# How Does 3' UTR Secondary Structure Program mRNA Transport in Myelination?

> **NIH NIH R21** · STANFORD UNIVERSITY · 2021 · $432,982

## Abstract

PROJECT SUMMARY
Recent successes in RNA medicine, including the first-in-class Spinraza treatment for spinal muscular atrophy,
demonstrate RNA gain-of-function as a novel therapeutic modality for previously intractable neurological disease
and raise the prospect of similar treatments for demyelinating diseases. Such treatments would target
oligodendrocytes – the myelinating cells of the central nervous system (CNS) – for a novel and specific strategy
for preventative or regenerative RNA medicine. To create myelin, oligodendrocytes extend cell projections that
encircle adjacent axons. These concentrically wrapped layers of cell membrane undergo a process called
compaction to generate mature myelin. Critical to this process is the localization of a subset of the
oligodendrocyte transcriptome to the nascent myelin sheath for local translation. By more than an order of
magnitude, the myelin basic protein (MBP) mRNA is the most highly abundant and most highly transported
protein-coding transcript in oligodendrocytes, and the drug-induced regulation of its expression, processing, and
transport could potentially augment myelination by these cells. Unfortunately, testing the viability of such a
strategy is not currently possible due to a lack of understanding of the RNA molecular and structural biology that
underlies MBP mRNA transport in oligodendrocytes. In partnership with oligodendrocyte biology collaborators,
we have recently begun to address this knowledge gap. We have applied newly invented chemical probing and
RNA sequencing technologies to reveal a previously unappreciated repertoire of secondary structures in the
MBP 3’ untranslated region (3’ UTR, a region that is known to be necessary for MBP mRNA transport) as well
as a catalog of hundreds of other highly transported oligodendrocyte mRNAs. These data suggest features that
may be targeted or mimicked with antisense oligonucleotides (ASOs) to modulate MBP mRNA function but need
to be rigorously tested. Here, we propose to complete this exploratory research by (1) testing the functional
importance of MBP 3’ UTR secondary structures with in-cell mutate-rescue experiments recently invented by our
lab and validating these structure-transport relationships through targeted structure perturbation or stabilization
facilitated by anti-sense oligonucleotides, and (2) designing a minimal transport-inducing 3’ UTR using insights
from high-throughput structure determination and structure-function characterization of all highly transported
transcripts in oligodendrocytes. We will evaluate success in both aims through multiple orthogonal methods,
including next-generation sequencing, biochemical structure determination, and quantitative single-molecule
RNA imaging that we have collaboratively developed for the study of oligodendrocyte projections. The proposed
basic science research establishes a previously missing RNA structural biology foundation needed for the design
and testing of Spinraza-like ASO ther...

## Key facts

- **NIH application ID:** 10288149
- **Project number:** 1R21NS123533-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** John B Zuchero
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $432,982
- **Award type:** 1
- **Project period:** 2021-08-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10288149

## Citation

> US National Institutes of Health, RePORTER application 10288149, How Does 3' UTR Secondary Structure Program mRNA Transport in Myelination? (1R21NS123533-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10288149. Licensed CC0.

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