Gene Therapy for NGLY1 Deficiency

Recruiting at 2 trial locations

Overseen By Regina Deck, RN/MSN/CCRP

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Grace Science, LLC

Must be taking: Anti-seizure medications

Disqualifiers: Active malignancy, Diabetes, Uncontrolled epilepsy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

Duration: 1 day

6 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The trial explores a new gene therapy called GS-100 (also known as AAV9-NGLY1 gene replacement therapy) for individuals with NGLY1 Deficiency, a rare condition causing developmental delays, movement disorders, and other issues. The researchers aim to determine if a single dose of this therapy, administered directly into the brain, can improve symptoms. Different groups will receive varying doses to identify the most effective amount. Eligible participants have been diagnosed with NGLY1 Deficiency and experience symptoms like developmental delays or movement issues. As a Phase 1/Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group, offering participants a chance to be among the first to potentially benefit from this innovative therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you have epilepsy and are on anti-seizure medications, you must be on a stable regimen for at least 28 days before joining the trial.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that GS-100, a new gene therapy for NGLY1 Deficiency, underwent animal testing before human trials. These early results suggest that GS-100 could be a promising treatment, with no serious side effects found in these tests.

As this is an early-stage study in humans, the main goal is to assess the safety of GS-100 and how well people tolerate different doses. The trial begins with a low dose, gradually increasing it to observe the body's reaction. This process helps doctors determine the safest dose for treatment. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard of care for NGLY1 deficiency, which primarily involves symptomatic treatments like physical therapy, enzyme replacement, and supportive care, GS-100 offers a new approach by directly addressing the genetic root of the condition. Researchers are excited about GS-100 because it uses gene therapy to potentially correct the underlying genetic defect that causes NGLY1 deficiency. This innovative treatment could revolutionize care by not just managing symptoms but potentially providing a more lasting solution to the disorder.

What evidence suggests that GS-100 might be an effective treatment for NGLY1 Deficiency?

Research shows that GS-100, a type of gene therapy, could help treat NGLY1 Deficiency. In animal studies, GS-100 improved symptoms when researchers delivered it directly into the brain's fluid spaces. This method uses a virus to replace the faulty gene causing the condition. Early results suggest it might address the root cause of NGLY1 Deficiency by restoring normal gene function. This trial will test different doses of GS-100 in separate cohorts, offering hope for those affected by this rare disorder. ^{1 2 3 4 6}

Are You a Good Fit for This Trial?

This trial is for children and teenagers aged 2 to 18 with a rare genetic condition called NGLY1 Deficiency. Participants must meet certain health standards, which are not specified here.

Inclusion Criteria

I am willing and able to follow the study's procedures and requirements.

I have been diagnosed with NGLY1 Deficiency through genetic testing.

I have symptoms like developmental delays, unusual movements, liver issues, dry eyes, or nerve pain.

Exclusion Criteria

I cannot take corticosteroids due to a condition or risk.

I do not have increased brain pressure or conditions that would make brain procedures unsafe.

My liver is not working properly according to recent tests.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single intracerebroventricular (ICV) administration of GS-100 gene therapy

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and efficacy, with assessments at baseline and 52 weeks

52 weeks

Multiple visits (in-person and virtual)

Long-term follow-up

Participants are followed for safety and efficacy for 5 years after treatment

5 years

What Are the Treatments Tested in This Trial?

Interventions

• GS-100

Trial Overview The study tests GS-100 gene therapy given once directly into the brain's ventricles (ICV) to see if it's safe and effective in treating NGLY1 Deficiency. It gradually increases doses among participants.

How Is the Trial Designed?

Group I: Cohort 3a Experimental Treatment 1 Intervention

6-18 years old, then 2-18 years old (High dose GS-100)

Group II: Cohort 2a Experimental Treatment 1 Intervention

13-18 years old, then 2-5 years old (Mid dose GS-100)

Group III: Cohort 1a Experimental Treatment 1 Intervention

13-18 years old, then 6-12 years old (Low dose GS-100)

Who Is Running the Clinical Trial?

Grace Science, LLC

Lead Sponsor

Trials

1

Recruited

6+

Published Research Related to This Trial

GS-100, a gene therapy using an AAV9 vector to deliver the human NGLY1 gene, shows promise as a treatment for NGLY1 Deficiency, significantly reducing harmful biomarker levels in the brain and cerebrospinal fluid of treated rats.

Administration of GS-100 via intracerebroventricular (ICV) injection led to improved behavioral outcomes in tests, indicating its potential efficacy, while intravenous (IV) administration alone did not yield similar benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AAV9-NGLY1 gene replacement therapy improves phenotypic and biomarker endpoints in a rat model of NGLY1 Deficiency. Zhu, L., Tan, B., Dwight, SS., et al.[2022]

NGLY1 deficiency is a rare genetic disorder caused by mutations in the NGLY1 gene, which is crucial for the function of the N-glycanase1 enzyme that helps break down certain proteins in the body.

