Gene therapy for children 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

This study is testing a new gene therapy for children aged 2 to 18 with NGLY1 deficiency to see if it can help improve their health and development.

Quick facts

• Phase: PHASE1; PHASE2
• Study type: Interventional
• Enrollment: 6 (estimated)
• Ages: 2 Years to 18 Years
• Sex: All
• Sponsor: Grace Science, LLC (industry)
• Locations: 3 sites (Oakland, California and 2 other locations)
• Trial ID: NCT06199531 on ClinicalTrials.gov

What this trial studies

This is a first-in-human, open-label, dose escalation study assessing the safety and efficacy of a gene replacement therapy for patients aged 2 to 18 with NGLY1 deficiency. The treatment involves a single intracerebroventricular injection of an adeno-associated viral vector carrying the NGLY1 gene. Participants will be monitored for safety and efficacy over a period of 52 weeks, with various outcomes assessed including cerebrospinal fluid biomarkers and developmental milestones. The study aims to provide insights into the potential benefits of gene therapy for this rare genetic condition.

Who should consider this trial

Good fit: Ideal candidates are children aged 2 to 18 with a confirmed diagnosis of NGLY1 deficiency and specific clinical features associated with the condition.

Not a fit: Patients without a documented diagnosis of NGLY1 deficiency or those who do not exhibit the necessary clinical features may not benefit from this study.

Why it matters

Potential benefit: If successful, this gene therapy could significantly improve the quality of life and developmental outcomes for children with NGLY1 deficiency.

How similar studies have performed: While gene therapy is a novel approach for NGLY1 deficiency, similar gene therapy studies for other genetic disorders have shown promising results.

Eligibility criteria

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:

* 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

Where this trial is running

Oakland, California and 2 other locations

• Oakland Children's Hospital (UCSF Benioff) — Oakland, California, United States (RECRUITING)
• Columbia University Irving Medical Center — New York, New York, United States (RECRUITING)
• Texas Children's Hospital (Baylor College of Medicine) — Houston, Texas, United States (RECRUITING)

Study contacts

• Study coordinator: Regina Deck, RN/MSN/CCRP

Conditions: NGLY1 Deficiency, Gene Therapy, Intervention study, Infusions, Intraventricular, Biomarker, Enzyme Replacement Therapy