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MeCP2 reactivation from the inactive X chromosome as treatment for Rett syndrome

Award Number: R01MH134519
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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MeCP2 reactivation from the inactive X chromosome as treatment for Rett syndrome - Project Summary Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder that mainly manifests in girls without effective treatment. RTT is caused by loss-of-function mutations of the Methyl CpG-binding Protein 2 gene (MECP2) on the X chromosome. The majority of RTT patients are females heterozygous for MECP2 mutation, in which random X chromosome inactivation (XCI) during development leaves ~50% of neurons without functional MeCP2 protein, thereby creating cell-autonomous neuronal dysfunction. Corresponding mutations in hemizygous males lead to severe neonatal encephalopathy and early death. Mice carrying null alleles of Mecp2 closely mimic symptoms seen in patients, including irregular breathing, stereotypical limb movements and shortened lifespan, and are thus faithful models of RTT. Male Mecp2-null mice start exhibiting symptoms as early as 30-60 days of age, with only half of the animals surviving beyond 75 days. Heterozygous females have a near-normal lifespan with neurologic deficits that are delayed (~6 months) and highly variable in severity. A major breakthrough in RTT research was the demonstration that RTT-like symptoms in adult mice can be reversed by genetic or viral restoration of MeCP2 protein. Thus, reactivation of the silenced wild type (WT) allele of MECP2 from the inactive X chromosome (Xi) presents an exciting therapeutic opportunity that attacks the root cause of this disease by restoring MeCP2 function. Our preliminary data demonstrate that targeted demethylation of the MECP2 promoter is sufficient to reactivate MECP2 from the Xi in human RTT ESCs and neurons in vitro as well as in vivo in the RTT mouse brain. This was accomplished using a dCas9-Tet1 protein targeted to the MECP2 locus via sgRNA, a DNA methylation editing tool pioneered by Dr. Shawn Liu. We hypothesize that reactivation of MECP2 from the Xi will rescue RTT-associated phenotypes in mice. We have developed two new transgenic mouse models (1,2) and two novel methods of delivery of epigenetic editors (3,4) for MECP2 reactivation in vivo including: 1) Xi-linked Mecp2-NanoLuciferase-tdTomato dual reporter mice, which enables high sensitivity detection and quantification of Mecp2 reactivation; 2) MeCP2-null heterozygous female model of severe RTT with exclusive inactivation of the X-chromosome harboring the WT Mecp2 for measuring reactivation-induced rescue which circumvents evaluating delayed and variable phenotypes in Mecp2 heterozygous with random XCI; 3) Cre recombinase-dependent dCas9-Tet1 transgenic line enables efficient and tissue-specific DNA methylation editing in vivo; and 4) dCasMini-Tet1, in which the bulky dCas9 (4.1 kb) is replaced with a compact dCasMini (1.6 kb) for delivery of a methylation editor via a single AAV9 vector. This combination of transgenic models to measure reactivation efficacy (1) and rescue (2) with those that enable efficient in vivo editing via genetic means (3) and single vector AAV9-mediated delivery (4) comprise a state-of- the-art tool kit to evaluate the in vivo feasibility of a MECP2 reactivation strategy for treatment of RTT and other X-linked disorders in females.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $797,991 )
2025	2025	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	000	3	8/27/2025	NON-COMPETING CONTINUATION	$797,991
														Subtotal = $797,991

Issue Date FY: 2024 ( Subtotal = $809,324 )
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	000	2	6/18/2024	NON-COMPETING CONTINUATION	$809,324
														Subtotal = $809,324

Issue Date FY: 2023 ( Subtotal = $848,974 )
2023	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	000	1	9/15/2023	NEW	$848,974
														Subtotal = $848,974

Grand Total All Awards = $2,456,289

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MeCP2 reactivation from the inactive X chromosome as treatment for Rett syndrome

Award Number: R01MH134519

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/15/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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