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Systemic delivery and regulated expression of paracrine genes for cardiovascular disease and other conditions

A regulated, transcriptional regulatory sequence technology, applied in the fields of cell and molecular biology and medicine, which can solve the problems of not providing shut-off transgene expression, not being able to treat heart disease, not being able to regulate transgenes, etc.

Active Publication Date: 2018-04-10
RGT UNIV OF CALIFORNIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However: 1) this protein is not under regulated expression and, therefore, cannot optimally regulate the level of the transgene in serum; 2) this system does not provide a means to switch off transgene expression in the event of an expected effect; and 3) the gene, Factor IX, is not a paracrine gene and does not have beneficial cardiovascular effects, and therefore, cannot be used to treat heart disease

Method used

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  • Systemic delivery and regulated expression of paracrine genes for cardiovascular disease and other conditions
  • Systemic delivery and regulated expression of paracrine genes for cardiovascular disease and other conditions
  • Systemic delivery and regulated expression of paracrine genes for cardiovascular disease and other conditions

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0158] Example 1: Intravenous delivery of AAV9 encoding urocortin-2 enhances cardiac function in normal mice

[0159] This example demonstrates the effectiveness of an exemplary embodiment of the invention: intravenous delivery of AAV9 / urocortin-2 (or AAV9 / UCn2) resulted in sustained increases in serum UCn2 and LV systolic function, demonstrating this exemplary embodiment of the invention. Effectiveness of a sexual embodiment in the treatment of heart failure.

[0160] In this study, we developed and tested the relative efficacy of two adeno-associated virus (AAV) serotypes (AAV5 and AAV9) encoding urocortin-2 (UCn-2), which -2 is a vasoactive peptide in the corticotropin-releasing factor family with diverse beneficial effects in animals and patients with heart failure. AAV5.Ucn-2 and AAV9.Ucn-2 (5×10 11 genome copies, gc). At four weeks (wk) after gene transfer, AAV DNA (qPCR) in liver (AAV5.UCn2: 2,601,839 copies / μg; AAV9.UCn2: 30,121,663 copies / μg) and heart (AAV5: 87,...

Embodiment 2

[0162] Example 2: Gene transfer for the treatment of cardiovascular disease

[0163] This example demonstrates the effectiveness of an exemplary embodiment of the invention in obtaining high yields of transgene expression in the heart in a manner that can be easily and safely administered.

[0164] In alternative embodiments, the invention provides methods of using expression vehicles (eg, vectors) encoding paracrine transgenes. In this embodiment, the transgene acts as a hormone and has a cardiac effect after release into the circulation from a distant site. In an alternative embodiment, this approach could circumvent the problem of achieving high yields of cardiac gene transfer and allow patients to be treated by systemic injection during office visits.

[0165] We tested multiple AAV serotype vectors and delivery methods and successfully completed a proof-of-concept study of paracrine gene transfer. Rats with severe dilated CHF received skeletal muscle delivery of an ad...

Embodiment 3

[0240] Example 3: Delivery of AAV8 Encoding Urocortin-2 Enhances Cardiac Function

[0241] This example demonstrates that in an alternative embodiment of the method of the invention, the paracrine transgene acts as a hormone and has a cardiac effect after being released into the circulation from a distant site. This exemplary approach circumvents the problem of achieving high yields of cardiac gene transfer and enables patients to be treated by systemic injection during office visits. Furthermore, this exemplary approach can eliminate the need for intravenous (IV) delivery of therapeutic peptides and thereby avoid repeated and prolonged hospitalizations, high morbidity, and substantial economic costs. In alternative embodiments, the most suitable vector to achieve these goals is adeno-associated virus type 8 (AAV8), which provides long-term and broad expression.

[0242] In an alternative embodiment of the method, urocortin-2, a recently discovered vasoactive peptide of th...

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Abstract

In alternative embodiments, the present invention provides a method for treating, ameliorating or preventing (preventing) a disease, infection or condition in an individual or patient responsive to elevated levels of a paracrine polypeptide, the method comprising: Provide a nucleic acid or gene encoding a paracrine polypeptide operably linked to a transcriptional regulatory sequence; or an expression vehicle, vector, recombinant virus or equivalent that already contains a nucleic acid or gene encoding a paracrine, and the expression vehicle, Vectors, recombinant viruses or equivalents are capable of expressing said paracrine-encoding nucleic acid or gene in a cell or in vivo; and administering or delivering said paracrine-encoding polypeptide operably linked to a transcriptional regulatory sequence to an individual or patient in need thereof nucleic acid or gene, or said expression vehicle, vector, recombinant virus or equivalent, thereby treating, ameliorating or preventing (preventing) said disease in said individual or patient responding to elevated levels of paracrine polypeptides, infection or condition.

Description

[0001] Statement Regarding Rights to Invention Made Pursuant to Federally Sponsored Research [0002] This invention was made with government support under Grant No. HL088426 awarded by DHHS from the National Institutes of Health (NIH). The government has certain rights in this invention. technical field [0003] The present invention relates to cellular and molecular biology and medicine. The invention provides compositions and in vitro and ex vivo methods. In alternative embodiments, the present invention provides methods for treating, ameliorating or preventing (preventing) a disease, infection or condition in an individual or patient responsive to elevated or sustained levels of a paracrine polypeptide in vivo, the method Including: providing a nucleic acid or gene encoding a paracrine polypeptide operably linked to a transcriptional regulatory sequence; or an expression carrier (vehicle), vector, recombinant virus or Equivalents, and said expression vehicles, vectors, ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K48/00A61K38/17A61K38/16A61K9/08A61K9/06A61P17/00A61P9/00
CPCA61K38/2221A61K38/2242A61K38/25A61K38/30A61K38/52C07K14/57509C07K14/65C12N15/86A61K48/005C12N2750/14143C12N2830/003A61K47/6901A61K31/436A61K31/65A61K38/2228A61P1/16A61P1/18A61P11/00A61P13/12A61P17/00A61P21/00A61P25/00A61P3/04A61P31/00A61P31/04A61P35/00A61P43/00A61P9/00A61P9/04A61P9/12A61P3/10A61K48/00C07K14/075C12N15/861C12N2710/10343A61K9/06A61K9/08A61K38/16A61K38/17A61K2121/00C12N15/8645
Inventor H·K·哈蒙德高美华
Owner RGT UNIV OF CALIFORNIA
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