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.

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