# Molecular Mechanism of long Noncoding RNAs in Phenylketonuria

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $468,169

## Abstract

Research Summary
 The functional roles and molecular mechanisms of non-coding RNAs (lncRNA) in human genetic disease
serve as promising new frontiers for establishing the foundation of future research directions and therapeutic
avenues for disorders that currently lack sufficient treatment options. The inborn metabolic disorder
phenylketonuria (PKU) has been considered to be caused by mutations in the phenylalanine hydroxylase (PAH)
gene, resulting in disruptions to its enzymatic activity and consequent accumulation of phenylalanine in the blood.
Our preliminary data demonstrated that the human lncRNA HULC is functionally conserved with mouse lncRNA
Pair. PKU patients harbor genomic variants of the HULC gene. Knockout of Pair leads to hypo-pigmentation,
growth retardation, progressive neurological symptoms, and seizures, which faithfully models human PKU.
Deletion of HULC in primary human hepatocytes leads to elevated cellular Phenylalanine, suggesting the
functional importance of HULC/Pair in PKU. We defined the RNA motifs of both HULC and Pair that are integral
to establishing lncRNA-enzyme interactions and designed peptide-tagged lncRNA mimics that restored the
enzymatic activity of PAH. Administration of HULC mimics in PKU mouse model successfully alleviated excess
phenylalanine levels in serum, providing mechanistic insight into the basis of inherited genetic diseases. The
proposed study seeks to establish long non-coding RNAs as important players in the initiation and progression
of inborn metabolic disorders and develop a lncRNA-based innovative approach for determining new strategies
to tackle the molecular basis of PKU.
 The central hypothesis is that the genetic mutation and deletion of lncRNA results in the enzymatic
deficiency of PAH, which could be alleviated through targeting therapies to enhance the protein stability and
enzymatic activity of PAH. Using iPS-differentiated hepatocytes derived from PKU patients, we will first
demonstrate the biological significance of HULC in the development and progression of PKU by addressing the
impact of common HULC mutations and assessing the correlations between mutations or deletions of HULC and
PKU symptoms. We will then elucidate the molecular mechanisms of lncRNA-mediated regulation of PAH
enzymatic activity. Finally, we will use the administration of liver-enriched lncRNA mimics and small molecule
agonists/antagonists to establish their mechanistic role in restoring impaired enzymatic function.
 The aforementioned research aims will not only elucidate the roles of lncRNAs in metabolic disorders,
but also illustrate the potential therapeutic value of lncRNA mimics and small molecule inhibitor-based medicine
in treating inborn genetic diseases. We anticipate that the results of this study will shift the current research and
clinical paradigm to incorporate the physiological and pathological aspects of non-coding genes and pave the
way for the development of future lncRNA-based medicines.

## Key facts

- **NIH application ID:** 10824287
- **Project number:** 5R01HD110520-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** VERNON R SUTTON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $468,169
- **Award type:** 5
- **Project period:** 2023-04-10 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10824287

## Citation

> US National Institutes of Health, RePORTER application 10824287, Molecular Mechanism of long Noncoding RNAs in Phenylketonuria (5R01HD110520-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10824287. Licensed CC0.

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