Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Genetically modified micro-organism – cell – or virus
Reexamination Certificate
1998-03-23
2002-01-29
Nguyen, Dave T. (Department: 1633)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Genetically modified micro-organism, cell, or virus
C514S04400A, C435S069100, C435S320100, C435S455000, C435S325000, C604S058000
Reexamination Certificate
active
06342214
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 W F, Human gene Therapy.
Science
256:808-813, 1992; Miller A D, Human gene therapy comes of age.
Nature
357:455-457, 1992). In recent years several clinical trials involving human gene therapy have been accepted by regulatory agencies. The first of the approved clinical trials which have initiated human gene therapy aim at treating both inherited diseases (such as severe combined immunodeficiency caused by lack of adenosine deaminase in peripherial T-lymphoctes, cystic fibrosis, and familial hypercholesterolemia) as well as noninherited disease such as cancer (Wolfe J H, Recent progress in gene therapy for inherited disease.
Curr. Opinion in Pediatr.
6:213-219, 1994; Sanda M G et al., Gene therapy for urologic cancer. J.
Urology
44:617-624, 1994; O'Malley B W et al., Somatic gene therapy in otolaryngology head and neck surgery.
Arch. Otolaryngol
. Head Neck Surgery 119:1191-1197, 1993; Engelhardt J F et al., Direct gene transfer of human CFTR into human bronchial epithelia of xenografts with Ei-deleted adenoviruses.
Nature Genetics
4:27-34, 1993; Lemarchand P et al., Adenovirus-mediated transfer of recombinant human alphal-antitrypsin cDNA to human endothelial cells.
PNAS
(
USA
) 89:6482-6486, 1992; Jaffe H A et al., Adenovirus-mediated in vivo gene transfer and expression in normal rat liver.
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. For example, retroviruses have been widely used, but a major disadvantage is that they can only be used as vectors which target actively dividing cells. In addition, retroviruses do not accomodate large DNA inserts readily. Adeno-associated viruses are also limited in the ability to accomodate large inserts, yet replication defective adenovirus has been successfully used for transfer of a variety of genes into cells in culture and in vivo. Adenoviruses can accomodate larger inserts than retroviruses, but extrachromasomal expression usually only lasts 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 has generated interest in the development of nonviral 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 GY.
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, issued Mar. 21, 1995, Anderson et al., hereby incorporated by reference). Direct injection into tissues, intravenous or intra-arterial administration, inhalation, or topical application have also 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 efficency 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.
One area of active research has been gene therapy into mammalian kidneys, but the results have been disappointing because of problems with efficiency of gene transfer (Woolf A S et al., Gene transfer into the mammalian kidney: First steps towards renal gene therapy.
Kidney Int.
43: Suppl. 39: S116-S119, 1993). Moullier et al. (Adenoviral-mediated gene transfer to renal tubular cells in vivo.
Kidney Int.
45: 1220-1225, 1994), showed some adenovirus-mediated transfer of lacZ gene into rat tubular but not glomerular cells following a combination of infusion of the virus into the renal altery and retrograde infusion into the vector. Simple infusion of soluble virus does not appear to be an efficient transfer system. Better results were obtained by Tomita et al., (Direct in vivo gene introduction into rat kidney.
Biochem. Biophys. Res. Commun.
186: 129-134, 1992), who infused a complex of Sendai virus and liposomes into the rat renal artery in vivo. This resulted in expression of the marker gene in about 15% of the glomerular cells.
It would be useful to the medical arts, to be able to have apparatus and methods for the efficient administration of gene therapy to target cells and tissues which overcomes the limitations inherent to each gene transfer vector.
SUMMARY OF THE INVENTION
In accordance with an aspect of the present invention, there is provided methods for the administration of pharmaceuticals to targets for functional use. (The term “pharmaceutical,” as used herein, includes chemical drugs, protein drugs, nucleic acid drugs, combination chemical/protein
ucelic acid drugs, and gene therapy vectors. The term “functional use,” as used herein, includes therapeutic treatment, prophylaxis, and/or production of recombinant proteins in vivo. The term “functional use” also includes the disruption of endogenous gene expression including the use of antisense, triplex forming, catalytic and otherwise disruptive pharmaceuticals. The term “functional use” also includes the expression of recombinant proteins in target tissues, whether of endogenous or exogenous origin. The term “target,” as used herein, includes cells, tissues and/or organs. The term “gene therapy vector” is meant to include nucleic acid constructs which are single, double or triplex stranded, linear or circular, that are expressible or non-expressible constructs which can either encode for and express a functional protein, or fragment thereof, or interfere with the normal expression of a target gene, gene transfer and/or expression vectors.)
The administration of pharmaceuticals may take place where the target is in situ in a living subject. The administration may also take place wherein the target is first removed from a subject, manipulated ex vivo, and returned to the original or alternatively a second recipeint subject. In a preferred embodiment, the target is situated such that the circulation of the blood supply into and out of the target is relatively isolated. In a most preferred embodiment, the blood circulation into and out of the target is mostly via a single, or readily identified entering arteries and exiting veins. There are of course certain amounts of limited leakage due to small blood and lymphatic vessels.
The methods of the instant invention allow for a prolonged period of administration of pharmaceuticals to a target by way of recirculating a pharmaceutical containing solution through the target such that a perfusion effect occurs. The methods of the instant invention allow for prolonged administration because of the unique use of the perfusion method and the oxygenation of the pharmaceutical containing solution. In one embodiment, the perfusion apparatus and target forms a closed system whereby the pharmaceuticals are administered at a starting concentration and not adjusted during the time course of treatment. In another embodiment, the pharmaceutical concentration is periodically adjusted so as to maintain or otherwise alter the concentration of pharmaceutical in the solution, or additional pharmaceuticals are added. In a preferred embodiment, the solution does not require replenishment during the course of treatment. In another embodiment, t
Heikkila Pirkko
Lukkarinen Olavi
Parpala Teija
Tryggvason Karl
Fay Sharpe Fagan Minnich & McKee LLP
Nguyen Dave T.
LandOfFree
Method for viral vector delivery 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 viral vector delivery, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method for viral vector delivery will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2819442