Orchard Therapeutics: Clinical Study on Gene Therapy With Modified Autologous Hematopoietic Stem Cells for Patients With Mucopolysaccharidosis Type IIIA
Mucopolysaccharidosis type IIIA (MPS-IIIA, also known as Sanfilippo syndrome type A) is a rare and life-threatening metabolic disease. People with MPS-IIIA are born with a mutation in the N-sulphoglucosamine sulphohydrolase (SGSH) gene, which, when healthy, helps the body break down sugar molecules called mucopolysaccharides, including heparan sulfate. The buildup of mucopolysaccharides in the brain and other tissues leads to intellectual disability and loss of motor function. MPS-IIIA occurs in approximately one in every 100,000 live births. Life expectancy of children born with MPS-IIIA is estimated to be between 10-25 years.
This study will be the first in human clinical trial to explore the safety, tolerability and clinical efficacy of ex vivo gene therapy (autologous CD34+ cells transduced with a lentiviral vector containing the human SGSH gene) in MPSIIIA patients. Following treatment with the gene therapy patients will be followed up for a minimum of 3 years.
University of Manchester
CTI Clinical Trial and Consulting Services
University College, London
Great Ormond Street Hospital for Children NHS Foundation Trust
Manchester University NHS Foundation Trust
Study Type: Interventional (Clinical Trial)
Estimated Enrollment: 5 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I-II, Study of Autologous CD34+ Haematopoietic Stem Cells Transduced ex Vivo With CD11b Lentiviral Vector Encoding for Human SGSH in Patients With Mucopolysaccharidosis Type IIIA (MPS IIIa, Sanfilippo Syndrome Type A)
Autologous CD34+ haematopoietic stem cells from MPS IIIA patients will be genetically modified ex vivo using CD11b.SGSH Lentiviral vector (LV), a self-inactivating LV expressing the SGSH gene codon optimized for human use and regulated by a human CD11b myeloid-specific promoter. Cells will be cryopreserved prior to patient administration.
Primary Outcome Measures:
- To evaluate the tolerability of the IMP in MPS IIIA patients: scale [ Time Frame: up to 3 years ]. Adverse events will be recorded and graded according to an adapted Pediatric Clinical Toxicity Scale from the National Institute Allergy and Infectious Diseases (NIAID), Autoimmuno-deficiency Syndrome (AIDS) Division
- To evaluate the biological efficacy of IMP post-treatment: expression of SGSH in total leukocytes [ Time Frame: 12 months post gene therapy ]. Measured by the expression of SGSH in total leukocytes within or above normal range at 12 months post-IMP treatment
- To assess the safety of the IMP in MPS IIIA patients [ Time Frame: up to 3 years ]. Presence of replication-competent virus and integration events in the leukocytes
- To evaluate overall survival [ Time Frame: up to 3 years ]. Overall survival at 36 months post IMP administration compared to natural history data
- To evaluate peripheral engraftment of the IMP [ Time Frame: within 42 days of treatments ]. Measured as absence of engraftment failure or delayed hematological reconstitution within the first 6 weeks of IMP delivery. Defined as three independent and consecutive days with absolute Neutrophil Count (ANC) >500/mm3 and/or Platelets >20,000/mm3 without transfusions, and/or Hb >8.0 g/dL without transfusions.
- Change in adaptive behaviour [ Time Frame: up to 3 years (multiple visits) ]. Measured using the Vineland Adaptive Behaviour scales against natural history of MPSIIIA
- Change in cognitive function [ Time Frame: up to 3 years (multiple visits) ]. Measurement of cognitive score (standard scores, age equivalent scores and development quotient) using the Bayley Scales of Infant Development, 3rd Edition [BSID-III] or Kaufman Assessment Battery for Children, 2nd Edition [KABC-II] against natural history of MPSIIIA
- Change in patient behaviour [ Time Frame: up to 3 years ]. Measured using the Sanfilippo Behaviour Rating Scale against natural history of MPSIIIA
- Change in patient quality of life [ Time Frame: Up to 3 years ]. Measured using the Infant Toddler Quality of Life questionnaire against natural history of MPSIIIA
- Change in patient's daily living [ Time Frame: Up to 3 years ]. Measured using the Children sleep Questionnaire against natural history data
- As of December 2020, preliminary results from the first patient treated with OTL-201 showed promising safety, tolerability, engraftment, and biomarker data over a follow-up period of three months. Certain data, including engraftment of gene-modified cells as measured by vector copy number, were unavailable at the time of the presentation due to the impact of COVID-19. Specifically, the results showed:
- The treatment was generally well-tolerated with no treatment-related adverse events or serious adverse events to date.
- Evidence of hematological engraftment as suggested by the recovery of neutrophils and platelets post myeloablative conditioning.
- N-sulphoglucosamine sulphohydrolase (SGSH) enzyme expression reached supra-physiological levels in plasma, total leukocytes and multiple cell subpopulations, including CD3+ and CD15+ cells, within 3 months of receiving OTL-201.
- Reduction of urinary heparan sulfate from 60.8 mg/mmol creatinine at baseline to the normal range by three months post-treatment with gene therapy.