Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1997-07-10
2001-04-03
Hauda, Karen M. (Department: 1632)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C424S093210, C424S199100, C424S093600, C424S204100, C424S205100, C424S233100, C435S320100, C435S375000
Reexamination Certificate
active
06211160
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the field of somatic gene therapy and methods useful therein.
BACKGROUND OF THE INVENTION
Immune responses of the recipient to the viral vectors used in somatic gene therapy, i.e., to the viral proteins of the vector, and/or to the transgene carried by the vector, and/or the virus-infected cells, have emerged as recurring problems in the initial application of gene therapy technology to animals and humans [Yang et al,
J. Virol.,
69:2004-2015 (1995) (Yang I)]. In virtually all models, including lung-directed and liver-directed gene therapy, expression of the transgene is transient and associated with the development of pathology at the site of gene transfer.
The transient nature of transgene expression from recombinant adenoviruses, for example, has been found to be due, in part, to the development of antigen specific cellular immune responses to the virus-infected cells and their subsequent elimination by the host. The collaboration of CTLs directed against newly synthesized viral proteins and viral specific T helper cells [Zabner et al,
Cell,
75:207-216 (1993); Crystal et al,
Nat. Genet.,
8:42-51 (1994)] leads to the destruction of the virus-infected cells. These immune responses have also been noted to cause the occurrence of associated hepatitis that develops in recipients of in vivo liver-directed gene therapy within 2-3 weeks of initial treatment, and myositis in recipients of in vivo muscle-directed gene therapy.
Another antigenic target for immune mediated clearance of virus-infected cells is the product of the transgene. CTLs are an important effector in the destruction of target cells with activation occurring in some cases in the context of the transgene product, as well as the viral-synthesized proteins, both presented by MHC class I molecules [Yang I; and Zsengeller et al,
Hum. Gene Thera.,
6:457-467 (1995)].
Another limitation of the use of recombinant virus vectors for gene therapy has been the difficulty in obtaining detectable gene transfer upon a second administration of virus. This limitation is particularly problematic in the treatment of single gene inherited disorders or chronic diseases, such as cystic fibrosis (CF), that will require repeated therapies to obtain life-long genetic reconstitution. Diminished gene transfer following a second therapy has been demonstrated in a wide variety of animal models following intravenous or intratracheal delivery of adenovirus vectors [T. Smith et al,
Gene Thera.,
5:397 (1993); S. Yei et al,
Gene Thera.,
1:192-200 (1994); K. Kozarsky et al,
J. Biol. Chem.,
269:13695 (1994)]. Similar difficulties have been noted when the viral vector is other than adenovirus, i.e., retrovirus, vaccinia, and the like. In each case, resistance to repeated gene therapy was associated with the development of neutralizing anti-virus antibodies, which thwarted successful gene transfer following a second administration of virus.
Proposed solutions to these anti-viral immune responses have to date involved new designs of the virus vectors which employ fewer viral genes, as well as the pre- or co-administration of immune modulators, such as anti-CD40 ligands and other modulators identified in the art [See, e.g., Yang et al.,
J. Virol.,
70(9) (September, 1996); International Patent Application No. WO96/12406, published May 2, 1996; and International Patent Application No. PCT/US96/03035, all incorporated herein by reference].
Nevertheless, the successful induction of specific immune tolerance to the new gene products (both virus products and transgene products) of the recombinant gene therapy vectors remains one of the most formidable challenges in gene therapy. Failure to establish immune tolerance to viral gene therapy vectors may lead to immune rejection of the transgene-expressing cells and therefore loss of transgenes.
There exists a need in the art for methods and compositions which enable the induction of specific immunologic tolerance to viral vector capsid proteins and both viral gene and transgene products being introduced and expressed in mammalian cells by general gene therapy methods.
SUMMARY OF THE INVENTION
The present invention provides a solution to the aforementioned need in the art by providing a method for eliminating the immune barrier impeding long-term gene therapy by selectively tolerizing a mammalian subject to multiple administrations of a live recombinant virus carrying a gene for delivery to a cell of said subject. This method involves administering to the subject a suitable amount of an inactivated virus prior to administration of a first live recombinant virus. The inactivated virus may be a whole virus, a replication defective virus, a previously inactivated copy of the live recombinant virus carrying a transgene, or a previously inactivated recombinant virus without a transgene. Inactivated virus is preferably administered via an oral or intravenous route. The administration of the inactivated virus essentially deactivates T cells specific for viral antigens, before the live recombinant virus carrying the transgene is administered.
