Safety and Efficacy of GS-100 Gene Therapy in Patients With NGLY1 Deficiency

A Phase 1/2/3 Open-label, Single Arm, Dose-finding Study to Investigate Long-term Safety, Tolerability and Efficacy of GS-100, an Adeno-associated Virus Serotype 9 (AAV9) Vector-mediated Gene Transfer of Human NGLY1, in Patients With NGLY1 Deficiency

A non-randomized, open-label, Phase 1/2/3 study of a single intracerebroventricular (ICV) administration of a gene replacement therapy (GS-100) in participants who are 2 to 18 years old with NGLY1 Deficiency.

Study Overview

• Status: Active, not recruiting
• Conditions: NGLY1 Deficiency
• Intervention / Treatment: Genetic: GS-100

Detailed Description

This study is a first in human (FIH) open-label study designed to assess the safety and efficacy of administration of an adeno-associated viral vector serotype 9 (AAV9) carrying the gene encoding N-glycanase 1 (NGLY1) in subjects ages 2-18 years old with NGLY1 Deficiency. The study treatment is delivered via intracerebroventricular (ICV) injection.

Phase 1/2 is the open-label dose finding part of the study designed to evaluate the safety and preliminary efficacy of GS-100 at 4 different dose levels and to select a safe and efficacious dose for the Phase 3 part of the study. Enrollment of 7 participants in the Phase 1/2 part of the study is complete.

Phase 3 is evaluating the efficacy and safety of GS-100 at the Selected Dose determined in the Phase 1/2 part of the study (Mid dose: 1e15 for 6-18-year-olds, 8.7e14 for 2-5-year-olds). Enrollment of 3 participants in the Phase 3 part of the study is complete.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • Oakland, California, United States, 94609
      • Oakland Children's Hospital (UCSF Benioff)
  • Texas
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital (Baylor College of Medicine)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients must be 2 to 18 years of age, inclusive, at the time of signing the informed consent form (ICF)
• Patients with a documented diagnosis of NGLY1 Deficiency based on detection of biallelic variants in the NGLY1 gene via molecular genetic sequencing
• Elevated GNA levels may be considered alongside genetic sequencing data and other clinical data to assist with diagnosis confirmation

• Patients with two or more of the following clinical features typical of NGLY1 Deficiency:

  1. Global developmental delay and/or intellectual disability
  2. Hyperkinetic movement disorder
  3. Transient elevation of transaminases
  4. (Hypo)alacrima
  5. Peripheral neuropathy
• For patients with epilepsy who require anti-seizure medications for seizure control: must be on a stable regimen for 28 days prior to enrollment
• Patients willing and capable per investigator opinion to comply with study procedures and requirements
• Females of childbearing potential must have a negative serum pregnancy test at screening and must agree to use an acceptable method of highly effective contraception from screening through the end of the study
• Patients or parent(s)/guardian(s) must be willing and able to provide written consent after the nature of the study has been explained and prior to performance of any research-related procedures

Exclusion Criteria:

• For Phase 1/2 only: Patients at Level 5 of both the Gross Motor Function Classification System Expanded and Revised (GMFCS E&R) and the Communication Function Classification System (CFCS) scales as assessed by the investigator
• Contraindication to use of corticosteroids or history of a condition that could worsen with corticosteroid therapy, as assessed, and determined by the investigator

• Signs / symptoms of increased intracranial pressure (ICP), history of space occupying lesion, or ventricular shunt that would preclude ICV procedures or safety assessments

  a. If clinical signs or symptoms of increased ICP are present (such as headache, vomiting, altered mental status), an ophthalmology examination will be performed to assess for papilledema and/or venous pulsations

• Any comorbid medical or behavioral condition that, in the opinion of the investigator, may adversely affect the safety and well-being of the participant during the study, interfere with completion of the study procedures or follow-up, or compound interpretation of the study results

• Vital signs outside age-based normative values:

