Gene-editing treatment for phenylketonuria caused by the P281L PAH mutation
Official title: LEAD PROJECT 1: PHENYLKETONURIA (PKU)
Funded at Children's Hosp of Philadelphia · NIH-11145249 · Data updated 2026-11-12
A lipid nanoparticle-delivered adenine base editor to correct the P281L PAH mutation in people with phenylketonuria.
Quick facts
| Grant type | NIH-funded research |
|---|---|
| Study type | NIH-funded research |
| Funding institution | Children's Hosp of Philadelphia NIH-funded |
| Lab location | 1 site (Philadelphia, United States) |
| Project start | August 1, 2023 |
| Project end | July 31, 2028 |
| Funding year | 2025 |
| Award (this year) | $1,843,290 |
| NIH project number | 5U19NS132301-03 |
| Project ID | NIH-11145249 on NIH RePORTER |
Who could benefit from this research
✓Could help
Ideal candidates are people with classical phenylketonuria who have a confirmed PAH c.842C>T (P281L) mutation and who meet health criteria for an early-phase gene therapy trial.
✕Less likely to help
People with PKU who do not carry the P281L mutation or those with advanced, irreversible neurological damage are unlikely to benefit from this targeted approach.
What this research studies
If you or your child have PKU with the common P281L PAH mutation, this project is developing a one-time gene-editing treatment delivered to the liver using lipid nanoparticles to fix the faulty gene. The team will use an adenine base editor to change the single DNA letter responsible for the mutation without cutting both strands of DNA. Over five years they plan preclinical testing, filing an IND with the FDA, and then starting a Phase 1/2 clinical trial to check safety and effects on blood phenylalanine. The work is intended to lower lifelong dietary restrictions and reduce reliance on daily enzyme injections.
Why it matters
Potential benefit: If successful, the treatment could durably lower blood phenylalanine and reduce or eliminate the need for a strict low-Phe diet or frequent enzyme injections.
How similar studies have gone: Base editing delivered by lipid nanoparticles has shown promising results in preclinical models and early translational work, but correcting PAH P281L in humans is a novel application with limited clinical precedent.
Where this research is happening
-
Children's Hosp of Philadelphia
Philadelphia, United States Active
Researchers
- Principal investigator: Musunuru, Kiran — Children's Hosp of Philadelphia
- Study coordinator: Musunuru, Kiran
Related research
Other NIH-funded projects on the same topics.
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LNP-based adenine base editing for PKU and urea cycle disorders
A front-line, patient-focused research project aims to develop safe gene-editing therapies that could lessen or correct the biochemical problems in PKU and related urea cycle disorders.
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PKU: a new gene-editing treatment for a common PAH mutation
A new therapy using lipid nanoparticles to correct a common PKU mutation could reduce the need for strict diets and dangerous enzyme injections.
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A new gene-editing approach to treat phenylketonuria (PKU)
A medical research project is testing a gene-editing strategy using AAV-delivered CRISPR tools to correct PAH gene defects in PKU patients.
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Phenylalanine and brain function in PKU carriers and non-carriers
We’re exploring how a single elevated nutrient (phenylalanine) affects thinking and brain function in adults who carry a PKU gene variant compared with those who don’t.
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Using gene editing to treat phenylketonuria
This study is exploring a new way to use gene editing to help people with phenylketonuria (PKU) by fixing the genetic issues that cause the condition, aiming to offer a better treatment than the current strict diets and medications.
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Investigating how elevated phenylalanine affects brain and cognitive function in adults who carry the PKU gene.
This study is looking at how higher levels of phenylalanine (Phe) might affect thinking and brain function in adults who carry the PKU gene but don’t have the condition, to help us understand if they might face any challenges related to Phe.
About this research
- This is an active NIH-funded research project — typically early-stage science, not a clinical trial accepting patient enrollment.
- Some NIH-funded labs run parallel clinical studies or seek volunteers for related work. To check, contact the principal investigator or institution listed above.
- For full project details, budget, and progress reports, visit the official NIH RePORTER page.