SNPMiner Trials by Shray Alag


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Report for Mutation S298P

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

There are 7 clinical trials

Clinical Trials


1 A Randomized, Controlled, Open-label, Multicenter, Phase IIb Safety and Efficacy Study of rhHNS (Recombinant Human Heparan N Sulfatase) Administration Via an Intrathecal Drug Delivery Device in Pediatric Patients With Early Stage Mucopolysaccharidosis Type IIIA Disease

Sanfilippo syndrome Type A, or Mucopolysaccharidosis (MPS) IIIA, is a rare lysosomal storage disease caused by deficiency of the enzyme heparan N-sulfatase (sulfamidase). In the absence of this enzyme, there is an accumulation of the glycosaminoglycan, heparan sulfate, resulting in progressive neurodegeneration. Symptoms are usually first noted in the 1st or 2nd year of life, although definitive diagnosis is often delayed, with an average age of diagnosis of 4.5 years. The disease is characterized by developmental delays initially, followed by neurological developmental arrest, then regression. These developmental deficits are typically associated with severe behavioral disturbances. Patients have a significantly reduced lifespan, with few surviving beyond the 2nd or 3rd decade. The purpose of this study is to evaluate the safety and efficacy of recombinant human heparan-N-sulfatase (rhHNS) in pediatric patients with Early Stage Mucopolysaccharidosis Type III A Disease.

NCT02060526 Sanfilippo Syndrome Drug: Recombinant human heparan N-sulfatase [rhHNS]
MeSH:Mucopolysaccharidosis III Syndrome

2. The presence of at least one S298P mutation in SGSH, associated with attenuated disease OR there is documentation of the S298P mutation in a sibling affected by MPS IIIA, provided parental consent is obtained to use this information. --- S298P ---

2. The presence of at least one S298P mutation in SGSH, associated with attenuated disease OR there is documentation of the S298P mutation in a sibling affected by MPS IIIA, provided parental consent is obtained to use this information. --- S298P --- --- S298P ---

Primary Outcomes

Description: The BSID--III is a series of measurements to assess the motor (fine and gross), language (receptive and expressive), and cognitive development of infants and toddlers and consists of a series of developmental play tasks. The development quotient (DQ) is a means to express a neurodevelopmental/cognitive delay which was computed as a ratio and expressed as a percentage using the age equivalent score divided by the age at testing ([age-equivalent score/chronological age] × 100; range: 0, 100). The BSID--III DQ score is based on the cognitive domain. A positive value indicates improvement in health and cognition. Overall response was the maximum decline in the DQ of 10 points or less over 48 weeks. Number of participants with the overall response were reported here.

Measure: Number of Participants With Overall Response Using Bayley Scales of Infant Development Assessment Third Edition (BSID-III)

Time: Baseline (Week 0) up to Week 48

Secondary Outcomes

Description: An adverse event (AE) was any noxious, pathologic, or unintended change in anatomical, physiologic, or metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in any phase of a clinical study, whether or not considered investigational product related. This included an exacerbation of a pre-existing condition. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; lifethreatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.

Measure: Number of Participants With Serious Adverse Events (SAE)

Time: Baseline (Week 0) up to Week 52

Description: An adverse event (AE) was any noxious, pathologic, or unintended change in anatomical, physiologic, or metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in any phase of a clinical study, whether or not considered investigational product related. This included an exacerbation of a pre-existing condition. TEAEs were defined as AE occurring on or after the time of first IDDD implantation or LP procedure to the end of study (EOS) visit (+30 days).

Measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs)

Time: Baseline (Week 0) up to Week 52

Description: A participant was considered positive if they had at least 1 positive result during the study. Once a participant reported antibody positive, they were considered positive for the remainder of the study.

