Phase I/II/III Gene Transfer Clinical Trial of scAAV9.U1a.hSGSH
Study Details
Study Description
Brief Summary
Open-label, dose-escalation clinical trial of scAAV9.U1a.hSGSH injected intravenously through a peripheral limb vein
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
Detailed 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.
This study was previously posted by Abeona Therapeutics, Inc and was transferred to Ultragenyx in August 2022.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Cohort 1 Low Dose Dose of 0.5 X 10^13 vg/kg |
Biological: ABO-102
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.
Other Names:
|
| Experimental: Cohort 2 Mid Dose Dose of 1 X 10^13 vg/kg |
Biological: ABO-102
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.
Other Names:
|
| Experimental: Cohort 3 High Dose Dose of 3 X 10^13 vg/kg |
Biological: ABO-102
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.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Product safety [24 months]
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.
- Change from baseline in age equivalent developmental score [24 months]
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
Secondary Outcome Measures
- Change from baseline of CSF heparan sulfate after treatment [24 months]
Change from baseline of CSF heparan sulfate after treatment at 1, 6, 12, and 24 months
- Change from baseline of plasma or urine glycosaminoglycans or heparan sulfate after treatment [24 months]
Change from baseline of plasma or urine glycosaminoglycans or heparan sulfate after treatment at Month 1, 6, 12, 18, 24
- Change from baseline in CSF or plasma or leukocyte SGSH enzyme activity levels after treatment [24 months]
Change from baseline in CSF or plasma or leukocyte SGSH enzyme activity levels after treatment at Month 1, 6, 12, 24
- Change from baseline in liver and/or spleen volumes after treatment [24 months]
Change from baseline in liver and/or spleen volumes after treatment as measured by MRI at Month 1, 6, 12, 24
- Change from baseline in brain volume after treatment [24 months]
Change from baseline in brain volume after treatment as measured by MRI at Month 1, 6, 12, 24
- Change from baseline in Cognitive Age Equivalent (Developmental Age) [24 months]
Change from baseline in Cognitive Age Equivalent (Developmental Age) compared to natural history study calculated using the Bayley Scales of Infant and Toddler Development or the Kaufman Assessment Battery for Children at Month 6, 12, 18, 24
- Change from baseline in Adaptive Age Equivalent score [24 months]
Change from baseline in Adaptive Age Equivalent score after treatment compared to natural history study data, as assessed by parent report using the Vineland Adaptive Behavior Scale II Survey form at Month 6, 12, 18, 24
- Change from baseline Developmental Quotient [24 months]
Change from baseline Developmental Quotient after treatment compared to natural history study data assessed by Mullen Scales of Early Learning or the Kaufman Assessment Battery for Children, based on chronological and developmental age, at Month 6, 12, 18, 24
- Change from baseline in the Sanfilippo Behavior Rating Scale [24 months]
Change from baseline in the Sanfilippo Behavior Rating Scale at Month 6, 12, 18, 24
- Change from baseline in the Leiter International Performance Scale - Revised [24 months]
Change from baseline in the Leiter-R at Month 6, 12, 18, 24
- Change from baseline in Pediatric Quality of Life Inventory (PedsQL) total score [24 months]
Change from baseline in Pediatric Quality of Life Inventory (PedsQL) total score at Month 6, 12, 18, 24
- Change from baseline in parent quality of life, using the Parenting Stress Index, 4th ed. [24 months]
Change from baseline in parent quality of life, using the Parenting Stress Index, 4th ed short form (PSI-4) at Month 12, 24
- Determination of vector shedding analysis [24 months]
Determination of vector shedding in plasma, saliva, urine, and feces to provide preliminary data for the Environmental Risk Assessment
Eligibility Criteria
Criteria
Inclusion Criteria:
-
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:
-
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
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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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Nationwide Children's Hospital | Columbus | Ohio | United States | 43205 |
| 2 | Children's Hospital of Pittsburgh | Pittsburgh | Pennsylvania | United States | 15224 |
| 3 | Women's and Children's Hospital | North Adelaide | South Australia | Australia | 5006 |
| 4 | Vall d'Hebron Barcelona Hospital Campus | Barcelona | Spain | 08035 | |
| 5 | Hospital Clínico Universitario de Santiago | Santiago De Compostela | Spain | 15706 |
Sponsors and Collaborators
- Ultragenyx Pharmaceutical Inc
- Abeona Therapeutics, Inc
Investigators
- Study Director: Medical Director, Ultragenyx Pharmaceutical Inc
Study Documents (Full-Text)
None provided.More Information
Publications
- Fu H, Cataldi MP, Ware TA, Zaraspe K, Meadows AS, Murrey DA, McCarty DM. Functional correction of neurological and somatic disorders at later stages of disease in MPS IIIA mice by systemic scAAV9-hSGSH gene delivery. Mol Ther Methods Clin Dev. 2016 Jun 8;3:16036. doi: 10.1038/mtm.2016.36. eCollection 2016.
- Fu H, Meadows AS, Pineda RJ, Kunkler KL, Truxal KV, McBride KL, Flanigan KM, McCarty DM. Differential Prevalence of Antibodies Against Adeno-Associated Virus in Healthy Children and Patients with Mucopolysaccharidosis III: Perspective for AAV-Mediated Gene Therapy. Hum Gene Ther Clin Dev. 2017 Dec;28(4):187-196. doi: 10.1089/humc.2017.109. Epub 2017 Oct 24.
- ABT001
- UX111-CL301
- 2015-003904-21