ASGCT 2026: GS-100 Gene Therapy Demonstrates Early Activity in NGLY1 Deficiency

Interim findings from the ongoing first-in-human phase 1/2/3 trial of GS-100 (Grace Sciences), an investigational intracerebroventricular (ICV) AAV9 gene therapy for NGLY1 Deficiency, showed early improvements in motor and cognitive function among treated children, alongside a dose-dependent safety profile that informed dose selection for the pivotal portion of the study.¹

Presented at the 2026 American Society of Gene and Cell Therapy (ASGCT) Annual Meeting by Becky Schweighardt, PhD, and colleagues, the analysis included 7 patients treated across 4 dose cohorts in the ongoing open-label study (NCT06199531). Investigators reported that lower and mid-dose regimens demonstrated acceptable tolerability and emerging signs of clinical benefit, while the highest tested dose was discontinued because of immune-mediated adverse events (AEs), including thrombotic microangiopathy (TMA).¹

NGLY1 Deficiency is an ultra-rare neurodevelopmental disorder caused by mutations in the NGLY1 gene, leading to impaired deglycosylation pathways and multisystem disease manifestations that can include developmental delay, movement disorders, seizures, liver dysfunction, and profound motor impairment. Currently, there are no approved therapies for the condition.²

GS-100 is an investigational AAV9-based gene replacement therapy designed to deliver a functional copy of the NGLY1 gene directly into the cerebrospinal fluid via ICV administration. The therapy previously received orphan drug designation and rare pediatric disease designation from the FDA in 2021, followed by fast track designation in 2024 and Regenerative Medicine Advanced Therapy (RMAT) designation earlier this year.²

In the phase 1/2 dose-escalation portion of the trial, investigators treated 7 patients at doses ranging from 4e14 vector genomes (vg) per individual up to 3e15 vg.¹ As of the September 30, 2025, data cutoff, cumulative exposure totaled 309 weeks, with a median follow-up of 45 weeks.

According to investigators, AE frequency increased with higher doses, with 56% of events occurring in the 3e15 vg cohort compared with 26% in the 1e15 vg group and 18% in the lowest-dose cohort. Most AEs were grade 1 or 2, with 1 grade 3 thrombocytopenia event reported at the highest dose. Serious AEs were similarly dose dependent, with 3 occurring in the high-dose cohort, 2 in the mid-dose cohort, and none in the low-dose group.

The highest tested dose was ultimately discontinued after multiple immune-mediated complications, including 2 cases of TMA requiring reactive immunosuppressive treatment. Investigators subsequently evolved the prophylactic immunosuppression regimen over the course of the study, moving from corticosteroids alone to combination prophylaxis with corticosteroids, rituximab, and sirolimus.

Despite these safety findings, investigators reported encouraging efficacy signals among patients treated at the 2 lower dose levels who had reached at least 52 weeks of follow-up. According to the presentation, some of the most severely affected patients demonstrated gains in motor milestones, including the ability to sit, stand, and walk with assistance, alongside improvements in attention and caregiver interaction.¹

“These include gains related to the ability to sit, stand, or walk with assistance and improvements in caregiver interaction and attention following GS-100 treatment,” the company noted in an April 2026 announcement discussing the program’s RMAT designation.²

Based on the interim findings, investigators selected the 1e15 vg dose for the pivotal portion of the phase 1/2/3 study, citing a balance between acceptable safety and observed clinical activity.¹ The ongoing study is expected to enroll 10 total patients with NGLY1 Deficiency.²

The updated findings build on momentum for the broader rare disease gene therapy field, where increasing emphasis has been placed on balancing efficacy with immune-related toxicities associated with systemic and CNS-directed AAV therapies. In particular, TMA has emerged as a recognized class-related safety concern across several high-dose AAV gene therapy programs.³

Outside of GS-100, there remains limited clinical development activity in NGLY1 Deficiency because of the rarity of the disease. The FDA’s START Pilot Program, which accepted GS-100 in 2024, was specifically designed to accelerate development for therapies targeting ultra-rare conditions through enhanced regulatory communication.

In the April 2026 release announcing the RMAT designation, Grace Science co-founder and CEO Matt Wilsey said the designation provided “a clear and potentially streamlined regulatory path forward” for the therapy.² Carolyn Bertozzi, PhD, co-founder and scientific advisory board member at Grace Science, added that GS-100 remains “the first and only treatment option in development specifically for NGLY1 Deficiency.”

REFERENCES
1. Schweighardt B, Landy H, Deck R, et al. Interim safety and efficacy data from a first-in-human Phase 1/2/3 clinical trial for GS-100, an ICV-administered AAV9 gene therapy for NGLY1 Deficiency. Presented at: 2026 American Society of Gene and Cell Therapy Annual Meeting; May 2026.
2. Grace Science. FDA grants RMAT designation to GS-100 for NGLY1 Deficiency. News release. April 2026. Accessed May 2026. https://www.businesswire.com/news/home/20260414519544/en/U.S.-FDA-Grants-RMAT-Designation-to-GS-100-Grace-Sciences-Gene-Therapy-to-Treat-NGLY1-Deficiency
3. Hordeaux J, Hinderer C, Goode T, et al. Toxicology study of intra-cisterna magna adeno-associated virus 9 expressing iduronate-2-sulfatase in rhesus macaques. Mol Ther Methods Clin Dev. 2018;10:79-88. doi:10.1016/j.omtm.2018.06.003