Prenatal Intravenous Gene Transfer With an AAV9 Vector Expressing Human Beta-galactosidase in Type I and Type II GM1 Gangliosidosis Clinical Trial

A Phase I Study of Prenatal Intravenous Gene Transfer With an AAV9 Vector Expressing Human Beta-galactosidase in Type I and Type II GM1 Gangliosidosis

This is a study for the administration of in utero AAV9 transfer in prenatally diagnosed Type I or Type II GM1.

Study Overview

• Status: Not yet recruiting
• Conditions: GM1 Gangliosidoses; GM1 Gangliosidosis, Type I; GM1 Gangliosidosis, Type 2
• Intervention / Treatment: Drug: Gene Transfer with an AAV9 Vector Expressing Human ß-galactosidase

• Study Type: Interventional
• Enrollment (Estimated): 5
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Fetal subject inclusion criteria:

3. Live fetuses at 28 0/7 weeks to 35 6/7 weeks gestation 4. Diagnosis of Type I or Type II GM1 in utero by genetic analyses performed on amniotic fluid, fetal blood, placental tissue, or other samples through chorionic villus sampling (CVS), amniocentesis, or cordocentesis.

1. In the event that parents are identified as genetic carriers of Type I or Type II GM1, diagnostic testing for the fetus would be performed to confirm the diagnosis
2. If the fetal genetic testing confirms known mutations, parental genetic testing would not be necessary to enroll the fetus.
3. If one of the mutations is a variant of unknown significance (VUS), but there is a family history (such as a sibling) with confirmed genetic diagnosis and phenotype of disease, this would fulfill the inclusion criteria.
4. The case must be reviewed and accepted by the enrollment advisory board (EAB) based on available clinical data (including age of onset and disease severity of affected family members), clinical presentation, literature review, available case studies, and available research assays (in addition to molecular testing as above).

Fetal subject exclusion criteria:

1. Fetuses with a concurrent severe structural anomaly, pathogenic genetic diagnosis, or other condition that presents a high risk of fetal mortality.

While all possible congenital or structural anomalies that may be exclusionary cannot be listed, the following will be hard exclusions:

• Cardiac anomaly requiring neonatal surgical intervention

• Esophageal or bowel atresia
• Sacrococcygeal teratomas
• Chromosomal anomalies (e.g. trisomies)
• Other severe genetic conditions that would impact survival early in life (e.g. muscular dystrophy)
• Placental malformation that would impact safety of prenatal intervention (e.g. placental accreta)

Examples of minor issues that would not be exclusionary include minor genetic or structural anomalies that can be readily treated and would not impact long-term survival, such as:

• Hearing loss that could be treated with hearing aids
• Missing digits
• Hypospadias that can be corrected with a routine postnatal surgery

Maternal subject inclusion criteria:

1. Pregnant women age 18 years or older, carrying a live fetus at 28 0/7 weeks to 35 6/7 weeks gestation
2. Identified through the above listed means to be carrying a fetus with GM1 Type I or II
3. Ability to give written informed consent oneself and comply with the requirements of the study

5. Maternal anti-AAV9 antibodies <1:50. 6. Consents to fetal autopsy in the event of fetal demise

Maternal subject exclusion criteria:

4. Pregnant women with one or more significant comorbidities that would preclude fetal intervention including, but not limited to:

1. inability to complete the procedure secondary to maternal body habitus or placental location
2. significant cardiopulmonary disease
3. mirror syndrome
4. end organ failure
5. altered mental status
6. placental abruption
7. active preterm labor
8. preterm premature rupture of membranes. 5. Pregnant women who require therapeutic dosing of anticoagulation within 24 hours prior to or following the intervention.

a. Maternal anti-AAV9 antibodies >1:50

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment; Participants receive investigational product	Drug: Gene Transfer with an AAV9 Vector Expressing Human ß-galactosidase; Prenatal administration of an AAV9 Vector Expressing Human ß-galactosidase

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety	Safety (maternal and fetal): adverse and serious adverse events including, but not limited to, death within 24 hours after the procedure, stillbirth, death prior to initial hospital discharge, and serious related or serious unexpected adverse events exceeding those expected with the natural history of treated disease during the first five years of life. This will also include pregnancy outcome.	5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immunity	Immunity: Assess maternal and neonatal immune responses to the gene transfer vector through measurement of antibody titers to AAV9 serum.	5 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility	Feasibility: successful administration of the full weight-based dose of AAV9 through the fetal umbilical vein and need for halting the intervention prior to administration of a full dose for maternal or fetal indications.	5 years

Collaborators and Investigators

• Sponsor: Tippi Mackenzie

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2027
• Primary Completion (Estimated): June 1, 2039
• Study Completion (Estimated): June 1, 2055

Study Registration Dates

• First Submitted: March 14, 2026
• First Submitted That Met QC Criteria: March 14, 2026
• First Posted (Actual): March 18, 2026

Study Record Updates

• Last Update Posted (Actual): August 31, 2026
• Last Update Submitted That Met QC Criteria: August 26, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Lipid Metabolism Disorders; Lysosomal Storage Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases, Nervous System; Sphingolipidoses; Lipidoses; Gangliosidoses; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Gangliosidosis, GM1; Investigative Techniques; Genetic Techniques; Genetic Engineering
• Other Study ID Numbers: MatFetalAAV-001

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No