  1. Blood pressure: values > 99th percentile as cited in the National Heart, Lung and Blood Institute (NHLBI) guidelines for blood pressure levels based on subject's age, height and sex (nhlbi.nih.gov/files/docs/guidelines/child_tbl.pdf)
  2. Temperature: evidence of fever such as body temperature (e.g., orally measured) of 38.0°C (100.3°F)
  3. Respiratory rate in breaths per minute: toddler (1-3 years old): 24-40; preschooler (4-5 years old): 22-34 breaths per minute; school-aged child (6-12 years old): 18-30 breaths per minute; adolescence (13-18 years old): 12-16.
  4. Oxygen saturation on room air < 92%
• Any condition that in the opinion of the investigator or the study medical monitor would prevent the patient from fully complying with the requirements of the study (including the corticosteroid treatment outline in the protocol) and/or would impact or interfere with the evaluation and interpretation of patient safety or efficacy results
• Known allergy or hypersensitivity to the GS-100 investigational product formulation
• Prior treatment with gene therapy
• Treatment with any investigational product (IP) within 30 days or 5 half-lives of the IP, whichever is longer, prior to screening period. For patients who have received a prior investigational product, all ongoing AEs experienced while receiving the investigational product must have been resolved prior to screening for this study
• Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study that does not interfere with the requirements of the current protocol and does not have the potential to impact the evaluation of safety and efficacy of GS-100

• Coagulation dysfunction at screening as defined by the following:

  a. INR: ≥1.4 x Upper Limit of Normal (ULN)

• Any current infection with hepatitis B virus (HBV) as evidenced by as evidenced by positive HBV surface antigen (HBsAg), and/or HBV core antibody (HBcAb) at screening. Isolated HBsAb positivity for HBV vaccination in conjunction with negative confirmatory HBV DNA testing at screening is not exclusionary
• Any prior or current infection with hepatitis C virus (HCV) as evidenced by positive HCV antibody testing and confirmed by positive polymerase chain reaction (PCR) RNA testing at screening

• Any of the following abnormal laboratory values:

  1. Hemoglobin level: < 9 g/dL
  2. Absolute neutrophil count: < 1000 cells/microliter
  3. Platelet count: < 100,000/mm3
  4. Creatinine: > 1.25 x ULN
• Have a major surgery planned during the screening period through 52 weeks following GS-100 infusion, including major dental procedures (e.g., wisdom tooth extraction)
• Pregnant or breastfeeding female patient
• Patients that demonstrate elevated serum adrenocorticotropic hormone (ACTH) 1.5 times the upper limit of normal for the reference range must be referred for consultation with a pediatric endocrinologist to rule out primary adrenal insufficiency prior to being enrolled into the study. Patients may re-screen for participation in the study after medical consultation and / or possible treatment has been initiated to address any adrenal insufficiency

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1; GS-100 Low Dose Level: 4e14 total vector genomes (vg) for 6-18-year-olds (fully enrolled, 2 participants)	Genetic: GS-100; A single intracerebroventricular (ICV) dose of GS-100
Experimental: Cohort 2; GS-100 Mid Dose Level: 1e15 total vector genomes (vg) for 13-18-year-olds, 8.7e14 total vg for 2-5-year-olds (fully enrolled, 2 participants)	Genetic: GS-100; A single intracerebroventricular (ICV) dose of GS-100
Experimental: Cohort 3; GS-100 High Dose Level: 3e15 total vector genomes (vg) for 6-18-year-olds, 2.6e15 vg for 2-5-year-olds (fully enrolled, 2 participants)	Genetic: GS-100; A single intracerebroventricular (ICV) dose of GS-100
Experimental: Cohort 4; GS-100 Intermediate Dose Level: 2e15 total vector genomes (vg) for 6-18-year-olds, 1.75e15 total vg for 2-5-year-olds (fully enrolled, 1 participant)	Genetic: GS-100; A single intracerebroventricular (ICV) dose of GS-100
Experimental: Pivotal Cohort; GS-100 Selected Dose Level: 1e15 total vector genomes (vg) for 6-18-year-olds, 8.7e14 total vg for 2-5-year-olds (fully enrolled, 3 participants)	Genetic: GS-100; A single intracerebroventricular (ICV) dose of GS-100