Measure: Number of Participants With Positive Anti-recombinant Human Heparan-N-Sulfatase (rhHNS) Antibody in Serum at Week 48

Time: Baseline (Week 0) up to Week 48

Description: The VABS-II test measures adaptive behaviors, including the ability to cope with environmental changes, to learn new everyday skills, and to demonstrate independence. The DQ is a means to express a neurodevelopmental/cognitive delay. The DQ was computed as a ratio and expressed as a percentage using the age-equivalent score divided by the age at testing ([age-equivalent score/chronological age] × 100; range, 0, 100). The overall DQ score is calculated from the mean age-equivalent score obtained by averaging out the age-equivalent scores for the all the sub-domains except for Gross and Fine motor skills. This test measures the following 5 key domains: communication, daily living skills, socialization, motor skills, and the adaptive behavior composite (a composite of the other 4 domains). A positive value indicates improvement in health and cognition.

Measure: Change From Baseline in Vineland Adaptive Behavior Scales Second Edition (VABS-II) Development Quotient (DQ) Score at Week 48

Time: Baseline (Week 0), Week 48

Description: The BSID--III is a series of measurements to assess the motor (fine and gross), language (receptive and expressive), and cognitive development of infants and toddlers and consists of a series of developmental play tasks. The DQ is a means to express a neurodevelopmental/cognitive delay which was computed as a ratio and expressed as a percentage using the age-equivalent score divided by the age at testing ([age-equivalent score/chronological age] × 100; range: 0, 100). The BSID--III DQ score is based on the cognitive domain. A positive value indicates improvement in health and cognition.

Measure: Change From Baseline in Development Quotient (DQ) Using Bayley Scales of Infant Development Assessment Third Edition (BSID-III) at Week 48

Time: Baseline (Week 0), Week 48

Description: The change from baseline in grey matter volume at Week 48 was assessed by magnetic resonance imaging (MRI).

Measure: Change From Baseline in Total Cortical Grey Matter Volume at Week 48

Time: Baseline (Week 0), Week 48

Description: Change from baseline in concentration of GAG in CSF at Week 48 was reported.

Measure: Change From Baseline in Concentration of Glycosaminoglycan (GAG) in Cerebrospinal Fluid (CSF) at Week 48

Time: Baseline (Week 0), Week 48

Description: The concentration of GAG in urine was normalized to the urine creatinine value and reported as milligram (mg) GAG per millimole (mmol) creatinine.

Measure: Change From Baseline in Concentration of GAG in Urine at Week 48

Time: Baseline (Week 0), Week 48

Description: Concentration of rhHNS in CSF was assessed using validated enzyme-linked immunosorbent assay (ELISA) method.

Measure: Concentration of Recombinant Human Heparan-N-Sulfatase (rhHNS) in Cerebrospinal Fluid (CSF)

Time: Pre-dose, 4, 48 hours on Week 0 and Week 48

Description: Cmax of rhHNS in serum was evaluated using enzyme-linked immunosorbent assay (ELISA) method and liquid chromatography tandem mass spectrometry (LC-MS) method.

Measure: Maximum Observed Drug Concentration (Cmax) of Recombinant Human Heparan-N-Sulfatase (rhHNS) in Serum

Time: Predose, 0.5 h, 1 h, 2 h, 4 h, 8 h, 12 h, 24 h, and 48 h post-dose on Week 0 and Week 48

2 Phase I/II Gene Transfer Clinical Trial of scAAV9.U1a.hSGSH for Mucopolysaccharidosis (MPS) IIIA

Open-label, dose-escalation clinical trial of scAAV9.U1a.hSGSH injected intravenously through a peripheral limb vein

NCT02716246 MPS IIIA Sanfilippo Syndrome Sanfilippo A Mucopolysaccharidosis III Biological: ABO-102
MeSH:Mucopolysaccharidoses Mucopolysaccharidosis III

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 6 months 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 - 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 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 6 months 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 - 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 MPS IIIA Sanfilippo Syndrome Sanfilippo A Mucopolysaccharidosis III Mucopolysaccharidoses Mucopolysaccharidosis III 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. --- S298P ---

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 6 months 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 - 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 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 6 months 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 - 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 MPS IIIA Sanfilippo Syndrome Sanfilippo A Mucopolysaccharidosis III Mucopolysaccharidoses Mucopolysaccharidosis III 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. --- S298P --- --- S298P ---

Primary Outcomes

Description: 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.

