Methods for targeted delivery of genetic material to the liver

A technology for hepatocytes and mammals, which is applied in the fields of genetic material components, genetic material delivery pathways, and drug devices, and can solve problems such as damage to target organs.

Inactive Publication Date: 2007-11-07
GENZYME CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this method requires the use of high pressure within the target organ
In order to raise the pressure sufficiently, large volumes of drug must be infused, and these larger doses may be disadvantageous for the reasons mentioned above
In addition, high pressure may risk damaging target organs

Method used

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  • Methods for targeted delivery of genetic material to the liver
  • Methods for targeted delivery of genetic material to the liver
  • Methods for targeted delivery of genetic material to the liver

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] Example 1: Catheter-Mediated Delivery of Adenoviral Gene Therapy Vectors to Rabbit Liver

[0084] For each experiment, New Zealand White rabbits (Millbrook Farms, Amherst, MA) each weighing approximately 4 kilograms were used. The adenoviral vector Ad2βgal used had a serotype 2 backbone with E1 deleted but E3 and E4 regions retained. The expression cassette consists of the cytomegalovirus (CMV) proximal early promoter and enhancer, the cDNA of nuclear localized β-galactosidase and the SV40 polyadenylation signal (Armentano, D. et al. (1997). J. Virol. 71: 2408-2416). Inject each rabbit with 1.5×10 12 Virus particles / kg (ratio of particles:infectious units=10:1) of Ad2[beta]gal virus.

[0085] An adenoviral gene therapy vector was delivered to the liver of a rabbit using an embodiment of the method of the invention as follows. To access the rabbit's vasculature, the jugular vein was exposed by a midline incision starting from the mandibular arch and extending to the ...

Embodiment 2

[0100] Example 2: Comparison of Topical and Systemic Administration in Naive Rabbits

[0101] To determine whether local delivery of viral vectors conferred advantages over systemic delivery, Ad2βgal virus was delivered to rabbits by: 1) local delivery using balloon catheter-mediated delivery as described in Example 1, or 2) Systemic delivery using intravenous injection. does not depend on the delivery route, the 1.5 x 10 12 Virus particles / kg of Ad2βgal virus was injected into each rabbit.

[0102] Systemic delivery of viral vectors was performed according to the following protocol. The terminal ear vein of the sedated rabbit was accessed using an ear-safe 20-gauge catheter needle and wrapped with gauze and medical bandage. A luer-lock flush was attached to the catheter, and diphenhydramine; 1 mg / kg, was administered IV to control possible allergic reactions. Physiological saline in an amount of 8 ml containing Ad2βgal virus was injected into the ear vein at a rate of abo...

Embodiment 3

[0115] Example 3: Comparison of Topical and Systemic Administration in Passively Immunized Rabbits

[0116] Local, catheter-mediated delivery of adenoviral vectors was compared with systemic injection in animals with antiviral immunity to examine whether local injection confers advantages over systemic injection in this case. To this end, the experiment in Example 2 was repeated in rabbits passively immunized with stored human serum of known titre against adenovirus type 2 (anti-Ad2).

[0117] The day before virus administration, the terminal ear vein of sedated rabbits was accessed using an ear-safe 20-gauge vascular catheter needle and wrapped with gauze and medical bandages. A luer-lock flush was attached to the catheter, and diphenhydramine (1 mg / kg) was administered intravenously to control possible allergic reactions. Forty milliliters of stock human serum (Valley Biomedical, Winchester, VA) containing anti-Ad2 ​​antibody was then injected at a rate of 0.1 ml / sec. This...

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PUM

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Abstract

The present invention provides methods for enhanced delivery of various therapeutic agents, such as gene therapy agents, to the vasculature of a target organ in a mammalian subject. The methods for targeted gene therapy in the mammalian liver as a whole, or in a single hepatic lobe, are disclosed. The disclosed methods rely on minimally invasive catheter-based procedures wherein a target organ is isolated and treated locally with a gene therapy agent. The methods offer more efficient and localized transfection of tissue and are wellsuited for gene therapy in human subjects.

Description

technical field [0001] The present invention relates to a method of delivering genetic material to a target organ in a living body using a balloon catheter. Background technique [0002] Gene therapy is the intracellular delivery of foreign genetic material that corrects existing defects or provides cells with new beneficial functions. The liver is an important target organ for gene therapy because of its important role in metabolism and production of serum proteins. There is a large number of known diseases, some of which are caused by defects in liver-specific gene products that would benefit from secreted protein liver products. Familial hypercholesterolemia, hemophilia, Gaucher's and Fabry's diseases are just a few examples. Gene therapy is available for many of these diseases (Siatskas et al., J. Inherit Metab. Dis. 2001, 24(Suppl. 2): 25-41; Barranger et al., Expert Opin. Biol. Then 2001, 1(5): 857-867; Barranger et al., Neurochem Res. 1999, 24(5):601-615). [0003...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K48/00A61M25/00A61M31/00A61F2/958
CPCA61K48/0075A61P1/16A61P3/00
Inventor R·K·朔伊伦B·L·霍奇斯
Owner GENZYME CORP
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