Gene Therapy Breakthrough Offers Hope for Children with Rare Brain Disorder Non-Ketotic Hyperglycinemia (Not peer-reviewed)

A team of scientists at the University of Notre Dame has developed a promising gene therapy that could offer life-saving treatment for children with a devastating rare condition known as Non-Ketotic Hyperglycinemia (NKH).

What is NKH?

NKH is a rare and often fatal genetic disorder that affects how the body processes glycine, a naturally occurring amino acid. In healthy people, glycine levels are carefully controlled. But in NKH, mutations in the GLDC gene prevent glycine from being broken down properly, leading to toxic build-up—especially in the brain.

Babies born with the severe form of NKH may experience seizures, breathing difficulties, and coma soon after birth. Many do not survive infancy. Those who do often face lifelong neurological impairments. Current treatments only manage symptoms and must be taken daily in large doses. There is no cure.

The New Breakthrough

In this study, scientists used CRISPR gene editing to create a mouse model with the same genetic mutation that causes NKH in humans. They then treated these mice using a new form of gene therapy, delivering a healthy copy of the GLDC gene into their bodies using a modified virus called AAV9, already known to reach the brain.

With just a single injection, the treated mice experienced:

• 100% survival, compared to nearly 40% death rate in untreated mice
• Restoration of key brain cells called astrocytes, which are normally reduced in NKH
• Reduction in toxic glycine levels in the blood
• Protection against brain shrinkage and neurological symptoms like seizures and sudden death

Importantly, the treatment did not cause brain inflammation, a common concern with gene therapy.

Why It Matters

This is the first time a gene therapy has been shown to reach the brain and reverse symptoms of NKH in an animal model. Since AAV9 is already FDA-approved for other conditions (like spinal muscular atrophy), this approach is especially promising for moving into human trials.

A Glimmer of Hope for Families

NKH is incredibly rare—affecting about 1 in 60,000 births—but for families affected by it, the disease is devastating. This new therapy could offer the first real hope of a long-term, one-time treatment.

The researchers believe that their approach could work even if administered in childhood or adolescence, meaning it might help both newly diagnosed infants and older children living with the disease.

What’s Next?

The next steps will involve:

• Testing safety and effectiveness in larger animal studies
• Preparing for clinical trials in humans

If successful, this gene therapy could be life-changing—not just for NKH, but as a model for treating other rare metabolic brain diseases.

Reference

Published in Biorxiv : Gene therapy prevents disease and death from non-ketotic hyperglycinemia | bioRxiv

Lopez-Ramirez, Alejandro, et al. “Gene Therapy Prevents Disease and Death from Non-Ketotic Hyperglycinemia.” bioRxiv, Cold Spring Harbor Laboratory, 1 Jan. 2025, www.biorxiv.org/content/10.1101/2025.03.26.645560v2.