AAV9 Vector Gene Therapy for GM1 Gangliosidosis

Overseen By Cynthia J Tifft, M.D.

Age: < 18

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Human Genome Research Institute (NHGRI)

Must not be taking: Miglustat, Tanganil

Disqualifiers: Cardiac disease, HIV, Hepatitis, others

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

Compensation: Varies

Number of Visits: 5

Duration: 1 week

54 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new gene therapy, AAV9-GLB1, for individuals with GM1 gangliosidosis, a disorder that damages nerve cells and currently lacks treatment. The researchers aim to determine if the gene therapy can help the body produce a crucial enzyme, potentially improving symptoms in those with Type I and Type II GM1. Suitable candidates include those with confirmed GM1 gangliosidosis and enzyme deficiencies, specifically Type I patients with symptoms starting before 6 months old or Type II patients with symptoms starting after their first year. Participants must reside near the study site for at least a month after treatment. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this innovative therapy.

Do I need to stop my current medications for the trial?

The trial does not specify if you need to stop your current medications, but you cannot participate if you have taken certain experimental therapies for GM1 gangliosidosis in the last 60 days. It's best to discuss your current medications with the trial team.

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

Research has shown that the AAV9-GLB1 gene therapy is generally safe and well-tolerated. Data from the first eight patients treated with a similar therapy, PBGM01, showed it was safe, with no serious side effects reported. Early results from other studies also suggest that a single dose of AAV9-GLB1 is safe for patients with GM1 gangliosidosis.

These findings are encouraging, but it is important to remember that this trial is still in its early stages. Early phase trials primarily focus on safety, so participation can help gather more information on how well the therapy is tolerated. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for GM1?

Unlike the standard of care for GM1 gangliosidosis, which primarily focuses on managing symptoms, AAV9-GLB1 is a gene therapy that targets the root cause of the disease. This treatment uses an AAV9 vector to deliver a healthy copy of the GLB1 gene directly to the patient's cells, potentially correcting the enzyme deficiency at the source. Researchers are excited about this approach because it offers the possibility of a one-time treatment that could halt or even reverse disease progression, something current therapies cannot achieve.

What evidence suggests that this gene therapy might be an effective treatment for GM1 gangliosidosis?

Research has shown that AAV9-GLB1 gene therapy could be a promising treatment for GM1 gangliosidosis. This therapy provides a healthy version of the GLB1 gene, which individuals with this disorder lack or have in a faulty form. In this trial, participants will receive varying dosages of the AAV9-GLB1 gene therapy to assess its safety and effectiveness. Early results from patients who received the treatment indicated that it is safe and generally well-tolerated. Initial evidence also suggests that it can improve symptoms by reducing harmful substances that accumulate in the brain. This indicates that AAV9-GLB1 might help manage GM1 gangliosidosis by targeting the disease's underlying cause. ^{1 2 4 6 7}

Who Is on the Research Team?

Cynthia J Tifft, M.D.

Principal Investigator

National Human Genome Research Institute (NHGRI)

Are You a Good Fit for This Trial?

This trial is for children with GM1 gangliosidosis, a fatal nerve cell disorder. Type I participants must be 6-12 months old, while Type II can be older than 12 months but younger than 12 years. They should have specific genetic mutations and low immune responses to AAV9 (antibody titers <=1:50). Participants need to stay near the study site post-treatment and cannot have had previous gene therapy or certain medical conditions.

Inclusion Criteria

I am a child aged 6 months to 12 years with Type II GM1 gangliosidosis, confirmed by tests, and live near the study site.

I am a baby aged 6-12 months with a confirmed diagnosis of Type I GM1 gangliosidosis.

I have a specific genetic mutation, low AAV9 antibody levels, and can stay near the study site for 1 month post-treatment.

Exclusion Criteria

Any prior participation in a study in which a gene therapy vector or stem cell transplantation was administered

Your lab test results show a significant health problem, according to the doctor.

I haven't had chemotherapy, radiotherapy, or immunosuppressive therapy in the last 30 days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (phone survey and medical history)

Baseline Assessment

Participants undergo various baseline tests including blood, urine, heart tests, EEG, MRI scans, and more

8-10 weeks

In-patient stay at NIH

Treatment

Participants receive gene therapy by IV and may stay at NIH for a week to monitor side effects

1 week

In-patient stay at NIH

Follow-up

Participants are monitored for safety and effectiveness after treatment with visits at 3 and 6 months, then every 6 months for 2 years, and a final visit at 3 years

3 years

Multiple visits (4-5 days each)

Extension Study

Participants return to NIH once a year for 2 years for additional tests

2 years

Annual visits

What Are the Treatments Tested in This Trial?

Interventions

• AAV9-GLB1

Trial Overview The trial tests a gene therapy using an AAV9 vector to deliver an enzyme-lacking in GM1 patients. It includes extensive pre-treatment assessments like blood tests, EEGs, MRIs, and cognitive exams. Post-therapy monitoring involves regular check-ups over three years to evaluate the treatment's effectiveness and safety.

How Is the Trial Designed?

Group I: 2 Experimental Treatment 21 Interventions

Following the last Stage 1 subject s 6 months visit, data will be reviewed, and Stage 2 dosing and assessments will be determined. If Stage 2 dosing is to proceed, it will be reflected in a protocol amendment.

Group II: 1 Experimental Treatment 21 Interventions

In Stage 1, up to 6 Type II subjects will receive 1.5E13 vg/kg of the gene transfer agent, up to 6 Type II subjects will receive 4.5E13 vg/kg, and up to 6 Type II subjects will receive 7.5E13 vg/kg of the gene transfer agent. In Stage 1, up to 3 Type I subjects will receive 1.5E13 of the gene transfer agent (Cohort 1) and up to 3 will then receive 4.5E13 of the gene transfer agent (Cohort 2).

