Brian Bigger, PhD, Professor of Advanced Therapeutics at the University of Edinburgh, discusses the first-in-human experience of autologous hematopoietic stem cell gene therapy (HSCGT) using a novel ex-vivo lentiviral (LV) platform to correct mucopolysaccharidosis II (MPS II).
MPS II is an inherited disorder of carbohydrate metabolism that occurs almost exclusively in males. It is caused by genetic changes in the IDS gene, leading to the accumulation of glycosaminoglycans (GAG), causing cellular dysfunction. Signs and symptoms include distinctive facial features, a large head, hydrocephalus, hepatosplenomegaly, umbilical or inguinal hernia, and hearing loss. Individuals with this condition may additionally have joint deformities and heart abnormalities involving the valves.
The goal of this study was to examine the first-in-human experience of autologous HSCGT using a novel ex-vivo LV platform to potentially correct MPS II as part of a phase 1/2 clinical trial (NCT05665166).
CD34+ cells were collected via leukapheresis. CD34+ hematopoietic stem cells were then transduced ex-vivo using a lentiviral vector containing the human IDS gene tagged with ApoEII driven by a human CD11b myeloid-specific promoter, allowing IDS to cross the blood-brain barrier. Following quality control, gene-modified cells were transplanted after busulfan-based conditioning.
Four patients have been recruited with one product infusion and three leukaphereses performed at the time of the data being presented at WORLDSymposium 2026. The first patient is over six months post-HSCGT with full engraftment of a drug product with vector copy number over two. At one month post-treatment, enzyme activity analysis shows supraphysiological activity in leucocytes, plasma and bone marrow. At 6-month post-treatment, sustained supraphysiological IDS activity in plasma, leucocytes and BM and normal urinary GAG levels were observed. CSF IDS activity was measurable by one month and is within the normal range at six months. By three months, corresponding substrate reduction with normalization of urinary GAG levels was observed.
Three serious adverse events have been recorded to date. Of these, one was unrelated to HSCGT (central line-related pyrexia) and two had unclear relationship to the HSCGT. A transient dip in both platelet and neutrophil count was noted at day 29 and 43 respectively, these resolved with G-CSF alone.
Dr. Bigger discusses next steps for this therapy including studying patients for 24 months and continuing to look at outcomes for effectiveness. He notes that the early results have been encouraging so far and patients are doing well.
To learn more about MPS II and other rare lysosomal storage disorders, visit https://checkrare.com/diseases/lysosomal-storage-disorders/