Measure: Product safety

Time: 24 months

Description: 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

Measure: Change from baseline in age equivalent developmental score

Time: 24 months

Secondary Outcomes

Description: Change from baseline of CSF heparan sulfate after treatment at 1, 6, 12, and 24 months

Measure: Change from baseline of CSF heparan sulfate after treatment

Time: 24 months

Description: Change from baseline of plasma or urine glycosaminoglycans or heparan sulfate after treatment at Month 1, 6, 12, 18, 24

Measure: Change from baseline of plasma or urine glycosaminoglycans or heparan sulfate after treatment

Time: 24 months

Description: Change from baseline in CSF or plasma or leukocyte SGSH enzyme activity levels after treatment at Month 1, 6, 12, 24

Measure: Change from baseline in CSF or plasma or leukocyte SGSH enzyme activity levels after treatment

Time: 24 months

Description: Change from baseline in liver and/or spleen volumes after treatment as measured by MRI at Month 1, 6, 12, 24

Measure: Change from baseline in liver and/or spleen volumes after treatment

Time: 24 months

Description: Change from baseline in brain volume after treatment as measured by MRI at Month 1, 6, 12, 24

Measure: Change from baseline in brain volume after treatment

Time: 24 months

Description: 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

Measure: Change from baseline in Cognitive Age Equivalent (Developmental Age)

Time: 24 months

Description: 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

Measure: Change from baseline in Adaptive Age Equivalent score

Time: 24 months

Description: 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

Measure: Change from baseline Developmental Quotient

Time: 24 months

Description: Change from baseline in the Sanfilippo Behavior Rating Scale at Month 6, 12, 18, 24

Measure: Change from baseline in the Sanfilippo Behavior Rating Scale

Time: 24 months

Description: Change from baseline in the Leiter-R at Month 6, 12, 18, 24

Measure: Change from baseline in the Leiter International Performance Scale - Revised

Time: 24 months

Description: Change from baseline in Pediatric Quality of Life Inventory (PedsQL) total score at Month 6, 12, 18, 24

Measure: Change from baseline in Pediatric Quality of Life Inventory (PedsQL) total score

Time: 24 months

Description: Change from baseline in parent quality of life, using the Parenting Stress Index, 4th ed short form (PSI-4) at Month 12, 24

Measure: Change from baseline in parent quality of life, using the Parenting Stress Index, 4th ed.

Time: 24 months

Description: Determination of vector shedding in plasma, saliva, urine, and feces to provide preliminary data for the Environmental Risk Assessment

Measure: Determination of vector shedding analysis

Time: 24 months

3 An Observational, Prospective, Multi-center, Natural History Study of Patients With Mucopolysaccharidosis Type IIIA (MPS IIIA)

Evaluate the clinical progression in patients with MPS IIIA who are untreated with any investigational product and to obtain standardized assessments: neurocognitive, behavioral, sleep-wake habits and effect of MPS IIIA on the quality of life of patients and their families.

NCT02746341 Mucopolysaccharidosis IIIA
MeSH:Mucopolysaccharidoses

- Homozygous or compound heterozygous for the S298P mutation or the investigator and/or trial steering committee considers the patient not to have the classical severe form of MPS IIIA. --- S298P ---

Primary Outcomes

Measure: The change from baseline in cognitive function using the Bayley scales of infant and toddler development third edition

Time: Baseline, and every 6 months, for up to 24 months

Secondary Outcomes

Measure: Change from baseline in the adaptive behavior composite standard score as measured by the Vineland Adaptive Behavior scale

