GM1 Gangliosidoses, GM1 Gangliosidosis, Type 2, GM1 Gangliosidosis, Type I
Conditions
Brief summary
This is a study for the administration of in utero AAV9 transfer in prenatally diagnosed Type I or Type II GM1.
Interventions
DRUGGene Transfer with an AAV9 Vector Expressing Human ß-galactosidase
Prenatal administration of an AAV9 Vector Expressing Human ß-galactosidase
Sponsors
Tippi Mackenzie
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety | 5 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Immunity | 5 years | Immunity: Assess maternal and neonatal immune responses to the gene transfer vector through measurement of antibody titers to AAV9 serum. |
Outcome results
None listed