Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Targeting MeCP2-Associated Disorders with miRNA Site-Blocking Oligonucleotides

Award Number: F32HD113386
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 05/01/2024
PERIOD OF PERFORMANCE END DATE: 01/06/2026

Group Awards By:

View Award Description

Targeting MeCP2-Associated Disorders with miRNA Site-Blocking Oligonucleotides - PROJECT SUMMARY / ABSTRACT Rett syndrome (RTT) is a neurodevelopmental disorder that results from loss-of-function mutations in a methyl- reader protein known as methyl CpG binding protein 2 (MeCP2); however, despite nearly 20 years of research, only minimal gains have been made in therapeutic development. While no “curative” intervention strategies exist, seminal studies show that RTT can be reversed if MeCP2 levels are restored in mouse models. On the surface, RTT appears to be an ideal candidate for gene therapy; however, MeCP2 is a dose-sensitive gene where even a 1-fold increase in dosage over baseline could result in a related neurodevelopmental disorder known as MeCP2 duplication syndrome (MDS). The practical challenge created by these narrow dosage requirements is that not only does MeCP2 delivery need to be efficient across the entire human brain, but each cell must receive the same, relatively small amount. The 3’untranslated region (UTR) is an essential site for post-transcriptional mRNA regulation where dozens of microRNAs (miRNA) and RNA binding proteins additively contribute to fine-tuning gene expression. The impact of each miRNA on protein levels is generally modest, making strategies that disrupt miRNA regulation of the 3’UTR potentially valuable tools for disorders where the therapeutic window of the target gene is narrow. The repressive role of miRNAs on MeCP2 expression has been reproducibly shown at multiple sites and when overexpressed and this strategy can reverse MDS symptoms in mice; however, the therapeutic potential in RTT remains understudied. Here we developed a novel strategy that uses a series of locked nucleic acid (LNA) site-blocking antisense oligonucleotides (sbASOs) designed to “out-compete” endogenous miRNAs for 3’UTR binding and increase / de-repress MeCP2 expression in a manner that is capped at sub-toxic levels. We anticipate that this strategy could be a viable intervention strategy for patients with missense and late-truncating MeCP2 mutations, where the partial loss of function can be offset by increased abundance. In Aim 1, we will conduct dose-response studies using patient fibroblasts and iPSC-derived neurons with common MeCP2 mutations to determine which subpopulations are responsive. In Aim 2, we will optimize sbASO delivery in vivo to female Mecp2T158M/+ mice to establish their capacity to 1) reverse RTT-like symptoms and 2) avoid MDS-like adverse effects. These experiments will establish proof of concept for the use of site-blocking ASOs in RTT and thereby provide a foundation to support formal development campaigns. This proposal will provide training in RNA therapeutics, iPSC modeling of disease, and mouse genetics, which represent three research focus areas that I have identified as critical for my career development. My mentors and I have developed a training plan composed of didactic and technical training to prepare me for an independent career in academic research.


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: 2026 ( Subtotal = -$20,788 )
2026	2025	LOYOLA UNIVERSITY OF CHICAGO	2160 S 1ST AVE	MAYWOOD	IL	60153	COOK	USA	Child Health and Human Development Extramural Research	000	2	1/15/2026	NON-COMPETING CONTINUATION	-$20,788
														Subtotal = -$20,788

Issue Date FY: 2025 ( Subtotal = $80,440 )
2025	2025	LOYOLA UNIVERSITY OF CHICAGO	2160 S 1ST AVE	MAYWOOD	IL	60153	COOK	USA	Child Health and Human Development Extramural Research	000	2	4/10/2025	NON-COMPETING CONTINUATION	$79,156
2025	2025	LOYOLA UNIVERSITY OF CHICAGO	2160 S 1ST AVE	MAYWOOD	IL	60153	COOK	USA	Child Health and Human Development Extramural Research	001	2	6/16/2025	NON-COMPETING CONTINUATION	$1,284
														Subtotal = $80,440

Issue Date FY: 2024 ( Subtotal = $76,684 )
2024	2024	LOYOLA UNIVERSITY OF CHICAGO	2160 S 1ST AVE	MAYWOOD	IL	60153	COOK	USA	Child Health and Human Development Extramural Research	001	1	5/10/2024	NEW	$0
2024	2024	LOYOLA UNIVERSITY OF CHICAGO	2160 S 1ST AVE	MAYWOOD	IL	60153	COOK	USA	Child Health and Human Development Extramural Research	000	1	5/10/2024	NEW	$76,684
														Subtotal = $76,684

Grand Total All Awards = $136,336

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Targeting MeCP2-Associated Disorders with miRNA Site-Blocking Oligonucleotides

Award Number: F32HD113386

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 05/01/2024

PERIOD OF PERFORMANCE END DATE: 01/06/2026

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer