Inflammatory peripheral neuropathies constitute one of the largest and least understood spectrums of neurologic disorders. Among these disorders is acute inflammatory demyelinating polyneuropathy (AIDP), a disabling inflammatory autoimmune disease of the peripheral nervous system. Inflammatory peripheral neuropathies collectively represent a major socioeconomic strain to our Veteran patient population and to the Veterans Health Administration. Despite overwhelming prevalence and socioeconomic impact, the treatment options available for Veterans suffering from inflammatory peripheral neuropathies, including AIDP, remain palliative, nonspecific, and ineffective. Immunization of susceptible strains of laboratory animals with peripheral nerve myelin P2 peptide and adjuvant induces experimental autoimmune neuritis (EAN), which closely models the pathogenicity of AIDP. Statins, a group of established cholesterol lowering agents, therapeutically attenuate EAN by inhibiting the transendothelial migration of autoreactive leukocytes into peripheral nerves. The effect of statins on the immune system is now known to be pleiotropic. Our lab has demonstrated that statins specifically attenuate TNF-? mediated release of the chemokine CCL2 from the peripheral nerve microvascular endoneurial endothelial cells (PNMECs) that form the blood-nerve barrier (BNB). Poor bioavailability necessitates high systemic doses to achieve the pleiotropic effects of statins, and rare but serious side effects preclude clinical translation. Biomaterials-based drug delivery represents a novel means by which to administer drugs that exhibit low bioavailability and high systemic toxicity. Poly(lactic-co- glycolic)acid (PLGA) can be used to form biodegradable nanoparticles that encapsulate hydrophobic compounds, including statins, for controlled release. In addition, PLGA can be modified to express moieties that direct circulating particles to sites of inflammation, allowing for targeted systemic administration. In this CDA-2 application, our objective is to determine the therapeutic potential of a novel, targeted drug delivery system to modulate endothelial GTPase signaling at the inflamed peripheral nerve. To accomplish this, we will utilize PLGA nanoparticles that encapsulate lovastatin and are surface-functionalized with purified macrophage plasma membranes. We hypothesize that targeted disruption of endothelial GTPase signaling with functionalized, lovastatin-encapsulating nanoparticles will therapeutically limit CCL2-dependent trafficking of autoreactive leukocytes in EAN. This will be tested using in vitro and in vivo approaches. First, we will assess the ability of surface-functionalized, PLGA nanoparticles to adhere to, migrate across, and deliver a payload within the activated BNB in vitro. Second, we will determine the therapeutic potential of targeting the inflamed BNB with systemically-administered, surface-functionalized, lovastatin-encapsulating nanoparticles in EAN. Third, we will elucidate the roles of Cdc42 and RalA GTPases in activation of the BNB in vitro under flow conditions. The immediate goals of this VA RR&D CDA-2 program are evaluating the therapeutic potential of targeted disruption of GTPase signaling in EAN while continuing to elucidate the mechanisms governing chemokine expression and pathological transendothelial migration at the blood-nerve barrier. Thus, this program will significantly advance the development of novel, selective immune-modulating strategies for the management and rehabilitation of Veterans with debilitating inflammatory peripheral neuropathies.
Inflammatory peripheral neuropathies remain an overwhelming social and economic burden to our Veteran patient population and to the Veterans Health Administration. Inclusive among these disorders is acute inflammatory demyelinating polyradiculopathy (AIDP), a debilitating autoimmune disease of unknown etiology that affects the peripheral nervous system. Despite considerable socioeconomic impact, the rehabilitative management of Veterans with acquired autoimmune neuropathies remains palliative and awaits the development of novel selective immune-modulating therapies. The goal of this CDA-2 research program is to optimize and implement a novel, biomaterials-based drug delivery system that targets mechanisms of inflammation within affected peripheral nerves using functionalized, lovastatin-encapsulating nanoparticles and an established model of autoimmune neuropathy.
