Mathematical Model Predicts that Acceleration of Diabetic Wound Healing is Dependent on Spatial Distribution of VEGF-A mRNA (AZD8601)

Abstract

Introduction Pharmacologic approaches for promoting angiogenesis have been utilized to accelerate healing of chronic wounds in diabetic patients with varying degrees of success. We hypothesize that the distribution of proangiogenic drugs in the wound area critically impacts the rate of closure of diabetic wounds. To evaluate this hypothesis, we developed a mathematical model that predicts how spatial distribution of VEGF-A produced by delivery of a modified mRNA (AZD8601) accelerates diabetic wound healing. Methods We modified a previously published model of cutaneous wound healing based on coupled partial differential equations that describe the density of sprouting capillary tips, chemoattractant concentration, and density of blood vessels in a circular wound. Key model parameters identified by a sensitivity analysis were fit to data obtained from an in vivo wound healing study performed in the dorsum of diabetic mice, and a pharmacokinetic model was used to simulate mRNA and VEGF-A distribution following injections with AZD8601. Due to the limited availability of data regarding the spatial distribution of AZD8601 in the wound bed, we performed simulations with perturbations to the location of injections and diffusion coefficient of mRNA to understand the impact of these spatial parameters on wound healing. Results When simulating injections delivered at the wound border, the model predicted that injections delivered on day 0 were more effective in accelerating wound healing than injections delivered at later time points. When the location of the injection was varied throughout the wound space, the model predicted that healing could be accelerated by delivering injections a distance of 1–2 mm inside the wound bed when compared to injections delivered on the same day at the wound border. Perturbations to the diffusivity of mRNA predicted that restricting diffusion of mRNA delayed wound healing by creating an accumulation of VEGF-A at the wound border. Alternatively, a high mRNA diffusivity had no effect on wound healing compared to a simulation with vehicle injection due to the rapid loss of mRNA at the wound border to surrounding tissue. Conclusions These findings highlight the critical need to consider the location of drug delivery and diffusivity of the drug, parameters not typically explored in pre-clinical experiments, when designing and testing drugs for treating diabetic wounds.

mRNA vaccines in disease prevention and treatment

“…In 2016, AstraZeneca developed AZD8601, an mRNA vaccine encoding VEGF-A165 with a minimal innate immune response. 213 – 215 AZD8601 used in preclinical models induced more blood vessels in local tissue and significantly accelerated the healing of chronic wounds in a dose-dependent manner. 213 – 215 A clinical trial was subsequently started in 2017 in patients with coronary artery disease undergoing coronary artery bypass grafting surgery (NCT03370887).…”

“… 213 – 215 AZD8601 used in preclinical models induced more blood vessels in local tissue and significantly accelerated the healing of chronic wounds in a dose-dependent manner. 213 – 215 A clinical trial was subsequently started in 2017 in patients with coronary artery disease undergoing coronary artery bypass grafting surgery (NCT03370887). Patients were randomly and equally divided into three groups and further treated with AZD8601 at different doses or placebo, with the evaluation of the safety of AZD8601 as the primary endpoint.…”

4-Hexylresorcinol: pharmacologic chaperone and its application for wound healing

“…In addition, high level of serum glucose level increases ROS production [ 81 ]. As a consequence, chronic inflammation with poor capillary regeneration is frequent in diabetic wound [ 82 ]. 4HR is strong M2 macrophage polarizing agent [ 26 , 83 ].…”