Phase I/II Gene Transfer Clinical Trial of scAAV9.U1a.hSGSH
study id #: NCT02716246
condition: MPS IIIA, Sanfilippo Syndrome, Sanfilippo A, Mucopolysaccharidosis III
Open-label, dose-escalation clinical trial of scAAV9.U1a.hSGSH injected intravenously through a peripheral limb vein
last updated: February 26, 2022
start date: March 2016
estimated completion: December 2024
last updated: January 24, 2022
phase of development: Phase 1/Phase 2
size / enrollment: 22
study description: Self-complementary adeno-associated virus serotype 9 carrying the human SGSH gene under the control of a U1a promoter (scAAV9.U1a.hSGSH) will be delivered one time through a venous catheter inserted into a peripheral limb vein. A tapering course of prophylactic enteral prednisone or prednisolone will be administered for a period of at least two months.
- Product safety
Determination of safety based on the development of unacceptable toxicity: defined as the occurrence of two or more unanticipated Grade III or higher treatment-related adverse events.
- 24 months
Change from baseline in age equivalent developmental score
Change from baseline in the Age Equivalent Developmental Score calculated by the Mullen Scales of Early Learning or the Kaufman Assessment Battery for Children, based on developmental age, compared with natural history study data at 6, 12, 18, and 24 months
- 24 months
- Change from baseline of CSF heparan sulfate after treatment
- Change from baseline of plasma or urine glycosaminoglycans or heparan sulfate after treatment
- Change from baseline in CSF or plasma or leukocyte SGSH enzyme activity levels after treatment
- Change from baseline in liver and/or spleen volumes after treatment
- Change from baseline in brain volume after treatment
- Change from baseline in Cognitive Age Equivalent (Developmental Age)
- Change from baseline in Adaptive Age Equivalent score
- Change from baseline Developmental Quotient
- Change from baseline in the Sanfilippo Behavior Rating Scale
- Change from baseline in the Leiter International Performance Scale - Revised
- Change from baseline in Pediatric Quality of Life Inventory (PedsQL) total score
- Change from baseline in parent quality of life, using the Parenting Stress Index, 4th ed.
- Determination of vector shedding analysis
• Eligible Sexes: all
Diagnosis of MPS IIIA confirmed by the following methods:
No detectable or significantly reduced SGSH enzyme activity by leukocyte assay, and
Genomic DNA analysis demonstrating homozygous or compound heterozygous mutations in the SGSH gene
Age: From birth to 2 years or children older than 2 years with a minimum cognitive Developmental Quotient (DO) of 60 or above (calculated by Bayley Scales of lnfant and Toddler Development - Third Edition)
exclusion criteria: Criteria:
Inability to participate in the clinical evaluation as determined by PI
Identification of two nonsense or null variants on genetic testing of the SGSH gene
At least one S298P mutation in the SGSH gene
Has evidence of an attenuated phenotype of MPS IIIA
Presence of a concomitant medical condition that precludes lumbar puncture or use of anesthetics
Active viral infection based on clinical observations
Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer or precludes the child from participating in the protocol assessments and follow up
Subjects with total anti-AAV9 antibody titers ≥ 1:100 as determined by ELISA binding immunoassay
Subjects with a positive response for the ELISPOT for T-cell responses to AAV9
Serology consistent with exposure to HIV, or serology consistent with active hepatitis B or C infection
Bleeding disorder or any other medical condition or circumstance in which a lumbar puncture (for collection of CSF) is contraindicated according to local institutional policy
Visual or hearing impairment sufficient to preclude cooperation with neurodevelopmental testing
Uncontrolled seizure disorder
Any item (braces, etc.) which would exclude the subject from being able to undergo MRI according to local institutional policy
Any other situation that precludes the subject from undergoing procedures required in this study
Subjects with cardiomyopathy or significant congenital heart abnormalities
The presence of significant non-MPS IlIA related CNS impairment or behavioral disturbances that would confound the scientific rigor or interpretation of results of the study
Abnormal laboratory values Grade 2 or higher as defined in CTCAE v4.03 for GGT, total bilirubin, creatinine, hemoglobin, WBC count, platelet count, PT and aPTT
Female participant who is pregnant or demonstrates a positive urine or bhCG result at screening assessment (if applicable)
Any vaccination with viral attenuated vaccines less than 30 days prior to the scheduled date of treatment (and use of prednisolone)
Previous treatment by Haematopoietic Stem Cell transplantation
Previous participation in a gene/cell therapy or ERT clinical trial
Molecular Analysis of Vietnamese Patients With Mucopolysaccharidosis Type IMucopolysaccharidosis type I (MPS I) is ...
In Silico Analysis of Potential Off-Target Sites to Gene Editing for Mucopolysaccharidosis Type I Using the CRISPR/C...Mucopolysaccharidosis type I (MPS I) is ...
Bob StevensBob Stevens is Group Chief Executive Off...
CHOC-Harbor UCLA MPS Multidisciplinary CenterCHOC and Harbor-UCLA Pediatrics together...
MPS and ML Overview: 2021 Insights and Overviewhttps://www.youtube.com/watch?v=e2tOMBvY...
Establishing a Core Outcome set for Mucopolysaccharidoses (MPS) in Children: Study Protocol for a Rapid Literature R...Mucopolysaccharidoses (MPS) are a group ...
Molecular Characterization of a Large Cohort of Mucopolysaccharidosis Patients: Iran Mucopolysaccharidosis Re-Diagno...Mucopolysaccharidoses (MPSs) are rare, h...