Researchers created an induced pluripotent stem cell (iPSC) line from a 2-year-old patient with NGLY1 deficiency, providing a valuable model for studying the disease and developing potential treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An induced pluripotent stem cell line (NCATS-CL9075) from a patient carrying compound heterozygote mutations, p.R390P and p.L318P, in the NGLY1 gene. Pradhan, M., Farkhondeh, A., Cheng, YS., et al.[2022]

Researchers successfully created two gene-corrected induced pluripotent stem cell (iPSC) lines from a patient with NGLY1 deficiency, a rare genetic disorder caused by mutations in the NGLY1 gene.

These corrected iPSC lines can serve as valuable controls for studying the disease mechanisms and testing potential therapies for NGLY1 deficiency.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Generation of two gene corrected human isogenic iPSC lines (NCATS-CL6104 and NCATS-CL6105) from a patient line (NCATS-CL6103) carrying a homozygous p.R401X mutation in the NGLY1 gene using CRISPR/Cas9. Pavlinov, I., Farkhondeh, A., Yang, S., et al.[2022]

Researchers created a human induced pluripotent stem cell (iPSC) line from a patient with NGLY1 deficiency, which is caused by mutations in the NGLY1 gene, providing a valuable tool for studying the disease's effects.

This iPSC line can be used to better understand the disease's pathophysiology and to develop potential treatments for NGLY1 deficiency.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Generation of an induced pluripotent stem cell line (TRNDi002-B) from a patient carrying compound heterozygous p.Q208X and p.G310G mutations in the NGLY1 gene. Li, R., Pradhan, M., Xu, M., et al.[2021]

NGLY1 deficiency is a rare genetic disorder caused by mutations in the NGLY1 gene, which is crucial for breaking down certain proteins, highlighting the importance of this gene in cellular function.

Researchers created an induced pluripotent stem cell (iPSC) line from a 16-year-old patient with a specific mutation, providing a valuable model for studying the disease and developing potential treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An induced pluripotent stem cell line (TRNDi010-C) from a patient carrying a homozygous p.R401X mutation in the NGLY1 gene. Yang, S., Cheng, YS., Li, R., et al.[2021]

Alipogene tiparvovec (Glybera) has been approved in Europe as a significant advancement in gene therapy for treating familial lipoprotein lipase deficiency, marking a milestone in the clinical application of gene therapies.

The review highlights important safety considerations for gene therapies using adeno-associated virus (AAV) vectors, including potential acute and immunological reactions, viral distribution, and risks of DNA integration and carcinogenicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety profile of recombinant adeno-associated viral vectors: focus on alipogene tiparvovec (Glybera®). Salmon, F., Grosios, K., Petry, H.[2014]

Recombinant adeno-associated virus (AAV) has emerged as a highly effective and safe vector for gene therapy, with several successful treatments like Glybera, Luxturna, and Zolgensma approved for genetic diseases.

Recent advancements in combining AAV with genome editing tools, such as CRISPR, are expanding treatment possibilities for previously untreatable conditions, although challenges and safety concerns remain in clinical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evolving AAV-delivered therapeutics towards ultimate cures. He, X., Urip, BA., Zhang, Z., et al.[2022]

AAV9 gene therapy delivering human NGLY1 cDNA to the brains of Ngly1-/- rats significantly restored NGLY1 expression and enzymatic activity, indicating a potential therapeutic approach for NGLY1 deficiency.

This treatment effectively normalized motor deficits in the rats, suggesting that targeting the central nervous system could be key in developing therapies for this rare genetic disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reversibility of motor dysfunction in the rat model of NGLY1 deficiency. Asahina, M., Fujinawa, R., Hirayama, H., et al.[2023]

Gene therapy (GT) has the potential to treat and even cure various medical conditions by genetically modifying living cells, primarily using adeno-associated virus (AAV) vectors, which dominate the market.

Despite its promise, AAV-based gene therapy raises unique safety concerns, including the risk of unintended gene expression and long-term effects, highlighting the need for thorough preclinical safety evaluations before human trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Considerations for Preclinical Safety Assessment of Adeno-Associated Virus Gene Therapy Products. Assaf, BT., Whiteley, LO.[2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9593239/

AAV9-NGLY1 gene replacement therapy improves phenotypic ... These data provide evidence that GS-100 could be an effective therapy for NGLY1 Deficiency using the ICV route of administration.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06199531

Safety and Efficacy of GS-100 Gene Therapy in Patients ... This study is a first in human (FIH) open-label, dose escalation study designed to assess the safety and efficacy of administration of an adeno-associated ...

3. clinicaltrials.ucsf.edu clinicaltrials.ucsf.edu/trial/NCT06199531

GS-100 Gene Therapy in Patients With NGLY1 Deficiency Efficacy outcomes will be assessed at baseline and 52 weeks. The co-primary outcomes will be change from baseline in cerebrospinal fluid (CSF) ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S2329050125001196

Preclinical pharmacology and safety studies to support an ... GS-100 is an AAV9 gene replacement therapy for the treatment of N-glycanase 1 (NGLY1) deficiency, an ultra-rare, recessive disorder characterized by ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36320418/

AAV9-NGLY1 gene replacement therapy improves ... These data provide evidence that GS-100 could be an effective therapy for NGLY1 Deficiency using the ICV route of administration.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40687377/

Preclinical pharmacology and safety studies to support an ... GS-100 is an AAV9 gene replacement therapy for the treatment of N-glycanase 1 (NGLY1) deficiency, an ultra-rare, recessive disorder ...