Modulation of angiogenesis

Inventors

Ambati, Balamurali KrishnaAmbati, JayakrishnaSingh, Nirbhai

Assignees

University of Kentucky

Publication Number

US-9198981-B2

Publication Date

2015-12-01

Expiration Date

2026-10-17

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Abstract

This invention relates to compounds, compositions, and methods for the treatment of traits, diseases and conditions that respond to the modulation of angiogenic growth factor bioavailability or biological activity.

Core Innovation

The invention provides compounds, compositions, and methods for modulating angiogenesis in target tissues by specifically regulating the bioavailability and biological activity of angiogenic growth factors such as VEGF (Vascular Endothelial Growth Factor) and PlGF (Placental Growth Factor). These agents, including nucleic acid molecules, antibodies, or gene ablation systems, work by disrupting or preventing the interaction between growth factors and their inactivating agents, which leads to higher levels of active growth factor and promotes angiogenesis in tissues where it is needed.

The underlying problem being addressed is that conditions or traits involving decreased vascularity—such as those encountered in ocular disorders, preeclampsia, wound healing disorders, cardiovascular and cerebrovascular diseases—can result from reduced levels or biological activity of angiogenic growth factors due to sequestration by inactivating agents like soluble Flt-1 (sflt-1) and membrane-bound Flt-1 (mbflt-1). Physiologically, these inactivating agents bind and sequester VEGF and PlGF, limiting their angiogenesis-promoting effects and contributing to insufficient vascular growth in critical tissues.

The invention details multiple means of intervening in these growth factor-inactivating agent interactions. For example, interfering RNA molecules (such as siRNA, shRNA, or miRNA) can be used to downregulate the expression of sflt-1 or mbflt-1, freeing more VEGF to promote vascular growth. Alternative methods include the use of purified antibodies that specifically bind and neutralize the inactivating agents, or inducible gene excision systems such as Cre-lox that allow conditional reduction of inactivating agent expression in vivo. These strategies can be combined with appropriate pharmaceutical carriers and administered via various delivery routes such as topical, intravenous, or oral administration to treat or prevent conditions involving decreased vascularity.

Claims Coverage

The independent claims define three main inventive features in the patent.

Treatment of conditions associated with decreased vascularity using nucleic acid molecules to increase VEGF bioavailability

A method for treating conditions linked to decreased vascularity in a subject, which comprises administering to the subject a compound that increases the bioavailability or biological activity of VEGF by reducing the bioavailability or biological activity of a VEGF inactivating agent (sflt-1 or mbflt-1), wherein the compound is a nucleic acid molecule. This treatment is sufficient to treat the condition by increasing vascularity. The conditions treated include preeclampsia, systemic hypertension, cerebrovascular disorders, cardiovascular disorders, peripheral vascular disease, vascular regeneration/recovery, and wound healing disorders.

Use of double-stranded nucleic acid molecules and interfering RNA targeting VEGF inactivating agents

The claims cover the use of a compound comprising a double-stranded nucleic acid molecule with one strand that is at least 95% complementary to at least a portion of a nucleic acid sequence encoding the VEGF inactivating agent. The nucleic acid can include interfering RNA molecules, such as shRNA, siRNA, or miRNA, with specific lengths (e.g., 10 to 40 nucleotides) targeting sflt-1 or mbflt-1, thereby reducing the activity or presence of these agents and increasing free VEGF.

Conditional reduction of VEGF inactivating agent expression via inducible excision systems

The method also claims the reduction in expression of sflt-1 or mbflt-1 using an inducible excision system, such as cre-lox or FLP/FRT, with excision facilitated by the introduction of exogenous Cre recombinase. This includes introduction by topical application of NLS-Cre and allows conditional, spatial, or time-regulated reduction of the inactivating agent, thereby increasing VEGF bioavailability and promoting angiogenesis.

The inventive features pertain to the use of nucleic acid molecules and gene excision systems to reduce the activity or expression of VEGF inactivating agents (such as sflt-1 and mbflt-1), resulting in increased VEGF bioavailability and angiogenesis for the treatment of various vascular insufficiency-related conditions.

Stated Advantages

The compounds, compositions, and methods can be used to treat or prevent conditions associated with decreased vascularity by increasing the bioavailability or biological activity of VEGF.

Regulating growth factor-inactivating agents allows modulation of angiogenesis in a targeted tissue, potentially benefiting conditions like preeclampsia, wound healing disorders, and cardiovascular diseases.

Use of nucleic acid molecules such as siRNA provides specificity in downregulating sflt-1 or mbflt-1 and thus selectively promotes vascular growth where desired.

Conditional gene excision approaches (e.g., Cre-lox) offer spatial and temporal control over the reduction of VEGF inactivating agents.

Documented Applications

Treatment or prevention of conditions associated with decreased vascularity, including preeclampsia, systemic hypertension, cerebrovascular disorders, cardiovascular disorders, peripheral vascular disease, vascular regeneration/recovery, and wound healing disorders.

Restoring or enhancing angiogenesis in tissues where vascularization is insufficient, such as for wound healing or tissue regeneration following injury, surgery, or transplantation.

Therapeutic application in ocular disorders where increased vascularity may be beneficial.

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