Exosome drug for tendinopathy

Project Summary Tendinopathy is an age-related tendon disorder characterized by tendon deterioration and is associated with pain, swelling and impaired performance, and often leads to tendon rupture. Given that there is no disease- modifying therapeutic on the market, our central goal is to develop and commercialize a novel biologic as an effective and safe treatment for tendinopathy. The product to be developed is Altenex, a disease-modifying biologic drug consisting of exosomes generated by allogeneic human bone marrow-derived mesenchymal stem cells (BM-MSCs) grown on a novel specialized 3D scaffold for the treatment of tendinopathy. Altenex is an exciting outcome for our effort in developing a stem cell-based biologic product based on a scalable production process. Human BM-MSCs from a readily available stem cell bank are cultured on uniquely engineered “NanoPrime” scaffolds fabricated with electrospun aligned polycaprolactone (PCL) fibers. These mass-produced scaffolds emulate the 3D microenvironment that carries the physical cues to “guide” the MSCs toward tenocytic differentiation and, in doing so, secrete exosomes with therapeutic potential in tendinopathy. In our preliminary studies, Altenex produced from xeno-free development-grade human BM-MSCs was characterized as typical exosomes. The exosome identity of Altenex was confirmed by its exosomal protein markers. Excitingly, we found intra-tendinous injection of Altenex, into rat Achilles tendons with tendinopathy mitigated histologic features of tendinopathy. These encouraging data support the feasibility of developing Altenex as a biologic drug for tendinopathy consisting of allogeneic exosomes and led us to hypothesize that Altenex exerts a therapeutic effect on mitigating tendinopathy with minimal, if any, adverse effects. To test the hypothesis, two specific aims are proposed. In Aim 1, we will determine the efficacies, safety and pharmacokinetics of Altenex using a collagenase-induced rat model of tendinopathy. Specifically, we will first identify the optimal dose and dose schedule for Altenex based on histologic scoring. Then, using the optimal dose and dose schedule, we will determine the therapeutic effect of Altenex on mitigating tendinopathy pathology, improving tendon mechanical properties, and relieving pain behaviors. Furthermore, we will evaluate the safety and pharmacokinetics of Altenex. In Aim 2, we will determine the efficacy and safety of Altenex on tendinopathy in rabbits. Rabbits with a severe stage of collagenase-induced Achilles tendinopathy will be treated with Altenex and compared against controls. The efficacy measurements will focus on the pathology and mechanical properties of the diseased tendon, the parameters that have been well-established in this rabbit model. Furthermore, the safety of Altenex treatment will be evaluated by clinical observations and clinical pathology, with particular attention to local toxicities due to interactions Altenex with the tissue at the site of administration. This preclinical study is a critical step that advances the translation of Altenex toward the clinical phase and ultimately an FDA-approved drug for tendinopathy.