Gene Therapy for Gangliosidosis

(Imagine-1 Trial)

Recruiting at 10 trial locations

Overseen By Physician Inquiries

Age: < 18

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Gemma Biotherapeutics

Must not be taking: Miglustat, Enzyme replacement

Disqualifiers: Neurocognitive deficit, Seizures, Cardiomyopathy, others

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

Compensation: Varies

Number of Visits: Unknown

26 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial requires that participants stop using miglustat 48 hours before the study and throughout the study. Additionally, enzyme replacement therapy must be stopped at least 5 half-lives before the study and is not allowed during the study.

What data supports the effectiveness of the treatment PBGM01 for gangliosidosis?

Research on similar gene therapies shows promise, as studies in animal models have demonstrated that gene therapy can increase enzyme activity, reduce harmful substance buildup in the brain, and improve motor functions. In particular, a study in cats with a similar condition showed that gene therapy significantly extended their lifespan and improved symptoms. ^{1 2 3 4 5}

What safety data exists for gene therapy treatments like PBGM01 for gangliosidosis?

In studies with animals, a gene therapy similar to PBGM01 showed no severe side effects, although some minor changes were noted in the spinal cord of nonhuman primates. Another study using a different gene therapy for a related condition found it to be relatively non-toxic and well-tolerated, with no severe adverse events. ^{1 2 3 6 7}

How does the treatment PBGM01 differ from other treatments for gangliosidosis?

PBGM01 is a gene therapy that uses an adeno-associated viral vector to deliver a therapeutic gene directly into the brain, which is unique because it targets the root cause of gangliosidosis by restoring the deficient enzyme activity in the central nervous system, unlike other treatments that may not address the underlying genetic defect. ^{1 2 4 6 8}

Research Team

May Orfali, MD

Principal Investigator

Gemma Biotherapeutics

Eligibility Criteria

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.

Inclusion Criteria

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

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

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

Exclusion Criteria

Acute illness requiring hospitalization within 30 days of enrollment, the history must be discussed with the sponsor's medical monitor before allowing the subject to be enrolled.

I have nerve damage in my hands or feet.

My heart muscle is weak (high troponin levels).

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Part 1 of the study involves dose escalation to assess three dose levels of PBGM01 in six independent cohorts

Duration not specified

Multiple visits

Confirmatory Cohorts

Part 2 of the study tests the safety and efficacy of PBGM01 in confirmatory cohorts with a dose chosen based on Part 1 data

2 years

Multiple visits

Safety Extension

A 3-year safety extension to monitor long-term safety of PBGM01

3 years

Multiple visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• PBGM01

Trial Overview 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.

Participant Groups

Group I: Part 2: Expansion Cohort designed to confirm the safety and efficacy of PBGM01 Experimental Treatment 1 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 PBGM01 Experimental Treatment 1 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 PBGM01 Experimental Treatment 1 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 PBGM01 Experimental Treatment 1 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)

Who Is Running the Clinical Trial?

Gemma Biotherapeutics

Lead Sponsor

Passage Bio, Inc.

Lead Sponsor

Trials

6

Recruited

112,000+

Findings from Research

Two pentasaccharide biomarkers, H3N2a and H3N2b, were identified as significantly elevated in patients with GM1 gangliosidosis, with H3N2b being detectable in a cat model and correlating negatively with β-galactosidase activity.

After AAV9 gene therapy treatment, levels of H3N2b decreased in both the cat model and a patient, indicating that this biomarker can effectively reflect the therapeutic efficacy of gene therapy for GM1 gangliosidosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pentasaccharide for monitoring pharmacodynamic response to gene therapy in GM1 gangliosidosis. Kell, P., Sidhu, R., Qian, M., et al.[2023]

LYS-GM101, a gene therapy vector designed to deliver the human GLB1 gene, showed promising efficacy in animal models of GM1 gangliosidosis, correcting the toxic accumulation of GM1 ganglioside in the central nervous system without observable adverse effects.

In nonhuman primates, LYS-GM101 led to a significant increase in β-galactosidase activity in the brain, indicating effective delivery and potential therapeutic benefit, although some asymptomatic adverse changes were noted in sensory pathways, warranting further clinical investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AAVrh10 vector corrects pathology in animal models of GM1 gangliosidosis and achieves widespread distribution in the CNS of nonhuman primates. Hocquemiller, M., Giersch, L., Mei, X., et al.[2022]

Intrathecal delivery of scAAV9 carrying a functional GM2 activator protein gene effectively prevents GM2 ganglioside accumulation in GM2AP-deficient mice, demonstrating its potential as a treatment for AB-variant GM2 gangliosidosis.

The treatment was found to be safe and well-tolerated, with no severe adverse events reported, and it showed dose-dependent efficacy in correcting GM2 accumulation in the central nervous system over a long duration (up to 104 weeks).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biochemical Correction of GM2 Ganglioside Accumulation in AB-Variant GM2 Gangliosidosis. Deschenes, NM., Cheng, C., Ryckman, AE., et al.[2023]

References

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

Hematopoietic stem cell gene therapy ameliorates CNS involvement in murine model of GM1-gangliosidosis. [2022]

2. Netherlands pubmed.ncbi.nlm.nih.gov

A pentasaccharide for monitoring pharmacodynamic response to gene therapy in GM1 gangliosidosis. [2023]

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

GM2 gangliosidosis AB variant: clinical and biochemical studies of a Japanese patient. [2019]

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

Sustained normalization of neurological disease after intracranial gene therapy in a feline model. [2021]

5. Germany pubmed.ncbi.nlm.nih.gov

Modulating action of the new polymorphism L436F detected in the GLB1 gene of a type-II GM1 gangliosidosis patient. [2019]

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

AAVrh10 vector corrects pathology in animal models of GM1 gangliosidosis and achieves widespread distribution in the CNS of nonhuman primates. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Biochemical Correction of GM2 Ganglioside Accumulation in AB-Variant GM2 Gangliosidosis. [2023]

8. Brazil pubmed.ncbi.nlm.nih.gov

Transient high-level expression of beta-galactosidase after transfection of fibroblasts from GM1 gangliosidosis patients with plasmid DNA. [2019]