| Use of rapamycin to inhibit response and induce tolerance to gene therapy vector and encoded transgene products -> Monitor Keywords |
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Use of rapamycin to inhibit response and induce tolerance to gene therapy vector and encoded transgene productsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai, Cyclopeptides, MonocyclicUse of rapamycin to inhibit response and induce tolerance to gene therapy vector and encoded transgene products description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20080096808, Use of rapamycin to inhibit response and induce tolerance to gene therapy vector and encoded transgene products. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] The present application is a continuation of co-pending U.S. Ser. No. 09/911,782 filed on Jul. 24, 2001 which is a continuation in part of U.S. Ser. No. 09/876,574 filed on Jun. 7, 2001 which claims priority to U.S. Provisional Application No. 60/221,738, filed Jul. 31, 2000. The contents of the above-referenced applications are hereby incorporated by reference into the present disclosure. BACKGROUND [0002] Immunosuppressant drugs have been used for purposes of preventing adverse immune responses, either a rejection of a transplanted organ, or an attack on the patients own body by its own immune system caused by an autoimmune disease, without unduly suppressing the ability of the patient's immune system to combat infection. Such immunosuppressants have included rapamycin [U.S. Pat. No. 5,694,950]; FK 506 [U.S. Pat. No. 5,365,948]; and cyclosporine. [0003] With the advent of gene therapy, a need exists for methods of repeat administration of gene therapy vectors, such as viral vectors, exists. Methods are needed which are able to effectively overcome the body's normal immune response to gene therapy vectors such as viral vectors. In order to overcome the immunologic problems associated with repeat administration of adenoviral vectors, the use of broad immunosuppressants (Engelhardt et al., Proc. Natl. Acad. Sci. USA 91:6196-6200 (1994)) and cytoablative agents (Dai et al., Proc. Natl. Acad. Sci. USA 92:1401-1405 (1995)) to overcome the immune response of the host to first generation Ad vectors have been tested. Transient co-administration of an immunoglobulin, CTLA4-Ig, along with an intravenous injection of Ad vector expressing a non-immunogenic transgene product (human oc-I anti-trypsin) has been shown to lead to persistent transgene expression from mouse liver (Kay et al., Nat. Genetics 11:191-197 (1995)). CTLA4-Ig blocks the B7-CD28 pathway of T cell co-stimulation, which is required for optional activation of T cells. (Jenkins et al., Immunity 1:443-446 (1994); Lenschow et al., Ann. Rev. Immunol. 14:233-258 (1996)). Although adenoviral-specific antibody levels were reduced in CTLA4-Ig treated mice, the inhibition was not sufficient to allow secondary gene transfer via repeat administration of the vector under the conditions tested (Kay et al., Nat. Genetics 11:191-197 (1995)). Thus, many immunosuppressant molecules are not effective for gene therapy purposes in which persistent expression of a foreign transgene is desired. Accordingly, a need exists for methods of employing immunosuppressant drugs which are effective when used with gene therapy vectors. SUMMARY OF INVENTION [0004] The present invention provides for transient co-administration of rapamycin together with a gene therapy vector encoding a transgene. The present invention is directed to inhibiting the immune response of a host to the administered gene therapy vector and to the encoded transgene product, thus allowing persistent transgene expression and repeated administration of the gene therapy product to the host. The present invention is also of relevance in genetic disease patients that mount immune responses to protein replacement therapies, in which case the present invention provides for transient co-administration of rapamycin together with protein replacement therapy. In a further aspect of the invention, co-administration of rapamycin could inhibit a secondary immune response in a host that has been pre-immunized with the gene therapy vector or pre-immunized with the protein product encoded by the trans gene. In preferred embodiments, the present invention relates to methods and compositions for blocking signal 2, but not signal 1, of the interaction between major histocompatibility complex [MHC] on antigen presenting cells [APC] binding to T-cell receptor [TCR], while at the same time blocking one or more of the co-stimulation pathways: B7-CD28 and CD40-CD40 ligand. Thus, compositions of the present invention comprise (1) an agent which blocks signal 2, but not signal I, of the MHCTCR interaction pathway; (2) an agent which blocks a co-stimulation pathway; and (3) a therapeutic agent. The agent which blocks signal 2, but not signal 1 of the MHC-TCR interaction is preferably rapamycin, but may also be a rapamycin analog, an antibody which binds to the MHC, blocking interaction with TCR, or an antibody to TCR, provided such antibody to TCR is antagonistic, and does not activate the T cell to which it binds. The agent which blocks a co-stimulation pathway is preferably selected from the group consisting of CTLA4-Ig, antibodies to B7-1, antibodies to B7-2, antibodies to CD28, and antibodies to CD40L. One antibody to CD40L which may be used in the present invention as the agent blocking co-stimulation is MRI. The therapeutic agent is preferably a gene therapy vector which encodes a therapeutic gene. Suitable gene therapy vectors include viral vectors, such as adenovirus, adeno-associated virus, retrovirus, including lentivirus vectors. Other gene therapy vectors include cationic or amphiphilic compounds, such as lipids, as well as polymers, liposomes and naked DNA. Useful therapeutic genes include those encoding lysosomal storage enzymes, such as glucocerebrosidase, alpha-galactosidase A, sphingomyelinase, iduronate sulfatase, alpha-glucosidase, galactosamine-6-sulfatase, beta-galactosidase, galactosamine-4 sulfatase (arylsulfatase B), alpha-glucosidase, and alpha-iduronidase. Other preferred therapeutic genes include those useful for the production of hemophilic proteins, most preferably Factor VIIA, Factor VII and Factor IX. In other embodiments, the therapeutic agent may be a polypeptide, or a combination of polypeptide and gene therapy vectors. BRIEF DESCRIPTION OF THE FIGURES [0005] FIG. 1 shows the anti-a-gal antibody titers for experiments in which Ad2 was co-administered with anti-CD40L and/or Rapamycin. [0006] FIG. 2 shows the anti-.alpha.