Technology

Problem

There are 8 million Americans living with PAD. In these patients, obstructed arteries result in poor blood flow (ischemia) to cardiac and peripheral tissues, and manifests in pain with walking (intermittent claudication). Prolonged ischemia inhibits wound healing, starves the muscles of oxygen and nutrients, and causes muscle wasting (atrophy) or cell death (necrosis). Given the high rate of surgical failure, the inevitable prognosis for advanced stage PAD (critical limb ischemia, CLI) is amputation (at 30%) and death (at 25%).


Current approaches to treating PAD

In the absence of an FDA-approved blood-vessel regeneration (revascularization) therapy, patients are limited to palliative treatments that mitigate acute complications, rather than reverse or cure the disease. Specifically,oral medications work to prevent acute complications from narrowed vessels and dilates the diseased vessels. Surgical/endovascular interventions such as surgical bypass grafts and endovascular stenting are not feasible options for many patients due to comorbidities and extent of disease.


NangioTx’s approach to treating PAD

NangioTx has a unique approach to treating PAD that is based on molecular mimicry of the body’s natural mechanism for blood vessel generation. The process is mediated by the engagement of the Vascular Endothelial Growth Factor (VEGF) to its cognate receptors (VEGFR). Towards this end, NangioTx has licensed “V-10”, the lead self-assembling peptide mimic of VEGF (otherwise known as the QK domain) for inducing angiogenesis and treating poor blood flow in PAD. V-10 was developed through 10+ years of research at Rice University, and consists of a novel multi-domain sequence of 31 amino acids, with each of the domains serving a unique purpose (Figure 1)1-8. V-10 is easily produced by solid phase peptide synthesis, and its shelf life at room temperature is longer than a year in a standard laboratory environment.

An important feature of the peptide design is that V-10 self-assembles into a nano-fibrous matrix that is compatible with the natural extracellular matrix. This peptide matrix can be sheared, only to reform due to the nature of the hydrophobic interactions and hydrogen bonds between individual peptide molecules. Domains of the V-10 peptide have been designed to enable peptide-controlled degradation, cell adhesion, and local stimulation of angiogenesis. Given these favorable physical properties, V-10 remains at the site of injection for three weeks, and imparts a sustained therapeutic effect.

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V-10 is an injectable hydrogel that stimulates the creation of new blood vessels. The active pharmaceutical ingredient (API) has been identified and the formulation has been worked out and published1,9. Upon injection into the muscle of mice, V-10 forms a hydrogel matrix in situ. The hydrogel offers remarkable epitope density owing to the presence of the bioactive domain on each peptide strand of the large polymer. High epitope density in turn enables large amounts of target receptor activation, clustering, induction of intracellular signaling, and protein production.

Through its VEGF mimic, V-10 provides the signal that induces the growth of mature blood vessels, a process known as angiogenesis1,9. At NangioTx, V-10 is currently being investigated for the treatment of peripheral artery disease (PAD). In vivo experiments conducted with V-10 have shown that the peptide forms a matrix that promotes and sustains the growth of robust, mature, non-leaky blood vessels even after the matrix degrades. V-10 is also fast acting, such that there were noticeable improvement in blood flow (perfusion) in aged mice in just 7 days after treatment compared to several months in control mice. For the duration of the experiments, V-10 proved not to be non-toxic to tissue; instead, the resulting nanofiber scaffold was permissive to the rapid infiltration of cells, and the matrix was degraded at 3 weeks post injection.

In relation to PAD, V-10 generates new “highways” – i.e., mature blood vessels – in ischemic muscles. These highways bypass the narrowed arteries in PAD mouse models, return blood flow to ischemic muscles, reverse tissue atrophy, and prevent the need for amputation in animal models for PAD. The results we have obtained thus far have all shown significantly greater perfusion of the ischemic leg than leading stem cell-based technologies currently undergoing clinical trials (Figure 2). Taken together, V-10’s stability and efficacy may offer maximal effectiveness for clinical treatment of PAD.

Preclinical efficacy. (A) Blood flow shows rapid restoration after induction of ischemia and injection of V-10. (B) Increase in blood flow shows a concomitant improvement in motor function. (C) Return of blood flow in this mouse model for peripheral artery disease with V-10 was 28-34% greater (at the same stage of development) than leading investigational therapies (that are already in clinical trials).

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