Time: Baseline and every 6 months up to 24 months

Measure: Sleep disturbances measured by Actigraphy

Time: Baseline and every 3 months up to 24 months

Measure: Patient Quality of Life Questionnaires

Time: Baseline and every 6 months up to 24 months

Measure: Change from baseline in total cortical grey matter volume

Time: Baseline, 12 months, 24 months

4 An Open, Non-controlled, Parallel, Ascending Multiple-dose, Multicenter Study to Assess Safety and Tolerability, Pharmacokinetics and Pharmacodynamics of SOBI003 in Pediatric MPS IIIA Patients

MPS IIIA, also known as Sanfilippo A, is an inherited lysosomal storage disease (LSD). MPS IIIA is caused by a deficiency in sulfamidase, one of the enzymes involved in the lysosomal degradation of the glycosaminoglycan (GAG) heparan sulfate (HS). The natural course of MPS IIIA is characterized by devastating neurodegeneration with initially mild somatic involvement. The aims of the present study is to assess the dose related safety, tolerability, PK and PD of SOBI003, a chemically modified recombinant human (rh) Sulfamidase developed as an enzyme replacement therapy (ERT).

NCT03423186 Sanfilippo Syndrome Type A (MPS IIIA) Drug: SOBI003
MeSH:Mucopolysaccharidosis III

At least one S298P mutation in the SGSH gene 2. Contraindications for anesthetic procedures, surgical procedure (venous access port) MRI scans and/or lumbar punctures 3. History of poorly controlled seizures 4. Patients is currently receiving psychotropic or other medications which in the investigator's opinion, would be likely to substantially confound test results 5. Significant non-MPS IIIA-related CNS impairment or behavioral disturbances, which in the investigator's opinion, would confound the scientific integrity or interpretation of study assessments 6. Prior administration of stem cell or gene therapy, or ERT for MPS IIIA 7. Concurrent or prior (within 30 days of enrolment into this study) participation in a study involving invasive procedures Inclusion Criteria: 1. Informed consent obtained from the patient's legally authorized representative(s) 2. Patients with MPS IIIA, as confirmed by both: - A documented deficiency in sulfamidase enzyme activity in concordance with a diagnosis of MPS IIIA, and - Normal enzyme activity level of at least one other sulfatase measured in leukocytes 3. Chronological age of ≥12 and ≤72 months (i.e., 1 to 6 years) at the time of the first SOBI003 infusion and a developmental age ≥12 months at screening as assessed by the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) 4. Medically stable patient who is expected to be able to comply with study procedures Exclusion Criteria: 1. --- S298P ---

At least one S298P mutation in the SGSH gene 2. Contraindications for anesthetic procedures, surgical procedure (venous access port) MRI scans and/or lumbar punctures 3. History of poorly controlled seizures 4. Patients is currently receiving psychotropic or other medications which in the investigator's opinion, would be likely to substantially confound test results 5. Significant non-MPS IIIA-related CNS impairment or behavioral disturbances, which in the investigator's opinion, would confound the scientific integrity or interpretation of study assessments 6. Prior administration of stem cell or gene therapy, or ERT for MPS IIIA 7. Concurrent or prior (within 30 days of enrolment into this study) participation in a study involving invasive procedures Sanfilippo Syndrome Type A (MPS IIIA) Mucopolysaccharidosis III This is an open-label, non-controlled, parallel, sequential ascending multiple-dose, multicenter study to assess the dose related safety, tolerability, PK and PD of SOBI003 in pediatric MPS IIIA patients. --- S298P ---

Primary Outcomes

Measure: Safety will be measured by adverse events frequencies (by type and severity)

Time: Week 24

Secondary Outcomes

Measure: The observed serum concentration immediately before the start of infusion of SOBI003 (CPre-dose)

Time: Weeks 1, 2, 3, 4, 5, 8, 12, and 24

Measure: The observed serum concentration at the end of infusion of SOBI003 (CEnd of inf)

Time: Weeks 1, 2, 3, 4, 8, 12, and 24

Measure: The time of the end of the infusion of SOBI003 (tEnd of inf)

Time: Weeks 1, 2, 3, 4, 8, 12, and 24

Measure: The maximum observed serum concentration (Cmax)

Time: Weeks 1, 4, 12, and 24

Measure: The time at which the maximum serum concentration is observed (tmax)