REFERENCES:
patent: WO91/12816 (1991-09-01), None
patent: WO95/27500 (1995-10-01), None
patent: WO 96/12406 (1996-05-01), None
patent: WO96/14874 (1996-05-01), None
patent: WO 96/26285 (1996-08-01), None
patent: WO96/39176 (1996-12-01), None
Madeley (1968) J. Hyg., vol. 66, 89-107.*
Chung et al. (1987) Vaccine, vol. 5, 175-178.*
McCray et al. (1995) J. Clin. Invest. , vol. 95, 2620-2632.*
Yei et al. (1994) Gene Therapy, vol. 1, 192-200.*
Yang et al. (Apr. 1995) Journal of Virology, vol. 69 (4), 2004-2015.*
Putnack et al. (1991) Am. J. Trop. Med. Hyg. , vol. 45 (2), 159-167.*
Y. Chen et al, “Peripheral Deletion of Antigen-Reactive T Cells in Oral Tolerance”,Nature, 376:177-180 (Jul. 13, 1995).
Y. Chen et al, “Oral Tolerance in Myelin Basic Protein T-Cell Receptor Transgenic Mice: Suppression of Autoimmune Encephalomyelitis and Dose-Dependent Induction of Regulatory Cells”,Proc. Natl. Acad. Sci. USA, 93:388-391 (Jan., 1996).
Y. Chen et al, “Regulatory T Cell Clones Induced by Oral Tolerance Suppression of Autoimmune Encephalomyelitis”,Science, 265:1237-1240 (Aug. 26, 1994).
Y. Ilan et al, “Oral Tolerization to Adenoviral Proteins Permits Repeated Adenovirus-Mediated Gene Therapy in Rats with Pre-Existing Immunity to Adednoviruses”,Hepatology, 27(5):1368-1376 (May, 1998).
Y. Ilan et al, “Oral Tolerization to Adenoviral Antigens Permits Long-Term Gene Expression Using Recombinant Adenoviral Vectors”,J. Clin. Invest., 99(5):1098-1106 (Mar., 1997).
H. Kagami et al, “Repetitive Adenovirus Administration to the Parotid Gland: Role of Immunological Barriers and Induction of Oral Tolerance”,Human Gene Therapy, 9(3):305-313 (Feb. 10, 1998).
M. Takahashi et al, “Long Term Correction of Bilirubin-UDP-glucuronosyltransferase Deficiency in Gunn Rats by Administration of a Recombinant Adenovirus During the Neonatal Period”,J. Biol. Chem., 271(43):26536-26542 (Oct. 25, 1996).
A. Kass-Eisler et al, “Circumventing the Immune Response to Adenovirus-Mediated Gene Therapy”,Gene Ther., 3(2):154-162 (Feb., 1996) (Abstract only).
J. Walter et al, “Successful Expression of Human Factor IX Following Repeat Administration of Adenoviral Vector in Mice”,Proc. Natl. Acad. Sci. USA, 93(7):3056-3061 (Apr. 2, 1996).
Y. Chen et al. “Inductive Event sin Oral Tolerance in the TCR Transgenic Adoptive Transfer Model”,Cellular Immunology, 178:62-68 (1997).
S. Yei et al., “Adenovirus-Mediated Gene Transfer for Cystic Fibrosis: Quantitative Evaluation of Repeated in Vivo Vector Administration to the Lung”,Gene Therapy, 1:192-200 (1994).
Z. Zsengeller et al., “Persistence of Replication-Deficient Adenovirus-Mediated Gene Transfer in Lungs to Immune-Deficient (nu
u) Mice”,Human Gene Therapy, 6:457-467 (Apr. 1995).
J. Zabner et al., “Adenovirus-Mediated Gene Transfer Transiently Corrects the Chloride Transport Defect in Nasal Epithelia of Patients with Cystic Fibrosis”,Cell, 75:207-216 (Oct. 22, 1993).
R. C
Chen Youhai
Wilson James M.
Hauda Karen M.
Howson and Howson
The Trustees of the University of Pennsylvania
LandOfFree
Method for tolerizing a mammalian patient to administration... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method for tolerizing a mammalian patient to administration..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method for tolerizing a mammalian patient to administration... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2435796