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Hypoxia regulated conditionally silenced AAV expressing angiogenic inducers

A technology of silencer and growth factor, applied in the direction of angiogenesis factor, growth factor/inducing factor, angiopoietin, etc., can solve the problem of small curative effect and so on

Inactive Publication Date: 2012-10-03
UNIV OF MIAMI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

These were only moderately successful, showing the safety of the procedure, but minimal efficacy

Method used

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  • Hypoxia regulated conditionally silenced AAV expressing angiogenic inducers
  • Hypoxia regulated conditionally silenced AAV expressing angiogenic inducers
  • Hypoxia regulated conditionally silenced AAV expressing angiogenic inducers

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0125] Example 1: Treatment of angiogenesis, angiogenesis and arteriogenesis in ischemic skeletal muscle with a conditionally silenced AAV9 gene therapy vector expressing human VEGF.

[0126] Hypothesis: Ischemia-regulated promoter-driven semi-permeable, muscle-tropic AAV9 vector delivery of VEGF gene would support directed angiogenesis followed by arteriogenesis and reestablishment of a functional vascular network with stable tissue reperfusion.

[0127] Materials and Methods: A human (h) VEGF gene driven by a PGK promoter containing a tandem array of HIF-Ia and NSF (silencer) binding sites was cloned into an AAV9 vector. Gene expression and regulation quantified in hypoxic skeletal muscle cells and ischemic hindlimbs of normal and atherosclerosis-prone mice. Arteriogenesis and angiogenesis therapy were evaluated in a mouse hindlimb ischemia model by intramuscular delivery of AAV9-CS-VEGF vector.

[0128] Results: The results shown here indicate for the first time that susta...

Embodiment 2

[0133] Example 2: Models of therapeutic angiogenesis

[0134] Expression profiles of conditional silencing gene therapy vectors: Conditional silencing is a new technique developed in this laboratory to provide tighter regulation of ischemic genes. The HIF-1α-binding element (HRE) binds to silencing elements (neuron-responsive silencing element (NRSE) and the non-tissue-specific silencer of the murine Igβ promoter), in tandem arrays upstream of tissue-specific and constitutive promoters. The elements are arranged so that under physiological oxygen tension (normal) the silencing element is active and represses gene expression. Under conditions of tissue hypoxia (or ischemia), HRE sites are activated, resulting in dual induction of the HIF-1 enhancer and repression of silencing elements. The net effect is very low normoxic gene expression strongly induced (>100-fold) by hypoxia. The high inducibility is largely due to the silencing of basal gene expression and does not involve ...

Embodiment 3

[0144] Example 3: Age-associated decline of various pro-angiogenic growth factors, reduced induction of hypoxia-regulated genes, and inhibition of EPC migration.

[0145] Age-Mediated Decline of Angiogenic Growth Factor Gene Expression in Murine BM-MSCs: MSCs can be isolated from tibias and femurs of 2- and 26-month-old mice in MesenCult Medium with MSC Supplement (Stem Cell Technologies) Attach and culture in medium, 4 mice per age group. Cells can be treated and passaged similarly to achieve homogeneity, as determined by FACS analysis of cell surface markers Sca-1, CD44, CD45 and CD11b. All cells were equally capable of differentiating into chondrocytes, bone cells and adipocytes when exposed to appropriate inducers. RNA was purified at 11 passages under the same culture conditions, and transcripts were analyzed by microarray. RT-PCR confirmed alterations in selected growth factor-related gene transcripts. Significant decreases in the following columns: Angiopoietin 2 (3 ...

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Abstract

Methods and compositions for the treatment of hypoxia associated disorders by directional angiogenesis / arteriogenesis. Conditionally silenced vectors expressing a therapeutic molecule under hypoxic conditions avoid chaotic vascularization and allow for the orderly growth of new vessels into damaged tissue.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Application No. 61 / 256,381, filed October 39, 2009, which is incorporated herein by reference in its entirety. field of invention [0003] Embodiments of the invention include the treatment of tissue hypoxia and related conditions. Specifically, directed therapeutic angiogenesis is induced in patients by expression of conditional silencing vectors expressing the desired factor. Background technique [0004] Therapeutic angiogenesis is a method developed for the treatment of ischemia in which new blood vessel growth is induced in the ischemic tissue in response to exogenous angiogenic factors delivered by genes or cells. The main clinical targets are myocardial and critical lower extremity ischemia caused by coronary and peripheral artery disease, respectively. Convincing clinical results of genes and precursor stem cells have resulted in a series of phase II / III clin...

Claims

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Application Information

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IPC IPC(8): C12N15/00
CPCC12N15/85C12N2830/32C12N2750/14143A61K48/00C12N2830/002C07K14/52C12N15/86A61K31/7088A61P9/00C12N7/00C07K14/515C12N2750/14121C12N2750/14132
Inventor K·A·韦伯斯特
Owner UNIV OF MIAMI
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