Systemic, Targeted Nanotherapies for the Treatment of Neuroinflammation in CNS Disorders: From Chemistry to Clinical Translation

Authors: 
Kannan, R., Johns Hopkins University School of Medicine
Neuroinflammation, caused by activated microglia and astrocytes, plays a key role in the pathogenesis of cerebral palsy (CP), autism, and other debilitating neurodegenerative disorders. Appropriate, targeted manipulation of neuroinflammation can bring novel approaches for treated diseases, increasing the efficacy and decreasing the side effects of drugs. 'Engineering' the functional response of activated glia can be a potent therapeutic strategy. However, targeted delivery of drugs to specific cells in the central nervous system is a challenge. We take advantage of the unique, intrinsic, pathology-dependent, brain uptake of dendrimers (with no targeting moieties) in diseases models of neurodegeneration. For example, upon systemic administration, hydroxyl poly(amidoamine) dendrimers localize selectively in activated microglia and astrocytes in animals with CP. Such selective localization is also seen in multiple brain and retinal injury small and large animal models. Building on these findings, we have designed and synthesized dendrimer-drug conjugates which have shown significant promise for translation. Two examples of this approach of targeting neuroinflammation the brain and the retina (from systemic administration) will be presented. We show that a single intravenous dose of dendrimer-drug conjugate, administered after birth to rabbit kits with CP, results in significant improvement in motor function along with decrease in neuroinflammation and oxidative/neuronal injury, followed by improved myelination, by 5 days of age.1 This improvement is sustained till adulthood, paving way for new approaches to pediatric/neonatal brain injuries. These dendrimer-drug conjugates are undergoing commercialization and clinical translation.

Reference: 1. Kannan S, Dai H, Navath RS, et al. Dendrimer-based postnatal therapy for neuroinflammation and cerebral palsy in a rabbit model. Sci Transl Med. 2012;4(130):130ra46. PMID: 22517883