Dendrimer nanotherapy targeting of glial dysfunction improves inflammation and neurobehavioral phenotype in adult female Mecp2-heterozygous mouse model of Rett syndrome

Elizabeth Smith Khoury; Ruchit V Patel; Caroline O'Ferrall; Amanda Fowler; Nirnath Sah; Anjali Sharma; Siddharth Gupta; Susanna Scafidi; Joshua S Kurtz; Sarah J Olmstead; Sapna R Kudchadkar; Rangaramanujam M Kannan; Mary E Blue; Sujatha Kannan

doi:10.1111/jnc.15960

Dendrimer nanotherapy targeting of glial dysfunction improves inflammation and neurobehavioral phenotype in adult female Mecp2-heterozygous mouse model of Rett syndrome

J Neurochem. 2023 Sep 30:10.1111/jnc.15960. doi: 10.1111/jnc.15960. Online ahead of print.

Authors

Elizabeth Smith Khoury¹, Ruchit V Patel¹, Caroline O'Ferrall¹, Amanda Fowler¹, Nirnath Sah¹, Anjali Sharma², Siddharth Gupta^{3

4}, Susanna Scafidi¹, Joshua S Kurtz¹, Sarah J Olmstead¹, Sapna R Kudchadkar^{1

5}, Rangaramanujam M Kannan^{2

6}, Mary E Blue^{4

7

8}, Sujatha Kannan^{1

8}

Affiliations

¹ Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
² Center for Nanomedicine, Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
³ Kennedy Krieger Institute, Baltimore, Maryland, USA.
⁴ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
⁵ Departments of Pediatrics and Physical Medicine and Rehabilitation, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
⁶ Departments of Chemical and Biomolecular Engineering, and Materials Science and Engineering, Johns Hopkins University, Baltimore, Maryland, USA.
⁷ Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
⁸ Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland, USA.

PMID: 37777475
PMCID: PMC11002961 (available on 2025-03-30)
DOI: 10.1111/jnc.15960

Abstract

Rett syndrome is an X-linked neurodevelopmental disorder caused by mutation of Mecp2 gene and primarily affects females. Glial cell dysfunction has been implicated in in Rett syndrome (RTT) both in patients and in mouse models of this disorder and can affect synaptogenesis, glial metabolism and inflammation. Here we assessed whether treatment of adult (5-6 months old) symptomatic Mecp2-heterozygous female mice with N-acetyl cysteine conjugated to dendrimer (D-NAC), which is known to target glia and modulate inflammation and oxidative injury, results in improved behavioral phenotype, sleep and glial inflammatory profile. We show that unbiased global metabolomic analysis of the hippocampus and striatum in adult Mecp2-heterozygous mice demonstrates significant differences in lipid metabolism associated with neuroinflammation, providing the rationale for targeting glial inflammation in this model. Our results demonstrate that treatment with D-NAC (10 mg/kg NAC) once weekly is more efficacious than equivalently dosed free NAC in improving the gross neurobehavioral phenotype in symptomatic Mecp2-heterozygous female mice. We also show that D-NAC therapy is significantly better than saline in ameliorating several aspects of the abnormal phenotype including paw clench, mobility, fear memory, REM sleep and epileptiform activity burden. Systemic D-NAC significantly improves microglial proinflammatory cytokine production and is associated with improvements in several aspects of the phenotype including paw clench, mobility, fear memory, and REM sleep, and epileptiform activity burden in comparison to saline-treated Mecp2-hetereozygous mice. Systemic glial-targeted delivery of D-NAC after symptom onset in an older clinically relevant Rett syndrome model shows promise in improving neurobehavioral impairments along with sleep pattern and epileptiform activity burden. These findings argue for the translational value of this approach for treatment of patients with Rett Syndrome.

Keywords: epilepsy; glial dysfunction; microglia targeting; nanomedicine, neurodevelopmental disorders; preclinical studies; sleep dysfunction.

Abstract

Grants and funding