Neurodevelopmental disorders such as cerebral palsy (CP) and autism are chronic disabilities with no effective cure, resulting in significant personal, social and economic burden. Neuroinflammation, mediated by activated microglia and astrocytes, plays a key role in the pathogenesis of cerebral palsy (CP) and autism. Targeting activated microglia/astrocytes in the brain may offer such an opportunity. This is a challenge at multiple levels. Our preliminary studies suggest that, upon intravenous administration, poly (amidoamine) (PAMAM) dendrimers (~4 nm), cross the blood-brain barrier (BBB), and further accumulate selectively in activated microglia and astrocytes in the brain of newborn rabbits with CP, but not in age-matched healthy controls. Importantly, a single 10 mg/kg drug dose in the form of this dendrimer-N-acetyl cysteine conjugate (D-NAC) administered on the day of birth (3 days after injury) intravenously to rabbit kits with CP, resulted in a significant improvement in motor function, attenuation of activated microglia, and decrease in neuronal injury and improved myelination by 5 days. Building on these promising findings, the long-term goal of this research is to develop dendrimer-based therapeutic approaches for the sustained postnatal treatment of neuroinflammation in CP. This will be achieved using the following specific aims: (1) determine whether increasing blood circulation time of dendrimers and using ligand targeting will improve microglial uptake and retention; (2) evaluate the toxicity of the dendrimer vehicle, and pharmacokinetics of NAC conjugated to dendrimers; (3) assess the sustained efficacy of the D-NAC conjugates, in improving motor function, decreasing microglial activation and brain injury up to 30 days. This study is significant because it: (1) explores the potential of targeted post-natal therapy in CP for improvement in motor phenotype, which has been a big challenge; (2) exploits the pathology-dependent differential uptake of PAMAM dendrimers by cells involved in neuroinflammation in CP; (3) will enable sustained attenuation of neuroinflammation during a crucial phase of brain development by providing tailored drug release; (4) uses NAC, a drug with a good safety profile in the perinatal and neonatal period, which can enable clinical translation. This study is innovative, because: (1) we evaluate therapeutic options in the postnatal period for a prenatal insult, to effect an improvement in motor function, with significan implications; (2) we seek to develop nanotherapeutic applications in the perinatal and neonatal period. Pediatric illnesses are often underserved by novel drug delivery technologies, which focus primarily on adults. This is the first study to bring nanotherapeutic approaches to childhood disorders such as CP.
The proposed research is relevant to public health because it will develop nanotechnology-based therapeutic approaches for the treatment of cerebral palsy, a neurodevelopmental disorder with no cure. Neuroinflammation plays an important role in cerebral palsy and autism. Designing targeted, sustained therapy for neuroinflammation will eventually benefit a large number of children affected by cerebral palsy, with implications in other neurological diseases.
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