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Clinical Trial Details — Status: Active, not recruiting

Administrative data

NCT number NCT04201405
Other study ID # R119861
Secondary ID
Status Active, not recruiting
Phase Phase 1/Phase 2
First received
Last updated
Start date January 7, 2020
Est. completion date October 30, 2024

Study information

Verified date February 2024
Source University of Manchester
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

Patients with MPS IIIA have a clinical disorder marked by severe and progressive brain disease and neurological symptoms due to the accumulation of undigested glycosaminoglycans in all cells of the body. 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.


Description:

MPS IIIA is caused by a deficiency of the heparan-N-sulfatase (SGSH) enzyme, leading to the accumulation of the glycosaminoglycan heparan sulphate in the lysosomes. Untreated patients of MPS IIIA experience rapid and progressive neurologic deterioration. To date, there is no effective disease-modifying treatment for patients suffering from MPS IIIA. This study aims to recruit 3 to 5 patients with MPS IIIA who satisfy the inclusion and exclusion criteria and provide full consent, between 3 months and 24 months of age. The investigational medicinal product (IMP) will be a cell-based gene therapy that uses genetically modified autologous CD34+ haematopoietic stem cells transduced with a lentiviral vector containing the human SGSH gene. Patients will be followed up for a minimum of 3 years after gene therapy.


Recruitment information / eligibility

Status Active, not recruiting
Enrollment 5
Est. completion date October 30, 2024
Est. primary completion date October 30, 2024
Accepts healthy volunteers No
Gender All
Age group 3 Months to 24 Months
Eligibility Inclusion Criteria: 1. Written informed consent of a legally authorized guardian(s) 2. Age at baseline =3 months and =24 months 3. Normal cognitive function or mild cognitive deterioration (subject has a Development Quotient (DQ) score =80) at baseline as determined by the Bayley Scale of Infant Development-third edition (BSID-III), cognitive domain) 4. Sibling or relative of known MPS IIIA patients with rapidly progressing phenotype, or genotype associated with rapidly progressing phenotype, or presence of somatic features predictive of rapid progression 5. SGSH activity =10% of the Lower Limit of Normal as measured in leukocytes, plus either (1) a normal enzyme activity level of at least one other sulfatase (to rule out multiple sulfatase deficiency) as measured in leukocytes or (2) two documented mutations in the SGSH gene. 6. Medically stable and able to accommodate the protocol requirements, including travel without placing an undue burden on the patient/patient's family, as determined by the CI. Exclusion Criteria: 1. The subject has received stem cell, gene therapy or enzyme replacement therapy (any route of administration) 2. Subject currently enrolled in other interventional clinical trials. 3. Contraindications for MRI scans. 4. The subject has a history of poorly controlled seizures. 5. Homozygous or compound heterozygous for the S298P mutation or any other mutation known to be associated to slow-progressing phenotype. 6. The subject is currently receiving psychotropic or other medications which, in the CI's opinion, would be likely to substantially confound test results. 7. The subject has received any investigational medicinal product (including Genistein) within 30 days prior to the Baseline visit or is scheduled to receive any investigational medicinal product during the course of the study. 8. Documented Human Immunodeficiency Virus (HIV) infection (positive HIV RNA and/or anti-p24 antibodies). 9. Malignant neoplasia (except local skin cancer) or a documented history of hereditary cancer syndrome. Subjects with a prior successfully treated malignancy and a sufficient follow-up to exclude recurrence (based on oncologist opinion) can be included after discussion and approval by the Medical Monitor. 10. Myelodysplasia, cytogenetic alterations characteristic of myelodysplastic syndrome and acute myeloid leukaemia, or other serious haematological disorders. 11. The subject has a medical condition or extenuating circumstance that, in the opinion of the CI, might compromise the subject's ability to comply with protocol requirements, the subject's well-being or safety, or the interpretability of the subject's clinical data. 12. Visual or hearing impairment sufficient to preclude cooperation with neurodevelopmental testing. 13. Severe behavioural disturbances due to reasons other than MPS IIIA and likely to interfere with protocol compliance, as determined by the CI. 14. Known sensitivity to busulfan. 15. The receipt of live vaccinations within 30 days prior to study start.

Study Design


Intervention

Drug:
Autologous CD34+ cells transduced with a lentiviral vector containing the human SGSH gene
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.