Time: Weeks 1, 4, 12, and 24

Measure: The minimum observed serum concentration (CTrough)

Time: Weeks 1, 4, 12, and 24

Measure: Clearance (CL)

Time: Weeks 1, 4, 12, and 24

Measure: The area under the plasma concentration-time curve from time 0 to last sample (AUC0-168h)

Time: Weeks 1, 4, 12, and 24

Measure: The half-life (t1/2)

Time: Weeks 1, 4, 12, and 24

Measure: SOBI003 concentration in cerebrospinal fluid

Time: Weeks 12 and 24

Measure: Proportion of patients having anti-drug antibodies in serum

Time: Weeks 2,4,8,12 and 24

Measure: Proportion of patients having anti-drug antibodies in cerebrospinal fluid

Time: Weeks 2,4,8,12 and 24

Measure: Change from baseline in Heparan Sulfate levels in cerebrospinal fluid

Time: Weeks 12 and 24

Measure: Change from baseline in Heparan sulfate levels in serum

Time: Weeks 2, 3, 4, 8, 12 and 24

Measure: Change from baseline in Heparan sulfate levels in urine

Time: Weeks 2, 3, 4, 8, 12 and 24

Description: Quotient between age equivalent score and age, 0 - 100%, where high values are desirable. The age equivalent score represent the age of the typical and normal individual who would achieve the same result as the one who was tested. The age equivalent scores are assessed by the Bayley Scales of Infant and Toddler Development®, third edition cognitive subtest or the Kaufman Assessment Battery for Children, Second edition. The Bayley Scales of Infant and Toddler Development-Third Edition is an individually administered test designed to assess developmental functioning of infants and toddlers. The Bayley-III assesses development in five areas: cognitive, language, motor, social-emotional, and adaptive behavior. The Kaufman Assessment Battery for Children (K-ABC) is a clinical instrument for assessing cognitive development.

Measure: Change from baseline in Neurocognitive Development Quotient

Time: Week 24

Description: The age equivalent score represent the age in months of the typical and normal individual who would achieve the same result as the one who was tested. The age equivalent scores are assessed by the Bayley Scales of Infant and Toddler Development®, third edition cognitive subtest or the Kaufman Assessment Battery for Children, Second edition. The Bayley Scales of Infant and Toddler Development-Third Edition is an individually administered test designed to assess developmental functioning of infants and toddlers. The Bayley-III assesses development in five areas: cognitive, language, motor, social-emotional, and adaptive behavior. The Kaufman Assessment Battery for Children (K-ABC) is a clinical instrument for assessing cognitive development.

Measure: Change from baseline in Age-equivalence score as assessed by BSID-III or KABC-II

Time: Week 24

Description: The age equivalent score represent the age in months of the typical and normal individual who would achieve the same result as the one who was tested. The age equivalent scores are assessed by Vineland™ Adaptive Behavior Scales, Expanded Interview Form, Second edition (VABS-II). The Vineland is designed to measure adaptive behavior of individuals from birth to age 90. The Vineland-II contains 5 domains each with 2-3 subdomains. The main domains are: Communication, Daily Living Skills, Socialization, Motor Skills, and Maladaptive Behavior.

Measure: Change from baseline in Age-equivalence score as assessed by VABS-II

Time: Week 24

Description: Grey matter contains most of the brain's neuronal cell bodies. The grey matter includes regions of the brain involved in muscle control, and sensory perception such as seeing and hearing, memory, emotions, speech, decision making, and self-control. The gray matter volume will be measured by volumetric magnetic resonance imaging (MRI).

Measure: Change from baseline in gray matter volume

Time: Week 24

Description: Pediatric Quality of Life Inventory (PedsQL™) is a modular approach to measuring health-related quality of life (HRQOL) in healthy children and adolescents and those with acute and chronic health conditions. Lower scores indicate better functioning. Min score = 0, and max score = 144.

