# Targeted Therapies for Rett Syndrome

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $400,082

## Abstract

PROJECT SUMMARY
Immune dysregulation in the brain and disruption of glutamate neurotransmission, both mediated by glia, have
been implicated in the pathogenesis and worsening of symptoms in Rett syndrome (RTT), a debilitating,
developmental disorder that is associated with seizures, intellectual disability, motor and autonomic
dysfunction, and non-purposeful hand movements. Microglia and astrocytes appear to mediate the immune
response, oxidative injury and glutamate toxicity in RTT. Therapies targeting these key mechanisms by
modulating the glial responses could have an impact in RTT by arresting the injury and promoting repair and
regeneration. Building on positive preliminary results in the Mecp2 null and Het mice with dendrimer
conjugated antioxidant N-acetyl cysteine (D-NAC), we propose an innovative nanotherapeutic approach to
attenuate/arrest the injury in RTT. Our overall hypothesis is that targeted delivery of a combination of an anti-
inflammatory/anti-oxidant agent, along with a potent glutaminase inhibitor to microglia and astrocytes in
Mecp2-null and Mecp2-heterozygous (HET) mice will lead to decreased oxidative injury and glutamate toxicity
resulting in improved long term neurobehavioral outcomes in Mecp2-null and HET mice and symptom free
survival in Mecp2-null mice. Our preliminary results in RTT demonstrates that (1) systemically administered
dendrimer nanoparticles localize specifically in microglia in the RTT mouse brain but not in the brain of wild
type mice; (2) D-NAC monotherapy administered systemically once a week to symptomatic Mecp2-null mice,
results in significant improvement in neurobehavioral scores at 6-7 weeks of age, while the free drug is not
effective; (3) D-NAC is effective in improving the behavioral phenotype and hippocampal glutathione levels in
HET mice; and (4) glutaminase, the enzyme responsible for glutamate synthesis, is upregulated in MeCP2
deficient microglia and is specifically inhibited by systemically administered dendrimer-glutaminase inhibitor
conjugate. Supported by an R21, we completed D-NAC monotherapy in Mecp2-null and HET mice, and
identified the glutamine antagonist DON (6-Diazo-5-Oxo-L-Norleucine) as a potent glutaminase. DON has
failed clinical trials due to severe toxicity profile. We propose to determine if 1) Systemic treatment with D-DON
results in specific inhibition of microglial glutaminase resulting in improved neurologic outcomes and decreased
glutamate toxicity while eliminating the severe peripheral toxicities of free DON, 2) combination therapy with D-
NAC+D-DON is more effective in improving survival and long-term neurologic outcomes in Mecp2-null and
HET mice, and 3) systemic treatment with D-NAC+D-DON results in improvement in immune response,
oxidative injury and function of Mecp2-null microglia isolated from RTT mouse brains. In vivo effects on
survival (Mecp2-null mice), behavior, respiration, sleep (HET) will be evaluated. If successful, these initial
proof-of-concept s...

## Key facts

- **NIH application ID:** 10132421
- **Project number:** 5R01NS113140-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Sujatha Kannan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $400,082
- **Award type:** 5
- **Project period:** 2019-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10132421

## Citation

> US National Institutes of Health, RePORTER application 10132421, Targeted Therapies for Rett Syndrome (5R01NS113140-03). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10132421. Licensed CC0.

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