Who Is Running the Clinical Trial?

National Human Genome Research Institute (NHGRI)

Lead Sponsor

Trials

273

Recruited

299,000+

Sio Gene Therapies

Industry Sponsor

Trials

4

Recruited

100,000+

Published Research Related to This Trial

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]

AAV9 and AAV-PHP.B vectors were developed to simultaneously deliver HEXA and HEXB genes, showing improved therapeutic efficacy in Sandhoff disease (SD) mice, which could potentially simplify treatment compared to previous methods requiring two separate vectors.

Mice treated with the new AAV constructs exhibited significant reductions in GM2 ganglioside levels, normal motor function, and over a fourfold increase in survival, with some living beyond two years, indicating a promising advance in gene therapy for this fatal disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pronounced Therapeutic Benefit of a Single Bidirectional AAV Vector Administered Systemically in Sandhoff Mice. Lahey, HG., Webber, CJ., Golebiowski, D., et al.[2021]

A single injection of an optimized AAV vector expressing human β-gal into the cerebrospinal fluid of a mouse model for GM1 gangliosidosis significantly increased β-gal activity in the brain.

This treatment not only reduced harmful lysosomal storage lesions but also prevented neurological symptoms and improved survival rates, highlighting its potential as a future therapy for GM1 gangliosidosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Single Injection of an Optimized Adeno-Associated Viral Vector into Cerebrospinal Fluid Corrects Neurological Disease in a Murine Model of GM1 Gangliosidosis. Hinderer, C., Nosratbakhsh, B., Katz, N., et al.[2021]

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]

The study demonstrated that systemic infusion of an adeno-associated virus (AAV) vector delivering β-galactosidase (βGal) significantly reduced GM1-ganglioside levels in the brains and spinal cords of GM1 gangliosidosis mice, leading to improved biochemical outcomes.

AAV9 treatment not only enhanced motor function and behavior in the mice but also extended their median survival to 316-576 days, compared to 250-264 days in untreated controls, indicating a promising therapeutic approach for this severe genetic disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic AAV9 gene transfer in adult GM1 gangliosidosis mice reduces lysosomal storage in CNS and extends lifespan. Weismann, CM., Ferreira, J., Keeler, AM., et al.[2018]

Intravenous administration of an AAV9 vector expressing β-galactosidase significantly increased the lifespan of GM1 gangliosidosis cats from an average of 8 months to 3.5 years, demonstrating a profound improvement in quality of life and neurological function.

The treatment normalized biomarkers in cerebrospinal fluid and urine, reduced ganglioside accumulation, and showed no signs of toxicity or tumorigenesis, indicating that intravenous gene therapy is a safe and effective approach for treating GM1 gangliosidosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous delivery of adeno-associated viral gene therapy in feline GM1 gangliosidosis. Gross, AL., Gray-Edwards, HL., Bebout, CN., et al.[2022]

AAV gene therapy in GM1 gangliosidosis cats led to significant improvements in biomarkers, including partial or full normalization of blood and cerebrospinal fluid (CSF) markers, and preservation of brain architecture after more than 5 years of treatment.

Despite some improvements, the therapy did not completely eliminate epileptiform activity in EEGs, indicating that while gene therapy is beneficial, it may not fully resolve all symptoms of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel Biomarkers of Human GM1 Gangliosidosis Reflect the Clinical Efficacy of Gene Therapy in a Feline Model. Gray-Edwards, HL., Regier, DS., Shirley, JL., et al.[2018]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04713475

NCT04713475 | Study of Safety, Tolerability and Efficacy ... PBGM01 is a gene therapy for GM1 gangliosidosis intended to deliver a functional copy of the GLB1 gene to the brain and peripheral tissues.

2. passagebio.com passagebio.com/investors-and-news/press-releases-and-statements/news-details/2023/Passage-Bio-Announces-Promising-Interim-Clinical-Data-from-First-Eight-Patients-with-GM1-Gangliosidosis-in-Imagine-1-Study/default.aspx

Press Releases and Statements Updated data from the first eight treated patients show that PGBM01 continues to have a favorable safety profile, is well tolerated and shows initial evidence ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40766118/

AAV9 Gene Therapy in GM1 Gangliosidosis Type II - PubMed The primary endpoint was safety after 3 years; secondary and exploratory efficacy outcomes included cerebrospinal fluid (CSF) GM1 ganglioside ...

4. medrxiv.org medrxiv.org/content/10.1101/2025.07.28.25332074v1.full-text

AAV9 Gene Therapy in GM1 Gangliosidosis Type II The primary endpoint was safety after 3 years; secondary and exploratory efficacy outcomes included cerebrospinal fluid (CSF) GM1 ganglioside ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT03952637

NCT03952637 | A Phase 1/2 Study of Intravenous Gene ... This is a non-randomized, Phase 1/2 clinical trial to study the safety and efficacy of a single dose gene transfer vector AAV9/GLB1 (AAV9-GLB1) by intravenous ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S1098360022003112

eP259: A phase 1/2 trial of AXO-AAV-GM1 gene therapy for ... GM1 gangliosidosis is uniformly fatal, and there are no disease-modifying treatments currently available. As this is a monogenic disorder, it is an ideal target ...

7. umassmed.edu umassmed.edu/news/news-archives/2021/11/sio-gene-therapies-reports-positive-interim-data-for-gene-therapy-trial/

Sio Gene Therapies reports positive interim data for gene ... Preclinical studies in murine and a naturally-occurring feline model of GM1 gangliosidosis have supported AXO-AAV-GM1's ability to increase β- ...