NPD1 therapeutic efficacy is evident in several in vivo models of relevance to neurological disease. In the Median Cerebral Artery Occlusion model loss of penumbral brain tissue was reduced by more than 70% and associated with improved function post-stroke. NPD1 attenuated epileptogenesis, both kindling and status epilepticus induced, and reduced micro-epileptoform was associated with markedly attenuated seizure clinical scores, and retained normal dendritic architecture. In the SOD1 murine model of ALS treatment with NPD1 from early signs of disease till death reduced the time spent with confirmed neurological deficit by 50%. In models of both inflammatory and neuropathic pain, NPD1 reduced pain by modulating neuronal plasticity indicating protection from changes that might lead to progressive chronic pain. The potential of NPD1 to restore innervation was shown in a model of LASIK surgery where following severe damage to the corneal innervation NPD1 promoted nerve regrowth and full restoration of corneal sensitivity.
NPD1 is not only neuroprotective but profoundly regulates pathological neovascularization as shown in three different ocular models: herpes simplex virus-induced corneal keratitis, laser-indiuced neovascularization as the reference model for wet AMD, and finally in oxygen-induced retinopathy (OIR) as the reference model for retinopathy of prematurity. Data from the models indicate that NPD1 regulates several pathways that are key in pathological blood vessel formation, with each pathway individually confirmed as a therapeutic target. In the OIR model NPD1 further prevented vasoobliteration. Efficacy was demonstrated also with delivery as an eye drop indicating the potential of NPD1 as a non-invasive retinal therapeutic. The effect profile of NPD1 also indicates significant therapeutic potential in corneal disease.
NPD1 protects from hearing loss. In a reference model of cisplatin-induced hearing loss injection of NPD1 trans-tympanically to allow diffusion from the middle ear to the inner ear prevented increases in hearing threshold caused by cisplatin. Studies in an inner ear cell line confirmed NPD1 to prevent ROS formation by inhibiting upregulation of both NOX3 and iNOS, to attenuate the inflammatory response, and reduce apoptotic cell loss.
Extensive pharmacological studies have confirmed that NPD1 broadly downregulates inflammation, including leukocyte migration, cytokine and chemokine secretion, and activation of Cox-2, without being immunosuppressive. Important in its control of the immune response NPD1 activates proresolution macrophages and microglia to promote rapid clearance and restoration of tissue architecture, while downregulating macrophage and microglia proinflammatory activity.
NPD1 protects cells in the affected host tissue from death by modulating levels of the bcl-2 family of proapoptotic proteins leading to reduced levels of Bax and Bad via up-regulation of unphosphorylated bcl-2 and bcl-xL. NPD1 additionally promotes survival by upregulating the pAkt/mTor pathway, with promotion of tissue repair and neurite outgrowth. Survival benefit by NPD1 has been demonstrated in neurons, including motor neurons, retina pigment epithelium, retinal cones, and inner ear cells exposed to different oxidative stresses and drugs, and in cells transfected with TDP-43, ataxin-1 82Q, or huntingtin 72Q.
Current data indicate NPD1 to be an exceptionally safe molecule that would be well suited to address therapeutic needs in a pediatric patient population.
(in the scientific literature NPD1 is also referred to as Protectin D1; PD1)