Study of AAVrh10-h.SGSH Gene Therapy in Patients With Mucopolysaccharidosis Type IIIA (MPS IIIA)

Study Overview
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Brief Summary
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MPS IIIA is predominantly a central nervous system disease causing cognitive disability, progressive loss of acquired skills, behavioral and sleep disturbance. LYS-SAF302 is a gene therapy which is intended to deliver a functional copy of the SGSH gene to the brain. This is a phase 2-3 study to assess the efficacy in improving or stabilizing the neurodevelopmental state of MPS IIIA patients.

Detailed Description
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The study is interventional, single arm and multi-center. Evolution under treatment will be compared to expected natural evolution based on natural history studies.

Official Title
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Open-label, Single-arm, Multi-center Study of Intracerebral Administration of Adeno-associated Viral (AAV) Serotype rh.10 Carrying Human N-sulfoglucosamine Sulfohydrolase (SGSH) cDNA for Treatment of Mucopolysaccharidosis Type IIIA

Conditions
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Mucopolysaccharidosis Type IIIA

Intervention / Treatment
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* Drug: LYS-SAF302


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented MPS IIIA diagnosis based on genotyping confirming the SGSH gene mutations Cognitive DQ score on BSID-III: 50% and above Exclusion Criteria: Homozygous for the S298P mutation or non-classical severe form of MPS IIIA, based on investigator's judgement. Participation in another gene or cell therapy clinical trial. Past use of SGSH enzyme replacement therapy for a period exceeding 3 months. A washout period of at least 2 months is required prior to screening. Current participation in a clinical trial of another investigational medicinal product. History of bleeding disorder or current use of medications that, in the opinion of the investigator, place them at risk of bleeding following surgery. Any condition that would contraindicate treatment with immunosuppressants such as tacrolimus, mycophenolate mofetil or steroids.

Ages Eligible for Study
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Minimum Age: 6 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AAV SGSH gene therapy (LYS-SAF302)<br>One-time intracerebral administration of adeno-associated viral vector serotype rh10 containing the human N-sulfoglucosamine sulfohydrolase (SGSH) cDNA. | Drug: LYS-SAF302<br>* Treatment will involve direct injections of the investigational product into both sides of the brain through image-guided tracks, in a single neurosurgical session.<br>* Other names: AAVrh10-h.SGSH;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in development quotient (DQ), compared to regression reported in natural history studies | Development Quotient will be measured for each patient using one of two standard instruments, the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) or the Kaufman Assessment Battery for Children, Second Edition (KABC-II), based on age and ability range. The development quotient (DQ) is a means to express a neurodevelopmental/cognitive delay which is computed as a ratio and expressed as a percentage using the development age (DA) score divided by the age at testing ([development age score/chronological age] × 100; range: 0 - 100, where high values are desirable). | Month 6, 12, 18, 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in the total adaptive behavior composite standard score as measured by the expanded interview Vineland Adaptive Behavior Scales (VABS-II) | The Vineland Adaptive Behavior Scales VABS-II test measures adaptive behaviors, including the ability to cope with environmental changes, to learn new everyday skills, and to demonstrate independence. The VABS-II is a norm-based instrument, where the child's adaptive functioning is compared to that of others his or her age. The total adaptive behavior composite score describe the child's functioning. The normative mean score is 100 (normative standard deviation is 15). Higher scores indicate better functioning. | Month 6, 12, 18, 24 | 
| Change in sleep pattern as measured by the Childrens Sleep Habits Questionnaire (CSHQ) | The Children's Sleep habits Questionnaire (CSHQ) measures sleep habits and behavioral sleep disorders in preschool and school-aged children. The abbreviated CSHQ is a 23-item multiple-choice questionnaire that is summed into 8 subscales (bedtime resistance, sleep onset delay, sleep duration, sleep anxiety, night waking, parasomnias, sleep-disordered breathing, and daytime sleepiness) and a CSHQ total score, where higher scores reflect greater disturbance in sleep pattern. Scores will be compared to scores from the Natural History control group, using the same tool and same timepoints. | Month 6, 12, 18, 24 | 
| Change from baseline in patient quality of life using the Infant and Toddler Quality of Life (ITQOL) questionnaire | The 47-item ITQOL questionnaire assesses physical, mental, and social well-being of the child and the quality of life of parent/caregiver. Scores range from 0 to 100, where higher scores reflect better quality of life. Change in score from baseline will be compared to scores from the Natural History control group, using the same tool and same timepoints. | Month 12, 24 | 
| Change from baseline in parent quality of life, using the Parenting Stress Index, 4th Edition (PSI-4) | The 36-item questionnaire (PSI-4) is used to identify parent-child problem areas, measuring 3 main domains (parental distress, parent-child dysfunctional interaction, and difficult child), which all combined form a total stress score. Higher scores reflect a higher level of stress. Change in score from baseline will be compared to scores from the Natural History control group, using the same tool and same timepoints. | Month 12, 24 | 
| Change from baseline in total cortical grey matter volume and white matter volume on MRI | The change from baseline in grey matter and white matter volume will be assessed by magnetic resonance imaging (MRI) | Month 12, 24 | 
| Incidence and severity of treatment-emergent adverse events and serious adverse events throughout the study | Descriptive summary tables for the surgical period, the evaluation period, and the follow-up period will be provided. | Month 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MPS IIIA, Sanfilippo syndrome Type A, Mucopolysaccharidosis Type IIIA, Lysosomal Storage Disease