-Ad2 antibody titers for experiments in which Ad2 was co-administered with anti-CD40L and/or Rapamycin. [0007] FIG. 3 shows the transgene expression for experiments in which Ad2 was co administered with anti-CD40L and/or Rapamycin. [0008] FIG. 4 shows the anti-.alpha.-gal antibody titers for experiments in which Ad2 was co-administered with anti-B7-1 and anti-B7-2 and/or Rapamycin. [0009] FIG. 5 shows the anti-.alpha.-Ad2 antibody titers for experiments in which Ad2 was co-administered with anti-B7-1 and anti-B7-2 and/or Rapamycin. DETAILED DESCRIPTION OF THE INVENTION [0010] Rapamycin is a natural product derived from a soil microorganism, which was originally described as an antibiotic and subsequently found to possess some immunosuppressive properties. Rapamycin has recently been approved for use in patients for kidney transplantation in combination with cyclosporine and corticosteroids. Recent reports in the literature claim that rapamycin in combination with co-stimulation blockade can induce tolerance to allografts in mice. [0011] The present invention provides for transient co-administration of rapamycin or an analog or derivative thereof, together with a gene therapy vector encoding a transgene. The present invention is directed to inhibiting the immune response of a host to the administered gene therapy vector and encoded trans gene product, thus allowing persistent transgene expression and repeated administration of the gene therapy product to the host. The present invention is also of relevance in genetic disease patients that mount immune responses to protein replacement therapies in which case the present invention provides for transient co-administration of rapamycin together with protein replacement therapy. In a further aspect of the invention, co-administration of rapamycin could inhibit a secondary immune response in a host that has been pre-immunized with the gene therapy vector or pre-immunized with the protein product encoded by the transgene. [0012] Wherever the present application refers to "rapamycin", in addition to naturally occurring forms of rapamycin, the present invention includes the use of rapamycin analogs and derivatives. Many such analogs and derivatives are known in the art, for example, including but not limited to those described in U.S. Pat. Nos. 6,015,809; 6,004,973; 5,985,890; 5,955,457; 5,922,730; 5,912,253; 5,780,462; 5,665,772; 5,637,590; 5,567,709; 5,563,145; 5,559,122; 5,559,120; 5,559,119; 5,559,112; 5,550,133; 5,541,192; 5,541,191; 5,532,355; 5,530,121; 5,530,007; 5,525,610; 5,521,194; 5,519,031; 5,516,780; 5,508,399; 5,508,290; 5,508,286; 5,508,285; 5,504,291; 5,504,204; 5,491,231; 5,489,680; 5,489,595; 5,488,054; 5,486,524; 5,486,523; 5,486,522; 5,484,791; 5,484,790; 5,480,989; 5,480,988; 5,463,048; 5,446,048; 5,434,260; 5,411,967; 5,391,730; 5,389,639; 5,385,910; 5,385,909; 5,385,908; 5,378,836; 5,378,696; 5,373,014; 5,362,718; 5,358,944; 5,346,893; 5,344,833; 5,302,584; 5,262,424; 5,262,423; 5,260,300; 5,260,299; 5,233,036; 5,221,740; 5,221,670; 5,202,332; 5,194,447; 5,177,203; 5,169,851; 5,164,399; 5,162,333; 5,151,413; 5,138,051; 5,130,307; 5,120,842; 5,120,727; 5,120,726; 5,120,725; 5,118,678; 5,118,677; 5,100,883; 5,023,264; 5,023,263; 5,023,262; all of which are incorporated herein by reference. [0013] In the sections which follow, detailed therapeutic regimens are provided for combination therapy of eight specific LSDs (i.e. Gaucher's, Fabry's, Niemann-Pick B, Hunter's, Morquio's, Maroteaux-Lamy, Pompe's, and Hurler's-Scheie's in its various clinical manifestations), as well as hemophilic factors Factor VI IA, Factor VIII and Factor IX. 1. Gaucher's [0014] Gaucher's disease is caused by inactivation of glucocerebrosidase and accumulation of glucocerebroside. 2. Fabry's [0015] Fabry's disease is caused by inactivation of alpha-galactosidase A and accumulation of GL-3. The enzymatic defect leads to systemic deposition of glycosphingolipids with terminal alpha-galactosyl moieties, predominantly globotriaosylceramide and, to a lesser extent, galabiosylceramide and blood group B substances. In addition to assay for specific activity of alpha-galactosidase A and accumulation of GL-3, assay for deposition of glycosphingolipid substrates in body fluids and in lysosomes of vascular endothelial, perithelial and smooth muscle cells of blood vessels. Other manifestations which can be useful for assay include proteinuria and other signs of renal impairment, such as red cells or lipid globules in the urine, and elevated erythrocyte sedimentation rate. Also, anemia, decreased serum iron concentration, high concentration of beta-thromboglobulin, and elevated reticulocyte counts or platelet aggregation. Desnick et al., in Scriver et al., Metabolic and Molecular Bases of Inherited Disease, (7th ed. 1995) p. 2741-2784. 3. Niemann-Pick B [0016] Niemann-Pick B disease is caused by inactivation of sphingomyelinase and accumulation of sphingomyelin. 4. 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