Prenatal AAV9 gene replacement therapy for patients with severe infantile GM1 gangliosidosis

Prenatal surgeries to treat anatomic malformations have been life-changing for thousands of patients and their availability continues to expand. The field now includes molecular therapies to treat patients with severe, early-onset genetic conditions such as in utero enzyme replacement therapy (IUERT) for early- onset lysosomal storage disorders (LSDs). While such medical therapies are not yet curative, they have demonstrated the feasibility of diagnosing genetic conditions early enough to intervene and the technical safety of prenatal infusions into the umbilical vein. As patients with genetic conditions still need definitive cures, developing a prenatal somatic cell gene therapy (PSCGT) that is safe for both the mother and fetus would be transformative. AAV9 gene therapies have been life-saving for children with neurologic conditions like Spinal Muscular Atrophy and appear to have a favorable risk/benefit profile for use in prenatal therapy. While decades of small and large animal preclinical data support the safety and efficacy of prenatal AAV gene therapies, a clinical trial has not been performed. After numerous discussions with scientists, clinicians, patient advocates, ethicists, and the FDA, we think the field is ready to consider an IND application in the right disease setting. GM1 gangliosidosis may be the ideal condition for a first-in-human approach: it is a severe, fatal neurodegenerative LSD resulting from biallelic mutations in the GLB1 gene. Patients suffer from progressive neurodegeneration characterized by spasticity, deafness, blindness, and seizures, and medical care is limited to symptomatic management. There is evidence of prenatal onset of disease, particularly in the two early-onset subtypes: Type I (infantile) and Type IIa (late infantile). An ongoing postnatal phase 1/2 clinical trial of AAV9- GLB1 therapy (PI: Dr. Cynthia Tifft) that has demonstrated excellent safety and partial efficacy, although the benefits are limited due to irreversible damage from demonstrated prenatal onset of disease and even patients treated as infants succumb to disease. We hypothesize that administration of the same AAV9-GLB1 vector in patients with infantile GM1 could improve outcomes. We have submitted a pre-IND application and are now ready to perform IND-enabling studies. In this grant, we will perform a pharmacology/toxicology study of the clinical vector in the prenatal lamb model (Aim 1). We will also develop amniotic fluid assays to detect efficacy of the vector (expression of the GLB1 construct and decreases in disease-specific biomarkers) and to quantify inflammatory markers after prenatal intervention (Aim 2). We will engage with patients to understand their attitudes towards this new treatment protocol (Aim 3). We will also perform regulatory activities, including developing a clinical protocol and internal IRB application, culminating in submission of an IND protocol to start a phase 1 clinical trial in prenatal patients with infantile GM1 gangliosidosis. Successful completion of these aims will provide critical important regarding the safety and feasibility of PSCGT and could enable the development of similar therapies for patients with other severe genetic conditions. Project Number: 1U01NS146166-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Tippi Mackenzie | Institution: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, SAN FRANCISCO, CA | Award Amount: $649,600 | Activity Code: U01 | Study Section: Special Emphasis Panel[ZRG1 NV-G (54)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11281711