# MicroRNA site-blocking oligonucleotides as a novel therapy for neurodevelopmental disorders

> **NIH NIH R21** · UNIVERSITY OF PENNSYLVANIA · 2021 · $474,874

## Abstract

Project Summary
Neuro-developmental disorders (NDD) are often caused by genetic mutations that lead to haploinsufficiency, or
a loss-of-gene function. Mutations that cause haploinsufficiency of neurodevelopmental genes affect over
200,000 births each year, and commonly result in congenital malformations, intellectual disability, epilepsy and
motor and behavioral impairments. While symptomatic treatments exist, for most conditions there are no
treatments that directly correct the reduced levels of the haploinsufficient gene. Recent research by our group
and others has revealed that many NDD-causing genes are normally under active repression by microRNAs,
small, non-coding RNAs that function in gene silencing. This raises the possibility of removing this microRNA
“brake” to increase gene expression and help restore normal function in NDD haploinsufficiency. We hypothesize
that the expression of downregulated genes can be restored through steric-blocking antisense oligonucleotides
(ASO) that specifically disrupt gene repression by microRNAs. Our preliminary data support this hypothesis and
demonstrate that ASOs that prevent a particular microRNA from binding to STXBP1 (a common NDD-causing
gene) robustly upregulate gene and protein expression. We propose a novel pipeline to systematically develop
ASOs to treat genetic NDD. First, we will use bioinformatic and wet lab experimental approaches to identify and
validate microRNAs that potently repress leading NDD-causing genes. Next, we will use a high-throughput
microRNA reporter assays to screen ASOs that can relieve this microRNA-mediated gene repression. Third, we
will take lead ASOs identified from the high-throughput screen and test them on neurons derived from patients
with genetically-defined NDD to determine if they can rescue gene expression and function. Together, this work
will establish pre-clinical efficacy for an ASO-based therapy targeting microRNAs to treat neurodevelopmental
disorders arising from haploinsufficiency, and lay the groundwork for first-in-human applications.

## Key facts

- **NIH application ID:** 10302244
- **Project number:** 1R21NS118280-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Benjamin Lears Prosser
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $474,874
- **Award type:** 1
- **Project period:** 2021-07-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10302244

## Citation

> US National Institutes of Health, RePORTER application 10302244, MicroRNA site-blocking oligonucleotides as a novel therapy for neurodevelopmental disorders (1R21NS118280-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10302244. Licensed CC0.

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