Transmembrane stem factor nanodiscs enhanced revascularization in a hind limb ischemia model in diabetic, hyperlipidemic rabbits.

Therapies to revascularize ischemic tissue have long been a goal for the treatment of vascular disease and other disorders. Therapies using stem cell factor (SCF), also known as a c-Kit ligand, had great promise for treating ischemia for myocardial infarct and stroke, however clinical development for SCF was stopped due to toxic side effects including mast cell activation in patients. We recently developed a novel therapy using a transmembrane form of SCF (tmSCF) delivered in lipid nanodiscs. In previous studies, we demonstrated tmSCF nanodiscs were able to induce revascularization of ischemia limbs in mice and did not activate mast cells. To advance this therapeutic towards clinical application, we tested this therapy in an advanced model of hindlimb ischemia in rabbits with hyperlipidemia and diabetes. This model has therapeutic resistance to angiogenic therapies and maintains long term deficits in recovery from ischemic injury. We treated rabbits with local treatment with tmSCF nanodiscs or control solution delivered locally from an alginate gel delivered into the ischemic limb of the rabbits. After eight weeks, we found significantly higher vascularity in the tmSCF nanodisc-treated group in comparison to alginate treated control as quantified through angiography. Histological analysis also showed a significantly higher number of small and large blood vessels in the ischemic muscles of the tmSCF nanodisc treated group. Importantly, we did not observe inflammation or mast cell activation in the rabbits. Overall, this study supports the therapeutic potential of tmSCF nanodiscs for treating peripheral ischemia.

Transmembrane Stem Factor Nanodiscs Enhanced Revascularization in a Hind Limb Ischemia Model in Diabetic, Hyperlipidemic Rabbits.

Therapies to revascularize ischemic tissue have long been a goal for the treatment of vascular disease and other disorders. Therapies using stem cell factor (SCF), also known as a c-Kit ligand, had great promise for treating ischemia for myocardial infarct and stroke, however clinical development for SCF was stopped due to toxic side effects including mast cell activation in patients. We recently developed a novel therapy using a transmembrane form of SCF (tmSCF) delivered in lipid nanodiscs. In previous studies, we demonstrated tmSCF nanodiscs were able to induce revascularization of ischemia limbs in mice and did not activate mast cells. To advance this therapeutic towards clinical application, we tested this therapy in an advanced model of hindlimb ischemia in rabbits with hyperlipidemia and diabetes. This model has therapeutic resistance to angiogenic therapies and maintains long term deficits in recovery from ischemic injury. We treated rabbits with local treatment with tmSCF nanodiscs or control solution delivered locally from an alginate gel delivered into the ischemic limb of the rabbits. After eight weeks, we found significantly higher vascularity in the tmSCF nanodisc-treated group in comparison to alginate treated control as quantified through angiography. Histological analysis also showed a significantly higher number of small and large blood vessels in the ischemic muscles of the tmSCF nanodisc treated group. Importantly, we did not observe inflammation or mast cell activation in the rabbits. Overall, this study supports the therapeutic potential of tmSCF nanodiscs for treating peripheral ischemia.

Syndecan-4 proteoliposomes enhance revascularization in a rabbit hind limb ischemia model of peripheral ischemia.

Regenerative therapeutics for treating peripheral arterial disease are an appealing strategy for creating more durable solutions for limb ischemia. In this work, we performed preclinical testing of an injectable formulation of syndecan-4 proteoliposomes combined with growth factors as treatment for peripheral ischemia delivered in an alginate hydrogel. We tested this therapy in an advanced model of hindlimb ischemia in rabbits with diabetes and hyperlipidemia. Our studies demonstrate enhancement in vascularity and new blood vessel growth with treatment with syndecan-4 proteoliposomes in combination with FGF-2 or FGF-2/PDGF-BB. The effects of the treatments were particularly effective in enhancing vascularity in the lower limb with a 2-4 increase in blood vessels in the treatment group in comparison to the control group. In addition, we demonstrate that the syndecan-4 proteoliposomes have stability for at least 28 days when stored at 4°C to allow transport and use in the hospital environment. In addition, we performed toxicity studies in the mice and found no toxic effects even when injected at high concentration. Overall, our studies support that syndecan-4 proteoliposomes markedly enhance the therapeutic potential of growth factors in the context of disease and may be promising therapeutics for inducing vascular regeneration in peripheral ischemia. STATEMENT OF SIGNIFICANCE: Peripheral ischemia is a common condition in which there is a lack of blood flow to the lower limbs. This condition can lead to pain while walking and, in severe cases, critical limb ischemia and limb loss. In this study, we demonstrate the safety and efficacy of a novel injectable therapy for enhancing revascularization in peripheral ischemia using an advanced large animal model of peripheral vascular disease using rabbits with hyperlipidemia and diabetes.

Transmembrane Stem Factor Nanodiscs Enhanced Revascularization in a Hind Limb Ischemia Model in Diabetic, Hyperlipidemic Rabbits.

Therapies to revascularize ischemic tissue have long been a goal for the treatment of vascular disease and other disorders. Therapies using stem cell factor (SCF), also known as a c-Kit ligand, had great promise for treating ischemia for myocardial infarct and stroke, however clinical development for SCF was stopped due to toxic side effects including mast cell activation in patients. We recently developed a novel therapy using a transmembrane form of SCF (tmSCF) delivered in lipid nanodiscs. In previous studies, we demonstrated tmSCF nanodiscs were able to induce revascularization of ischemia limbs in mice and did not activate mast cells. To advance this therapeutic towards clinical application, we tested this therapy in an advanced model of hindlimb ischemia in rabbits with hyperlipidemia and diabetes. This model has therapeutic resistance to angiogenic therapies and maintains long term deficits in recovery from ischemic injury. We treated rabbits with local treatment with tmSCF nanodiscs or control solution delivered locally from an alginate gel delivered into the ischemic limb of the rabbits. After eight weeks, we found significantly higher vascularity in the tmSCF nanodisc-treated group in comparison to alginate treated control as quantified through angiography. Histological analysis also showed a significantly higher number of small and large blood vessels in the ischemic muscles of the tmSCF nanodisc treated group. Importantly, we did not observe inflammation or mast cell activation in the rabbits. Overall, this study supports the therapeutic potential of tmSCF nanodiscs for treating peripheral ischemia.

Reshaping de Novo Protein Switches into Bioresponsive Materials for Biomarker, Toxin, and Viral Detection.

De novo designed protein switches are powerful tools to specifically and sensitively detect diverse targets with simple chemiluminescent readouts. Finding an appropriate material host for de novo designed protein switches without altering their thermodynamics while preserving their intrinsic stability over time would enable the development of a variety of sensing formats to monitor exposure to pathogens, toxins, and for disease diagnosis. Here, a de novo protein-biopolymer hybrid that maintains the detection capabilities induced by the conformational change of the incorporated proteins in response to analytes of interest is generated in multiple, shelf-stable material formats without the need of refrigerated storage conditions. A set of functional demonstrator devices including personal protective equipment such as masks and laboratory gloves, free-standing films, air quality monitors, and wearable devices is presented to illustrate the versatility of the approach. Such formats are designed to be responsive to human epidermal growth factor receptor (HER2), anti-hepatitis B (HBV) antibodies, Botulinum neurotoxin B (BoNT/B), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This combination of form and function offers wide opportunities for ubiquitous sensing in multiple environments by enabling a large class of bio-responsive interfaces of broad utility.