Brian Bigger, PhD, Professor of Advanced Therapeutics at the University of Edinburgh, discusses hematopoietic stem cell gene therapy (HSCGT) in patients with mucopolysaccharidosis IIIA (MPS IIIA; Sanfilippo syndrome type A).
MPS IIIA is a genetic neurodegenerative disorder characterized by the inability to break down large sugar molecules called glycosaminoglycans (GAG). Specifically, people with this condition are unable to break down a GAG called heparan sulfate due to mutations in the SGSH gene. Affected individuals can have severe neurological symptoms, including progressive dementia, aggressive behavior, hyperactivity, seizures, deafness, loss of vision, and an inability to sleep for more than a few hours at a time.
This clinical trial is a phase 2/3 study of autologous ex-vivo lentiviral gene therapy (HSCGT) designed to deliver functional SGSH in children with MPS IIIA. A total of five patients under two years of age were enrolled and treated with HSCGT. Following myeloablative conditioning, patients received autologous hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with a lentiviral vector expressing SGSH under the CD11b myeloid promoter. This interim analysis includes all patients at a follow-up of 36-months post-treatment.
All five patients engrafted within 52 days of transplant and there was no evidence of abnormal clonal expansion, leukoproliferation or replication competent lentivirus generation. SGSH enzyme activity in leukocytes, selected lineages and plasma was rapidly observed within one month of transplant and was sustained at 36 months.
SGSH enzyme activity was also present in cerebrospinal fluid (CSF) within or above normal range by six months post-therapy and was sustained at 36 months. Accumulated heparan sulphate at baseline was rapidly reduced in CSF, plasma and urine following transplant, with a normalization of urine glycosaminoglycan ratios.
Improvements were observed in the neurologic phenotype of disease, with four out of five patients continuing to acquire cognitive skills and transitioning from the Bayley to the more advanced, age-appropriate Kaufman assessment tool. Treatment with HSCGT in patients with MPS IIIA resulted in rapid and sustained engraftment, with supraphysiological SGSH activity, HS reduction, and improved neurological outcomes in patients.
To learn more about MPS IIIA and other rare lysosomal storage disorders, visit https://checkrare.com/diseases/lysosomal-storage-disorders/
