What side effects are associated with this type of intervention?

Gene therapy treatments for GM1 gangliosidosis, such as PBGM01, can have side effects including immune reactions, where the body may attack the introduced gene or vector, causing inflammation or other immune responses. There can also be off-target effects, potentially causing mutations or disrupting other genes. Short-term side effects may include fever, headache, and injection site reactions.

What prior FDA approvals exist?

As of now, there are no specific FDA-approved gene therapies for GM1 Gangliosidosis that deliver a functional GLB1 gene to restore beta-galactosidase enzyme activity. PBGM01 is currently being studied for its safety, tolerability, and efficacy in treating GM1 Gangliosidosis by delivering a functional copy of the GLB1 gene to the brain and peripheral tissues. This represents a novel approach in the treatment landscape for this condition.

What other types of research exist?

Promising alternatives to PBGM01 for GM1 Gangliosidosis include: 1) Enzyme replacement therapy (ERT) with recombinant human beta-galactosidase, which aims to supplement the deficient enzyme directly. 2) Substrate reduction therapy (SRT) using small molecules to reduce the accumulation of GM1 gangliosides. 3) Other gene therapies under investigation that deliver functional copies of the GLB1 gene or use CRISPR/Cas9 technology for gene editing. These approaches are in various stages of research and clinical trials, showing potential for treating GM1 Gangliosidosis.

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Gene Therapy

Gene Therapy for Gangliosidosis (Imagine-1 Trial)

Q: What is the mechanism of action of this treatment?

Gene therapy, such as PBGM01, aims to treat GM1 Gangliosidosis by delivering a functional copy of the GLB1 gene to the brain and peripheral tissues. This gene encodes the enzyme beta-galactosidase, which is deficient in GM1 Gangliosidosis patients. By restoring the activity of this enzyme, gene therapy can potentially halt or reverse the accumulation of GM1 gangliosides in cells, which is the primary cause of the neurodegenerative symptoms seen in this disorder. This approach is significant because it addresses the root cause of the disease at a genetic level, offering the potential for long-term therapeutic effects and improved quality of life for patients.

Phase 1 & 2

Waitlist Available

Research Sponsored by Passage Bio, Inc.

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Early onset infantile (Type 1) must be ≥1 month and <12 months of age at enrollment and have signs and/or symptoms of GM1 gangliosidosis that started before 6 months of age with specific minimum developmental milestones remaining.

Late onset infantile (Type 2a) must be ≥6 months and ≤24 months of age at enrollment and have signs and/or symptoms of GM1 gangliosidosis that started between 6 and 18 months of age with specific minimum developmental milestones remaining including the ability to sit independently at screening as defined by the WHO Multicenter Growth Reference Study (WHO-MGRS) criteria of being able to sit up unsupported with head erect for at least 10 seconds.

Must not have

Peripheral neuropathy

Cardiomyopathy (screening troponin level above the ULN).

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 5 years (multiple visits)

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing PBGM01, a gene therapy designed to treat GM1 gangliosidosis by delivering a healthy copy of a gene to the brain. It targets young children with severe forms of the disease who lack an important enzyme. The therapy uses a harmless virus to carry the gene, aiming to help their bodies produce the missing enzyme. This approach has shown success in animal models for treating GM1 gangliosidosis.

Who is the study for?

This trial is for children with GM1 gangliosidosis, a genetic disorder. Infants (Type 1) must be 1-12 months old with symptoms starting before 6 months and meet certain developmental milestones. Older infants (Type 2a), aged 6-24 months, should show symptoms between 6-18 months and can sit independently. Participants cannot have had recent vaccines, gene therapy, or certain medical conditions that could affect the study.

What is being tested?

The trial tests PBGM01, a gene therapy aimed at delivering a functional GLB1 gene to brain and peripheral tissues of kids with Type 1 or Type 2a GM1 gangliosidosis. It's designed in two parts to evaluate safety, tolerability and effectiveness of this treatment.

