Study of Safety, Tolerability and Efficacy of PBGM01 in Pediatric Subjects With GM1 Gangliosidosis
This study is a prospective multi-cohort, open-label, dose-escalation assessment of the safety and efficayc of PBGM01, an AAVHu68, intra-cisternal magna delivered gene therapy for the treatment of GM1 gangliosidosis in infants 1-24 months of age.
• All Patients: Documented GM1 gangliosidosis diagnosis based on genotyping confirming 2 mutations in the GLB1 gene and documented deficiency of beta-galactosidase enzyme by laboratory testing
• Age: 4 to 36 months (first cohort will be 12-36 months) Subjects:
• Early onset infantile (Type 1): Subjects who have signs and/or symptoms of GM1 gangliosidosis that started at or before 6 months of age and have specific developmental milestones remaining
• Late onset infantile (Type 2a): Subjects who have signs and/or symptoms of GM1 gangliosidosis that started between 6 and 18 months of age and have specific developmental milestones remaining
• Any clinically significant neurocognitive deficit not attributable to GM1 gangliosidosis or any other condition that may, in the opinion of the investigator, confound interpretation of study results.
• If a subject had an acute illness requiring hospitalization within 30 days of enrollment, the history must be discussed with the sponsor's medical monitor before allowing the subject to be enrolled.
• History of ventilation assisted respiratory support or a need for tracheostomy as a result of their disease.
• Intractable seizure or uncontrolled epilepsy defined as having had an episode of status epilepticus, or seizures requiring hospitalization within 30 days prior to dosing of PBGM01.
• Any contraindication to the ICM administration procedure, including contraindications to fluoroscopic imaging and anesthesia or any condition that would increase the risk of adverse outcomes from the ICM procedure including, but not limited to, the presence of a space occupying lesion causing mass effects or signs of increased intracranial pressure, space occupying lesion in the posterior fossa or foramen magnum, aberrant vascular anatomy such as a large midline posterior inferior cerebellar artery, aberrant venous anatomy such as a large cerebellar vein or occipital sinus, or congenital anatomical abnormalities such as a Chiari malformation.
• Any contraindication to MRI or lumbar puncture (LP).
• Prior gene therapy.
• Use of miglustat within 48 hours prior to dosing of PBGM01. The use of miglustat is prohibited throughout the study.
• Use of enzyme replacement therapy or other investigational therapy within 5 half-lives prior to dosing of PBGM01. The use of enzyme replacement is prohibited throughout the study.
• Receipt of a vaccine within 14 days of dosing.
• Estimate glomerular filtration rate (eGFR) <30 mL/minute based on creatinine
• Coagulopathy (INR > 1.5) or activated partial thromboplastin time [aPTT] > 40 seconds
• Thrombocytopenia (platelet count < 100,000 per μL.
• AST or ALT > 3 times the upper limit of normal (ULN) or total bilirubin > 1.5x ULN
• Cardiomyopathy (screening troponin level above the ULN).
• Peripheral neuropathy
• Medical conditions or laboratory or vital sign abnormalities that would increase risk of complications from intra-cisterna magna injection, anesthesia, fluoroscopy, LP, and/or MRI including temperature over 38°C, oxygen saturation below 95% on room air or baseline oxygen requirement, heart rate or respiratory rate abnormal for age of the subject, abnormal blood pressure for age, or evidence of infection.
• Any condition (e.g., history of any disease, evidence of any current disease, any finding upon physical examination, or any laboratory abnormality) that, in the opinion of the investigator, would put the subject at undue risk during the administration procedure or would interfere with evaluation of PBGM01 or interpretation of subject safety or study results.
GM1 Gangliosidosis, GM1 Gangliosidosis, Type I, GM1 Gangliosidosis, Type 2, Beta-Galactosidase-1 (GLB1) Deficiency
Infantile, Late Infantile, Rare disease, Lysosomal storage disease