Measure: Change from baseline in Pediatric Quality of Life Inventory (PedsQL™) total score

Time: Week 24

Description: Pediatric Quality of Life Inventory (PedsQL™) is a modular approach to measuring health-related quality of life in healthy children and adolescents and those with acute and chronic health conditions. The Total Score is the sum of all 36 items in the test divided by the number of items answered. Higher scores indicate better functioning.

Measure: Change from baseline in PedsQL™ Family Impact Module total score

Time: Week 24

5 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

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.

NCT03612869 Mucopolysaccharidosis Type IIIA Drug: LYS-SAF302
MeSH:Mucopolysaccharidoses Mucopolysaccharidosis III

Descriptive summary tables for the surgical period, the evaluation period, and the follow-up period will be provided.. 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. --- S298P ---

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. --- S298P ---

Primary Outcomes

Description: 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).

Measure: Change from baseline in development quotient (DQ), compared to regression reported in natural history studies

Time: Month 6, 12, 18, 24

Secondary Outcomes

Description: 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.

Measure: Change from baseline in the total adaptive behavior composite standard score as measured by the expanded interview Vineland Adaptive Behavior Scales (VABS-II)

Time: Month 6, 12, 18, 24

Description: 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.

Measure: Change in sleep pattern as measured by the Childrens Sleep Habits Questionnaire (CSHQ)

Time: Month 6, 12, 18, 24

Description: 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.

Measure: Change from baseline in patient quality of life using the Infant and Toddler Quality of Life (ITQOL) questionnaire

Time: Month 12, 24

Description: 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.

Measure: Change from baseline in parent quality of life, using the Parenting Stress Index, 4th Edition (PSI-4)

Time: Month 12, 24

Description: The change from baseline in grey matter and white matter volume will be assessed by magnetic resonance imaging (MRI)

Measure: Change from baseline in total cortical grey matter volume and white matter volume on MRI

Time: Month 12, 24

Description: Descriptive summary tables for the surgical period, the evaluation period, and the follow-up period will be provided.

Measure: Incidence and severity of treatment-emergent adverse events and serious adverse events throughout the study

Time: Month 24

6 A Phase I/II Open Label, Single-dose, Gene Transfer Study of scAAV9.U1a.hSGSH (ABO-102) in Patients With Middle and Advanced Phases of MPS IIIA Disease

Open-label, clinical trial of scAAV9.U1a.hSGSH injected intravenously through a peripheral limb vein

NCT04088734 MPS IIIA Sanfilippo Syndrome Sanfilippo A Mucopolysaccharidosis III Drug: ABO-102
MeSH:Mucopolysaccharidoses Mucopolysaccharidosis III

No detectable or significantly reduced SGSH enzyme activity by leukocyte assay and 2. Genomic DNA analysis demonstrating homozygous or compound heterozygous mutations in the SGSH gene - Cognitive Development Quotient (DQ) lower than 60 (calculated by Bayley Scales of Infant and Toddler Development - Third Edition) - Must be ambulatory, though may receive assistance with ambulation Exclusion Criteria: - Inability to participate in the clinical evaluation as determined by Principal Investigator - 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 - Participants with total anti-AAV9 antibody titers greater than or equal to 1:100 as determined by ELISA binding immunoassay - Participants 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 - Any item (braces, etc.) which would exclude the participant from being able to undergo MRI according to local institutional policy - Any other situation that precludes the participant from undergoing procedures required in this study - Participants 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 v4.0 for GGT, total bilirubin (except in subjects diagnosed with Gilbert's syndrome), creatinine, hemoglobin, WBC count, platelet count, PT and aPTT - Female participant who is pregnant or demonstrates a positive urine or beta-hCG 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 - Participants who are anticipated to undergo a procedure involving anesthesia within 6 months post- drug administration - Dysphagia present at Grade 3 or higher, as defined in CTCAE v4.0 Inclusion Criteria: - Diagnosis of MPS IIIA confirmed by the following methods: 1. --- S298P ---