What are the potential side effects?

While specific side effects are not listed here, potential risks may include reactions related to gene therapy such as immune response to the introduced genes or complications from delivery methods like injection into the spine.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My infant is 1-11 months old with early signs of GM1 gangliosidosis noted before 6 months.

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My child is 6-24 months old, showed GM1 gangliosidosis symptoms between 6-18 months, and can sit up alone.

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I have GM1 gangliosidosis confirmed by genetic testing and enzyme deficiency.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have nerve damage in my hands or feet.

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My heart muscle is weak (high troponin levels).

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I have not taken miglustat in the last 48 hours and will not take it during the study.

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My kidney function is low, with an eGFR under 30 mL/min.

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I don't have health issues that would make certain medical procedures risky.

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I have undergone gene therapy before.

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I haven't used enzyme therapy or experimental treatments recently.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 5 years (multiple visits)

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 5 years (multiple visits)

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 5 years (multiple visits) for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Change from Baseline in Developmental Milestones as Assessed by the Bayley Scale of Infant and Toddler Development, Third Edition

Number of Participants with Treatment Related AEs and SAEs as Characterized by CTCAEv5.0

Secondary study objectives

Change from Baseline in Developmental Milestones as Assessed by the Vineland Adaptive Behavior Scale-II

Change in Baseline in Biomarkers of Beta-Galactosidase Activity in Blood and CSF

Change in Baseline in Biomarkers of Beta-Galactosidase Substrates in Blood and CSF

+4 more

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

4Treatment groups

Experimental Treatment

Group I: Part 2: Expansion Cohort designed to confirm the safety and efficacy of PBGM01Experimental Treatment1 Intervention

Confirmatory Cohorts: Late Onset Infantile GM1 Gangliosidosis (Type 2a) and Early Onset Infantile GM1 Gangliosidosis (Type 1) Assigned Intervention: PBGM01 Single dose of PBGM01, via intra cisterna magna Dose to be determined

Group II: Part 1: Dose III of Dose Escalation Cohorts designed to identify the optimal dose of PBGM01Experimental Treatment1 Intervention

Assigned Intervention: PBGM01 Dose III: 2.2 x 10\^11 GC/g estimated brain weight, single dose of PBGM01 via intra cisterna magna in Late Onset Infantile GM1 Gangliosidosis (Type 2a) and Early Onset Infantile GM1 Gangliosidosis (Type 1)

Group III: Part 1: Dose II of Dose Escalation Cohorts designed to identify the optimal dose of PBGM01Experimental Treatment1 Intervention

Assigned Intervention: PBGM01 Dose II: 1.1 x 10\^11 GC/g estimated brain weight, single dose of PBGM01 via intra cisterna magna in Late Onset Infantile GM1 Gangliosidosis (Type 2a) and Early Onset Infantile GM1 Gangliosidosis (Type 1)

Group IV: Part 1: Dose I of Dose Escalation Cohorts designed to identify the optimal dose of PBGM01Experimental Treatment1 Intervention

Assigned Intervention: PBGM01 Dose I: 3.3 x 10\^10 GC/g estimated brain weight, single dose of PBGM01 via intra cisterna magna in Late Onset Infantile GM1 Gangliosidosis (Type 2a) and Early Onset Infantile GM1 Gangliosidosis (Type 1)

0 / 10Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Gene therapy, such as PBGM01, aims to treat GM1 Gangliosidosis by delivering a functional copy of the GLB1 gene to the brain and peripheral tissues. This gene encodes the enzyme beta-galactosidase, which is deficient in GM1 Gangliosidosis patients. By restoring the activity of this enzyme, gene therapy can potentially halt or reverse the accumulation of GM1 gangliosides in cells, which is the primary cause of the neurodegenerative symptoms seen in this disorder. This approach is significant because it addresses the root cause of the disease at a genetic level, offering the potential for long-term therapeutic effects and improved quality of life for patients.