2; 96(5): 2345-9.), an LC model rat was prepared using Dimethylnitrosamine (DMN) in an amount that was increased by 20% over the normal amount. In this model, a total of 4 intraportal administrations were carried out in the 1st and 2nd weeks. Administration details were: PBS, Lip-gp46siRNA, VA-Lip-random siRNA, and VA-Lip-gp46siRNA (n=7 for each group). After the 3rd week, all of the controls (the group to which PBS had been administered, the group to which VA-Lip-random siRNA had been administered, and the group to which Lip-gp46siRNA had been administered) were dead, but 6 out of 7 survived for the group to which VA-Lip-gp46siRNA had been administered (FIG. 16). Furthermore, in azan staining of the liver on the 21st day, an apparent decrease in the amount of fiber was observed for the group to which gp46siRNA had been administered (FIG. 17).
In another experiment, intraportal administration was carried out from the 3rd week for LC model rats (1% DMN 1 mg/kg intraperitoneally administered 3 times a week) prepared in accordance with the method by Qi Z et al. and a method by Ueki T et al. (Nat Med. 1999 February; 5(2): 226-30), as shown in the table below (n=6 for each group). PBS was added to each substance to be administered so as to make a total volume of 200 μL, and the frequency of administration was once a week.
liposome 100 nmol, gp46siRNA 20 μg
10-1 VA
10-2 Lip-gp46siRNA
10-3 VA-Lip-random
VA 200 nmol, liposome 100
nmol, random-siRNA 100 μg
10-4 VA-Lip-
gp46siRNA
nmol, gp46siRNA 100 μg
10-5 PBS
10-6 VA
10-7 VA-Lip
10-8 Lip-gp46siRNA
10-9 VA-Lip-random
nmol, random-siRNA 150 μg
VA-Lip-
nmol, gp46siRNA 150 μg
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