INTEGENE INTERNATIONAL LLC

The Future of 
Vascular Bio-Technology


INDICATIONS
Integene's breakthrough gene-switch represents a platform technology that opens up the possibility of safe and curative gene therapy for multiple cardiovascular indications and cancerous tumors.

Our most advanced program targets Peripheral Artery Disease (PAD) a complex and progressive condition for which no effective pharmacologic or biotechnologic treatment is available.


Peripheral Artery Disease (PAD)
PAD is caused by a gradual build up of atherosclerotic plaque on the walls of limb arteries, usually above the knees that impedes blood flow to connected arterioles and capillaries of the extremities where it causes microvascular disease, ischemia and tissue injury.  Key risk factors include genetics, diet, exercise, tobacco use, age and diabetes. Leg pain during walking that progresses to constant pain at rest are among the first symptoms of PAD.  They are followed by tissue damage and cell death evidenced by discoloration of the toes, feet and lower limbs, non-healing ulcers, and necrosis/gangrene. At this stage a diagnosis of critical limb ischemia (CLI) is indicated.  Many PAD patients with even the first signs of ischemic injury are untreatable by conventional procedures including surgical reconstruction, and limb loss (amputation) may be inevitable.  Integene gene therapy is indicated as a preventative strategy to block disease progression and preserve limb integrity at all stages following a diagnosis of PAD.  Our philosophy is that successful treatment requires a minimum dual therapy to target arteriogenesis and collateral remodeling at the sites of vessel occlusion, usually above the knee, and directional angiogenesis to target and reverse microvascular disease at the extremities (feet and toes) where ischemic damage first occurs.  Integene treatments are indicated at all stages of the disease but should be implemented as early as possible after a PAD diagnosis.  Direct targeting of microvascular disease and reversal of gangrenous spread at the extremities is a unique feature of Integene technology.

4.3% of all Americans (>12 million), 14.5% of Americans over 69 and >50 million people worldwide suffer from PAD.

About 200,000 PAD-related amputations are performed annually in the U.S. 

   


Hypoxic Tumor Layers

Hypoxia develops inside solid tumors when the rapidly proliferating cells at the tumor surface outgrow the oxygen supply (see illustration on Technology page).  Cells within the hypoxic regions are quiescent but fully viable and may harbor cancer stem cells that are capable of regenerating the entire tumor as single cells when activated.  Hypoxic tumor cells are resistant to chemo- and radiation therapy and may contribute significantly to the metastatic potential of the tumor.  Hypoxic cells pose a major hurdle to successful cancer treatments because they can be recruited to the proliferating layers to replace cells lost to chemo- and radiation therapy, because they provide a source of migrating cells for metastasis, and because they contribute to creating the tumor microenvironment (TME), a unique state that supports survival and aggressive, unregulated growth of tumor cells in an otherwise hostile environment.  At Integene we propose to target the TME to induce cell death.

Hypoxic tumor cells produce large amounts of acid because of high rates of anaerobic glycolysis and Warbug effects however, the intracellular pH of most tumor cells is maintained at levels that are higher even than those of normal cells due to activated proton extrusion and neutralization pathways.  Tumor cells express high levels of pH regulating systems including the proton translocators NHE1 and H+ pump V-ATPase, and the CO2/H+ metabolizing enzyme carbonic anhydrase.  This is achieved at least in part through the actions of hypoxia-inducible factors (HIFs) in response to tumor hypoxia. Such pH regulation allows tumor cells to escape apoptotic cell death that would otherwise block tumor growth.  Recent work in the Integene laboratories has indeed shown that inhibition of the V-ATPase in breast cancer cells induces apoptosis via a Bcl-2-dependent pathway and confers tumor regression (Graham et al, 2014; Oncotarget, 5(5)).  Integene scientists are currently assessing multiple strategies to target tumor TMEs selectively within the hypoxic cell layers using our proprietary gene switch to direct systemically delivered gene vectors to express only in hypoxic tumor cells. 

It is estimated that >18 million Americans will be cancer patients or survivors in 2020.  Of these, four basic tumor types, breast, colorectal, lung, and prostate account for about 60% of all cancers in the US.  Each of these has a significant component of solid tumor hypoxic cells.

The overall cost of cancer in the US is estimated to be >$250 Billion, of which >$100 Billion involves direct medical care.
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