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1/2 (Dose Finding): Safety and Tolerability of GS-100	Incidence of adverse events (AEs) and serious AEs (SAEs)	Baseline through Week 52
Phase 3 (Pivotal): Efficacy of GS-100 at the Selected Dose	Improvement in one or more domains of the 88-item Gross Motor Function Measure (GMFM-88) from Baseline to Week 52	Baseline through Week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Individual domains of the Bayley Scales of Infant and Toddler Development 4th Ed (BSID-4) for the Cognitive, Language, and Motor scales	Change in total Raw Scores and Growth Score Values (GSVs) will be analyzed. Raw Scores range 0-162; GSVs range 428-559; a higher score reflects a higher level of skill.	Baseline through Week 52
Clinical Global Impression of Change (CGI-C)	Change in value relative to Baseline; range of values is 1-7, with 1 being marked improvement	Baseline through Week 52
Clinical Global Impression of Severity (CGI-S)	Change in value; range of values is 1-7, with 1 being normal/no impairment	Baseline through Week 52
Videotaped movement disorder assessments	Change in movement disorder as captured by videotaped assessment	Baseline through Week 52
Sitting/standing assessment	Change in ability to sit, come to sitting, stand, come to standing, and walk	Baseline through Week 52
Failure to thrive	Change in weight (Z-score)	Baseline through Week 52
Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV)	Change in standard scores; standard scores are based on a mean of 100 and a standard deviation of 15; a higher score reflects a higher level of skill	Baseline through Week 52
Caregiver Global Impression of Change (CaGI-C)	Change in value relative to Baseline; range of values is 1-7, with 1 being marked improvement	Baseline through Week 52
Caregiver Global Impression of Severity (CaGI-S)	Change in value; range from 1-7, with 1 being normal/no impairment	Baseline through Week 52
Nerve conduction velocity (NCV)	Change in peripheral nerve function	Baseline through Week 52
Seizure frequency in subjects with seizures	Change in seizure frequency as measured by seizure diaries	Baseline through Week 52

Collaborators and Investigators

• Sponsor: Grace Science, LLC

Publications and helpful links

General Publications

• Tong S, Ventola P, Frater CH, Klotz J, Phillips JM, Muppidi S, Dwight SS, Mueller WF, Beahm BJ, Wilsey M, Lee KJ. NGLY1 deficiency: a prospective natural history study. Hum Mol Genet. 2023 Sep 5;32(18):2787-2796. doi: 10.1093/hmg/ddad106.
• Stanclift CR, Dwight SS, Lee K, Eijkenboom QL, Wilsey M, Wilsey K, Kobayashi ES, Tong S, Bainbridge MN. NGLY1 deficiency: estimated incidence, clinical features, and genotypic spectrum from the NGLY1 Registry. Orphanet J Rare Dis. 2022 Dec 17;17(1):440. doi: 10.1186/s13023-022-02592-3.
• Levy RJ, Frater CH, Gallentine WB, Phillips JM, Ruzhnikov MR. Delineating the epilepsy phenotype of NGLY1 deficiency. J Inherit Metab Dis. 2022 May;45(3):571-583. doi: 10.1002/jimd.12494. Epub 2022 Mar 11.
• Zhu L, Cook JW, Newton A, Dwight SS, Beahm B, Wilsey M, Mueller WF, Schweighardt B. Preclinical pharmacology and safety studies to support an AAV9 NGLY1 gene therapy clinical trial for the treatment of NGLY1 deficiency. Mol Ther Methods Clin Dev. 2025 Jun 25;33(3):101524. doi: 10.1016/j.omtm.2025.101524. eCollection 2025 Sep 11.

Study record dates

Study Major Dates

• Study Start (Actual): February 13, 2024
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): March 1, 2031

Study Registration Dates

• First Submitted: November 21, 2023
• First Submitted That Met QC Criteria: December 29, 2023
• First Posted (Actual): January 10, 2024

Study Record Updates

• Last Update Posted (Actual): May 4, 2026
• Last Update Submitted That Met QC Criteria: April 28, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Gene Therapy; Enzyme Replacement Therapy; Intervention study; Infusions, Intraventricular
• Additional Relevant MeSH Terms: Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Carbohydrate Metabolism, Inborn Errors; NGLY1 deficiency; d-limonene-medium-chain monoglyceride
• Other Study ID Numbers: GS-100-A301

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No