Locations

Country Name City State
United Kingdom Manchester University NHS Foundation Trust Manchester

Sponsors (6)

Lead Sponsor Collaborator
University of Manchester CTI Clinical Trial and Consulting Services, Great Ormond Street Hospital for Children NHS Foundation Trust, Manchester University NHS Foundation Trust, Orchard Therapeutics, University College, London

Country where clinical trial is conducted

United Kingdom, 

References & Publications (5)

Ellison SM, Liao A, Wood S, Taylor J, Youshani AS, Rowlston S, Parker H, Armant M, Biffi A, Chan L, Farzaneh F, Wynn R, Jones SA, Heal P, Gaspar HB, Bigger BW. Pre-clinical Safety and Efficacy of Lentiviral Vector-Mediated Ex Vivo Stem Cell Gene Therapy for the Treatment of Mucopolysaccharidosis IIIA. Mol Ther Methods Clin Dev. 2019 Apr 6;13:399-413. doi: 10.1016/j.omtm.2019.04.001. eCollection 2019 Jun 14. — View Citation

Ghosh A, Shapiro E, Rust S, Delaney K, Parker S, Shaywitz AJ, Morte A, Bubb G, Cleary M, Bo T, Lavery C, Bigger BW, Jones SA. Recommendations on clinical trial design for treatment of Mucopolysaccharidosis Type III. Orphanet J Rare Dis. 2017 Jun 26;12(1):117. doi: 10.1186/s13023-017-0675-4. — View Citation

Holley RJ, Wood SR, Bigger BW. Delivering Hematopoietic Stem Cell Gene Therapy Treatments for Neurological Lysosomal Diseases. ACS Chem Neurosci. 2019 Jan 16;10(1):18-20. doi: 10.1021/acschemneuro.8b00408. Epub 2018 Aug 23. — View Citation

Langford-Smith A, Wilkinson FL, Langford-Smith KJ, Holley RJ, Sergijenko A, Howe SJ, Bennett WR, Jones SA, Wraith J, Merry CL, Wynn RF, Bigger BW. Hematopoietic stem cell and gene therapy corrects primary neuropathology and behavior in mucopolysaccharidosis IIIA mice. Mol Ther. 2012 Aug;20(8):1610-21. doi: 10.1038/mt.2012.82. Epub 2012 May 1. — View Citation

Sergijenko A, Langford-Smith A, Liao AY, Pickford CE, McDermott J, Nowinski G, Langford-Smith KJ, Merry CL, Jones SA, Wraith JE, Wynn RF, Wilkinson FL, Bigger BW. Myeloid/Microglial driven autologous hematopoietic stem cell gene therapy corrects a neuronopathic lysosomal disease. Mol Ther. 2013 Oct;21(10):1938-49. doi: 10.1038/mt.2013.141. Epub 2013 Jun 7. — View Citation

Outcome

Type Measure Description Time frame Safety issue
Other To evaluate the effect of the IMP on heparan sulphate concentration in cerebrospinal fluid (CSF), plasma and urine Measure change in ng/ml glycosaminoglycans in CSF from baseline following IMP administration 6 months and 12 months post-IMP treatments and multiple other visits over time
Other To evaluate the effect of the IMP on SGSH activity in CSF, plasma and peripheral blood mononuclear cells. Change in SGSH activity measured from baseline 6 months and 12 months post-IMP treatments and multiple other visits over time
Other To evaluate clinical efficacy of the IMP on brain imaging biomarkers Measure change in brain volume (total brain, grey and white matter, ventricle volume) by MRI and compare to baseline and natural history data to help assess brain development up to 3 years
Other To explore the presence of anti-SGSH antibodies following treatment with the IMP Measure whether an immune response is generated against the SGSH enzyme up to 3 years
Primary To evaluate the tolerability of the IMP in MPS IIIA patients: scale 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 up to 3 years
Primary To evaluate the biological efficacy of IMP post-treatment: expression of SGSH in total leukocytes Measured by the expression of SGSH in total leukocytes within or above normal range at 12 months post-IMP treatment 12 months post gene therapy
Primary To assess the safety of the IMP in MPS IIIA patients Presence of replication competent virus and integration events in the leukocytes up to 3 years
Secondary To evaluate overall survival Overall survival at 36 months post IMP administration compared to natural history data up to 3 years
Secondary To evaluate peripheral engraftment of the IMP 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. within 42 days of treatments
Secondary Change in adaptive behaviour Measured using the Vineland Adaptive Behaviour scales against natural history of MPSIIIA up to 3 years (multiple visits)
Secondary Change in cognitive function 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 up to 3 years (multiple visits)
Secondary Change in patient behaviour Measured using the Sanfilippo Behaviour Rating Scale against natural history of MPSIIIA up to 3 years
Secondary Change in patient quality of life Measured using the Infant Toddler Quality of Life questionnaire against natural history of MPSIIIA Up to 3 years
Secondary Change in patient's daily living Measured using the Children sleep Questionnaire against natural history data Up to 3 years
See also
  Status Clinical Trial Phase
Completed NCT02037880 - Natural History Studies of Mucopolysaccharidosis III N/A
Recruiting NCT06181136 - Study of DNL126 in Pediatric Participants With Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome Type A) Phase 1/Phase 2
Active, not recruiting NCT03612869 - Study of AAVrh10-h.SGSH Gene Therapy in Patients With Mucopolysaccharidosis Type IIIA (MPS IIIA) Phase 2/Phase 3