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

Trial Summary

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.

What data supports the effectiveness of the treatment GS-100, AAV9-NGLY1 gene replacement therapy for NGLY1 Deficiency?

Research in rats with NGLY1 Deficiency showed that the GS-100 treatment improved movement and reduced a specific biomarker in the brain and spinal fluid, suggesting it could be effective for this condition. ^{1 2 3 4 5}

Is the AAV9-NGLY1 gene replacement therapy safe for humans?

The safety of AAV9-NGLY1 gene replacement therapy in humans is not directly addressed in the available research, but adeno-associated virus (AAV) vectors, like those used in this therapy, have shown good safety profiles in other gene therapies. However, there are general safety concerns with AAV-based therapies, such as immune reactions and long-term effects, which are important to consider. ^{1 2 6 7 8}

How is the GS-100 treatment different from other treatments for NGLY1 Deficiency?

GS-100 is unique because it is a gene therapy that uses a virus (AAV9) to deliver a working copy of the NGLY1 gene directly to the brain and spinal cord, which helps improve symptoms in a rat model of NGLY1 Deficiency. Unlike other treatments, it specifically targets the central nervous system and has shown potential in reversing motor dysfunction. ^{1 2 3 5 9}

What is the purpose of this trial?

A non-randomized, open-label, dose escalation study of a single intracerebroventricular (ICV) administration of a gene replacement therapy in subjects who are 2 to 18 years old with NGLY1 Deficiency.

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

AAV9-NGLY1 gene replacement therapy improves phenotypic and biomarker endpoints in a rat model of NGLY1 Deficiency. [2022]

2. England 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. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Reversibility of motor dysfunction in the rat model of NGLY1 deficiency. [2023]

4. England 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. [2022]

5. England 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. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Safety profile of recombinant adeno-associated viral vectors: focus on alipogene tiparvovec (Glybera®). [2014]

7. United States pubmed.ncbi.nlm.nih.gov

Considerations for Preclinical Safety Assessment of Adeno-Associated Virus Gene Therapy Products. [2019]

8. Germany pubmed.ncbi.nlm.nih.gov

Evolving AAV-delivered therapeutics towards ultimate cures. [2022]

9. England 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. [2021]