First Clinical Trial for NGLY1 Deficiency Coming to Evaluate New Gene Therapy


The trial will follow a phase 1/2/3 design and will evaluate GS-100 in pediatric patients with NGLY1 deficiency.

Carolyn Bertozzi, PhD

Carolyn Bertozzi, PhD

The FDA has granted investigational new drug (IND) clearance to Grace Science’s adeno-associated virus (AAV) vector (AAV9) gene therapy, GS-100, to be evaluated in people with NGLY1 deficiency.1

NGLY1 deficiency is due to recessive mutations in the NGLY1 gene. People with the congenital disease experience global developmental delay, cognitive impairment, hypoalacrima, movement disorders, and other neurological symptoms.

“We are thrilled to obtain FDA clearance to advance GS-100 into the clinic and are excited about the prospect of what this new treatment may mean for NGLY1 Deficiency patients and families,” Carolyn Bertozzi, PhD, the cofounder of Grace Science as well as the Anne T. and Robert M. Bass Professor of Chemistry and Professor of Chemical & Systems Biology and Radiology (by courtesy) at Stanford University, and an investigator of the Howard Hughes Medical Institute, said in a statement.1 “This is an important milestone for NGLY1 Deficiency families, as well as for our company. This is the first Grace Science program to receive FDA clearance to enter the clinic and the first gene therapy clinical trial for NGLY1 Deficiency.”

READ MORE: University of Manchester Launches MPS II Gene Therapy Trial, Picking Up Where AVROBIO Left Off

The single-protocol trial, which Grace Science plans to soon initiate, will be a single-arm, open-label, dose-finding phase 1/2/3 trial that will evaluate the long-term safety and efficacy of GS-100 gene administered by intracerebroventricular (ICV) infusion to pediatric patients with NGLY1 deficiency between 2 and 18 years of age.

“Dr. Bertozzi and I started Grace Science to save lives across the rare disease community — and beyond. We knew that the best way to do that was to approach science and drug development in a different way,” Matt Wilsey, cofounder and chief executive officer, Grace Science, added to the statement.1 “Today’s news is an exciting validation of that approach. We would not be here without the hundreds of people who developed the drug from patients, families, and our incredible partners.”

Clinical Takeaways

  • The FDA has granted IND clearance to Grace Science's AAV gene therapy, GS-100, for evaluation in pediatric patients with NGLY1 deficiency, a congenital disease causing global developmental delay and neurological symptoms.
  • GS-100, a first-in-class gene therapy, delivers the full-length human NGLY1 gene through intracerebroventricular infusion.
  • An upcoming phase 1/2/3 trial will assess its long-term safety and efficacy in patients aged 2 to 18.

GS-100 gene therapy delivers a full-length version of the human NGLY1 gene and has been granted orphan drug designation by the FDA and the European Medicine Agency (EMA), as well as Rare Pediatric Disease Designation by the FDA, with the potential for a Priority Review Voucher.

The therapy is supported by preclinical data showing that ICV administration of GS-100 significantly reduced levels of the substrate biomarker N-acetylglucosamine-asparagine in cerebrospinal fluid and brain tissue compared with untreated rats lacking the NGLY1 gene, with treated rats also displaying behavioral improvements in rotarod and rearing tests.2 The study, published in late 2022, also supported the use of GNA7 as a biomarker of efficacy in evaluating disease-modifying activity within NGLY1 deficiency, as it showed consistent negative correlation with hNGLY1 DNA, mRNA, and protein expression in brain tissue.

“Based on these results, additional non-clinical studies using ICV administration are being carried out to explore the optimal dose for potential future clinical studies. The correlation between hNGLY1 protein expression and substantial benefit to Ngly1-/- rats in the absence of related toxicities supports advancement of GS-100 into the clinic,” the study’s authors wrote.2

1. Grace Science announces FDA clearance of investigational new drug (IND) application to initiate a phase 1/2/3 trial for the treatment of NGLY1 deficiency with GS-100, an AAV9 NGLY1 gene therapy. News release. November 7, 2023.
2. Zhu L, Tan B, Dwight SS, et al. AAV9-NGLY1 gene replacement therapy improves phenotypic and biomarker endpoints in a rat model of NGLY1 Deficiency. Mol Ther Methods Clin Dev. 2022 (27): 259-271. doi: 10.1016/j.omtm.2022.09.015
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