Systemic delivery of virus vectors encoding urocortin-2 and related genes to treat diabetes-related cardiac dysfunction and congestive heart failure

A technology for urocortin and heart failure, applied in gene therapy, corticotropin releasing factor, skin diseases, etc., can solve problems such as adverse effects and weight gain

Inactive Publication Date: 2017-02-22
RGT UNIV OF CALIFORNIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, many oral T2DM drugs have adverse effects in subjects with CHF and are associated with weight gain

Method used

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  • Systemic delivery of virus vectors encoding urocortin-2 and related genes to treat diabetes-related cardiac dysfunction and congestive heart failure
  • Systemic delivery of virus vectors encoding urocortin-2 and related genes to treat diabetes-related cardiac dysfunction and congestive heart failure
  • Systemic delivery of virus vectors encoding urocortin-2 and related genes to treat diabetes-related cardiac dysfunction and congestive heart failure

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0207] Example 1: Intravenous delivery of AAV8 encoding urocortin-2 increases cardiac function in normal mice

[0208] This example demonstrates the effectiveness of exemplary embodiments of the invention. In an alternative embodiment, adeno-associated virus vector serum encoding urocortin-2 (UCn2), a peptide of the corticotropin-releasing factor (CRF) family, using a single intravenous (IV) injection is provided. Type-8 (AAV8) composition and method for treating and improving type 2 diabetes mellitus (T2DM) and diabetic heart disease. In an alternative embodiment, the vector (AAV8.UCn2) comprises a regulated expression cassette to enable controlled expression. In alternative embodiments, exemplary vectors are delivered by intravenous injection, eg, into a brachial vein, during an outpatient visit.

[0209] We have demonstrated that a single intravenous injection of AAV8.UCn2 in mice resulted in a 15-fold increase in plasma UCn2 levels (which persisted for at least 7 month...

Embodiment 2

[0229] Example 2: Intravenous delivery of AAV8-encoded urocortin-2 increases function of failing hearts in mice

[0230] This example demonstrates the effectiveness of an exemplary embodiment of the invention that intravenous delivery of AAV8.UCn2 increases the function of failing hearts. In conclusion, myocardial infarction (MI, by coronary artery ligation) was used to induce heart failure, which was assessed by echocardiography 3 weeks after MI. Mice with LV ejection fraction (EF) 11 gc) or saline intravenous delivery, and echocardiography 5 weeks later showed increased LV EF in mice receiving UCn2 gene transfer (p=0.01). In vivo physiological studies showed a 2-fold increase in the peak rate of LV pressure rise (LV+dP / dt; p2+ The magnitude of the transient was associated with the rate of Ca+ decline and increased SERCA2a expression. Additionally, UCn2 gene transfer decreased Thr286 phosphorylation of Cam kinase II and increased expression of myomyosin light chain kinase,...

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Abstract

In alternative embodiments, provided are methods for treating, ameliorating or protecting (preventing) congestive heart failure (CHF) or a diabetes-related cardiac dysfunction, comprising: providing a urocortin 2-encoding and / or a urocortin 3-encoding nucleic acid, transcript or message, or gene, operatively linked to a transcriptional regulatory sequence, optionally contained in an expression vehicle or a vector such as an adeno-associated virus (AAV), e.g., an AAV8 serotype; and administering to an individual or a patient in need thereof, such as a type 2 diabetic (T2DM), e.g., by IV administration, thereby treating, ameliorating or protecting against (preventing) the T2DM and / or the diabetes-related cardiac dysfunction in the individual or patient.

Description

[0001] related application [0002] This application claims the benefit of priority to United States Provisional Patent Application Serial Number (USSN) 61 / 974,662, filed April 3, 2014. The above application is expressly incorporated herein by reference in its entirety for all purposes. [0003] Statement Concerning Rights to Inventions Made Based on Federally Sponsored Research [0004] This invention was made under grant numbers 306402 (HK066941), P01HL66941, HL088426, HL081741, and HL107200 awarded by the National Institutes of Health (NIH) Department of Health and Human Services (DHHS); and P01HL066941-11A1; and Veterans Completed with government support from Veteran's Administration (VA) Merit Grants I01 BX001515 and 1101bBX000783. The government has certain rights in this invention. technical field [0005] The present invention relates generally to cell and molecular biology, gene therapy and medicine, and more particularly to methods for treating, ameliorating or pr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K48/00
CPCA61K48/005C07K14/57509A61K38/2228A61P1/16A61P11/00A61P13/12A61P17/00A61P21/00A61P25/00A61P3/04A61P43/00A61P7/04A61P9/04A61P9/10A61P9/12A61P3/10A61K48/00
Inventor H·K·哈蒙德高美华
Owner RGT UNIV OF CALIFORNIA
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