No detectable or significantly reduced SGSH enzyme activity by leukocyte assay and 2. Genomic DNA analysis demonstrating homozygous or compound heterozygous mutations in the SGSH gene - Cognitive Development Quotient (DQ) lower than 60 (calculated by Bayley Scales of Infant and Toddler Development - Third Edition) - Must be ambulatory, though may receive assistance with ambulation Exclusion Criteria: - Inability to participate in the clinical evaluation as determined by Principal Investigator - 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 - Participants with total anti-AAV9 antibody titers greater than or equal to 1:100 as determined by ELISA binding immunoassay - Participants 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 - Any item (braces, etc.) which would exclude the participant from being able to undergo MRI according to local institutional policy - Any other situation that precludes the participant from undergoing procedures required in this study - Participants 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 v4.0 for GGT, total bilirubin (except in subjects diagnosed with Gilbert's syndrome), creatinine, hemoglobin, WBC count, platelet count, PT and aPTT - Female participant who is pregnant or demonstrates a positive urine or beta-hCG 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 - Participants who are anticipated to undergo a procedure involving anesthesia within 6 months post- drug administration - Dysphagia present at Grade 3 or higher, as defined in CTCAE v4.0 MPS IIIA Sanfilippo Syndrome Sanfilippo A Mucopolysaccharidosis III Mucopolysaccharidoses Mucopolysaccharidosis III This is an open-label, single dose clinical trial. --- S298P ---

Primary Outcomes

Description: The incidence, type, and severity of treatment-related adverse events and serious adverse events

Measure: Adverse Events and Serious Adverse Events

Time: 24 months

Description: Change from baseline in CSF heparan sulfate levels after treatment

Measure: CSF Heparan Sulfate

Time: 1, 6, 12, 24 months

Description: Change from baseline in liver and/or spleen volumes after treatment, as measured by MRI

Measure: Liver and/or Spleen Volumes

Time: 1, 6, 12, 24 months

Secondary Outcomes

Description: Change from baseline in plasma or urine glycosaminoglycans or heparan sulfate after treatment

Measure: Glycosaminoglycans or Heparan Sulfate

Time: 1, 6, 12, 18, 24 months

Description: Change from baseline in CSF or plasma or leukocyte SGSH enzyme activity levels after treatment

Measure: SGSH Enzyme Activity

Time: 1, 6, 12, 24 Months

Description: Change from baseline in brain volume after treatment, as measured by MRI

Measure: Brain Volume

Time: 1, 6, 12, 24 months

Description: Change from baseline in the Developmental Age after treatment compared to Natural History Study data calculated by the Mullen Scales of Early Learning or the Kaufman Assessment Battery for Children, 2nd edition, based on chronological and developmental age

Measure: Developmental Age

Time: 6, 12, 18, 24 months

Description: Change from baseline in the Cognitive Developmental Age after treatment compared to Natural History Study, calculated using the Bayley Scales of Infant and Toddler Development - Third edition or the Kaufman Assessment Battery for Children. Second Edition, based on developmental age

Measure: Cognitive Developmental Age

Time: 6, 12, 18, 24 months

Description: Change from baseline in the 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

Measure: Adaptive Age Equivalent Score

Time: 6, 12, 18, 24 months

Description: Change from baseline in the Sanfilippo Behavior Rating Scale

Measure: Sanfilippo Behavior Rating Scale

Time: 6, 12, 18, 24 months

Description: Change from baseline in sleep pattern as measured by the modified Children's Sleep Habits Questionnaire (CSHQ)

Measure: Sleep Pattern

Time: 6, 12, 18, 24 months

Description: Change from baseline in Pediatric Quality of Life Inventory (PedsQL™) Core Generic Scales total score

Measure: Pediatric Quality of Life Inventory

Time: 6, 12, 18, 24 months

Description: Change from baseline in parent quality of life, using the Parenting Stress Index, 4th Edition (PSI-4)

Measure: Parent Quality of Life

Time: 6, 12, 18, 24 months

Description: Change from baseline in gastrointestinal symptoms using the PedsQL™ Gastrointestinal Symptoms Scales

