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

Conditions

1. Sanfilippo Syndrome

Interventions

1. 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 ---

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

NCT02716246

Conditions

1. MPS IIIA
2. Sanfilippo Syndrome
3. Sanfilippo A
4. Mucopolysaccharidosis III

Interventions

1. 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: 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 - 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: 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 - 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: 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 - 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: 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 - 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 ---

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

Conditions

1. 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 ---

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

Conditions

1. Sanfilippo Syndrome Type A (MPS IIIA)

Interventions

1. 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 ---

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

Conditions

1. Mucopolysaccharidosis Type IIIA

Interventions

1. 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 ---

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

NCT04088734

Conditions

1. MPS IIIA
2. Sanfilippo Syndrome
3. Sanfilippo A
4. Mucopolysaccharidosis III

Interventions

1. 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 - Age range of 2 years up to 18 years (excluded) 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 v4.03 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 v4.03 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 - Age range of 2 years up to 18 years (excluded) 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 v4.03 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 v4.03 MPS IIIA Sanfilippo Syndrome Sanfilippo A Mucopolysaccharidosis III Mucopolysaccharidoses Mucopolysaccharidosis III This is an open-label, single dose clinical trial. --- S298P ---

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

Conditions

1. Mucopolysaccharidosis Type IIIA

Interventions

1. 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 ---