Measure: Gastrointestinal Symptoms

Time: 6, 12, 18, 24 months

Description: Change from baseline in Parent Global Impression Score

Measure: Parent Global Impression Score

Time: 6, 12, 18, 24 months

Description: Change from baseline in Clinical Global Impression Improvement Scale

Measure: Clinical Global Impression Improvement Scale

Time: 6, 12, 18, 24 months

Description: Change from baseline in Parent Symptoms Score Questionnaire

Measure: Parent Symptoms Score Questionnaire

Time: 6, 12, 18, 24 months

Description: Change from Baseline in Body Mass Index after treatment

Measure: Body Mass Index

Time: 6, 12, 18, 24 months

Description: Incidence and Change from baseline in abnormalities in standard awake 60-minutes- EEG monitoring

Measure: EEG Monitoring

Time: 6, 12, 18, 24 months

Description: Detection of the AAV9 viral DNA in plasma, saliva, urine and feces will be performed until two consecutive samples are negative

Measure: AAV9 Viral DNA Detection

Time: 24 months

7 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)

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.

NCT04201405 Mucopolysaccharidosis Type IIIA Drug: Autologous CD34+ cells transduced with a lentiviral vector containing the human SGSH gene
MeSH:Mucopolysaccharidoses Mucopolysaccharidosis III

5. Homozygous or compound heterozygous for the S298P mutation or any other mutation known to be associated to slow-progressing phenotype. --- S298P ---

Primary Outcomes

Description: 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

Measure: To evaluate the tolerability of the IMP in MPS IIIA patients: scale

Time: up to 3 years

Description: Measured by the expression of SGSH in total leukocytes within or above normal range at 12 months post-IMP treatment

Measure: To evaluate the biological efficacy of IMP post-treatment: expression of SGSH in total leukocytes

Time: 12 months post gene therapy

Description: Presence of replication competent virus and integration events in the leukocytes

Measure: To assess the safety of the IMP in MPS IIIA patients

Time: up to 3 years

Secondary Outcomes

Description: Overall survival at 36 months post IMP administration compared to natural history data

Measure: To evaluate overall survival

Time: up to 3 years

Description: 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.

Measure: To evaluate peripheral engraftment of the IMP

Time: within 42 days of treatments

Description: Measured using the Vineland Adaptive Behaviour scales against natural history of MPSIIIA

Measure: Change in adaptive behaviour

Time: up to 3 years (multiple visits)

Description: 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

Measure: Change in cognitive function

Time: up to 3 years (multiple visits)

Description: Measured using the Sanfilippo Behaviour Rating Scale against natural history of MPSIIIA

Measure: Change in patient behaviour

Time: up to 3 years

Description: Measured using the Infant Toddler Quality of Life questionnaire against natural history of MPSIIIA

Measure: Change in patient quality of life

Time: Up to 3 years

Description: Measured using the Children sleep Questionnaire against natural history data

Measure: Change in patient's daily living

Time: Up to 3 years

Other Outcomes

Description: Measure change in ng/ml glycosaminoglycans in CSF from baseline following IMP administration

Measure: To evaluate the effect of the IMP on heparan sulphate concentration in cerebrospinal fluid (CSF), plasma and urine

Time: 6 months and 12 months post-IMP treatments and multiple other visits over time

Description: Change in SGSH activity measured from baseline

Measure: To evaluate the effect of the IMP on SGSH activity in CSF, plasma and peripheral blood mononuclear cells.

Time: 6 months and 12 months post-IMP treatments and multiple other visits over time

Description: Measure change in brain volume (total brain, greey and white matter, ventricle volume) by MRI and compare to baseline and natural history data to help assess brain development

Measure: To evaluate clinical efficacy of the IMP on brain imaging biomarkers

Time: up to 3 years

Description: Measure whether an immune response is generated against the SGSH enzyme

Measure: To explore the presence of anti-SGSH antibodies following treatment with the IMP

Time: up to 3 years


HPO Nodes