Phase I/II/III Gene Transfer Clinical Trial of scAAV9.U1a.hSGSH

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 heterozygousmutations in the SGSH gene (based upon review of documented results from aqualified laboratory, and with confirmation with Medical Monitor)

• Age:

• For Cohort 1-3: From birth (participating sites in USA and Australia) OR 6months (participating sites in Spain) to 2 years of age with no BSITD-IIICognitive Development Quotient (DQ) requirement, or older than 2 years with aBSITD-III Cognitive DQ of 60 or above (participating sites globally).

• For Cohort 4 (participating sites in Spain): 3 months to ≤ 2 years of age withno BSITD-III Cognitive DQ requirement, or > 2 years of age with a BSITD-IIICognitive DQ of 60 or above at Screening Visit 1. Up to 2 additional patients > 2 years and ≤ 5 years of age with a BSITD-III Cognitive DQ < 60 at ScreeningVisit 1 may be enrolled to characterize the optimized prophylactic IM therapyin this more advanced disease patient population.

• Cohort 4 only: Vaccination status based on age according to country-specificguidelines that is up to date 30 days prior to Screening as verified bydocumentation from the subject's primary care physician, and willing to defervaccines through 6 months after completion of the subject's IM medication, or longerper Principal Investigator (PI) judgment. Emergency use authorization of coronavirusdisease (COVID) vaccines is included unless there is an accepted medical exemption.

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 (based upon review of documented results from a qualified laboratory, and withconfirmation with Medical Monitor)

• At least one S298P mutation in the SGSH gene (based upon review of documentedresults from a qualified laboratory, and with confirmation with Medical Monitor)

• Has evidence of an attenuated phenotype of MPS IIIA, in the judgement of the PI

• Presence of a concomitant medical condition that precludes lumbar puncture or use ofanesthetics

• Active viral infection based on clinical observations

• Concomitant illness or requirement for chronic drug treatment that in the opinion ofthe PI creates unnecessary risks for gene transfer or precludes the child fromparticipating in the protocol assessments and follow up

• Cohorts 1-3 only: Subjects with total anti-AAV9 antibody titers ≥ 1:100 equivalentto a positive screen as determined by ELISA in serum, Cohort 4: Subjects testingpositive for total anti-AAV9 antibodies as determined at Screening

• Cohorts 1-3 only: Subjects with a positive response for the enzyme-linkedimmunosorbent spot (ELISpot) for T-cell responses to AAV9

• Cohorts 1-3 only: Serology consistent with exposure to human immunodeficiency virus (HIV), or serology consistent with active hepatitis B or C infection, Cohort 4:Current clinically significant infections (including any requiring systemictreatment including, but not limited to, HIV; hepatitis A, B, or C; varicellazosters virus; human T-cell lymphotropic virus type 1 [HTLV-1]; tuberculosis; orCOVID-19) that would interfere with participation in the study.

• Bleeding disorder or any other medical condition or circumstance in which a lumbarpuncture (for collection of CSF) is contraindicated according to local institutionalpolicy

• Visual, hearing, or other impairment sufficient to preclude cooperation withneurodevelopmental testing

• Uncontrolled seizure disorder

• Any item (braces, etc.) or circumstance which would exclude the subject from beingable to undergo MRI according to local institutional policy

• Any other situation that precludes the subject from undergoing procedures requiredin this study

• Subjects with cardiomyopathy or significant congenital heart abnormalities

• The presence of significant non-MPS IlIA related CNS impairment or behavioraldisturbances that would confound the scientific rigor or interpretation of resultsof the study

• Cohorts 1-3: Abnormal laboratory values Grade 2 or higher as defined in commonterminology criteria for adverse events (CTCAE) v4.03 for gamma-glutamyl transferase (GGT), total bilirubin, creatinine, hemoglobin, white blood cell (WBC) count,platelet count, prothrombin time (PT) and activated partial thromboplastin time (aPTT), Cohort 4: Any of the following abnormal laboratory values from screeningassessment:

• Aspartate aminotransferase (AST), alanine aminotransaminase (ALT), and/or GGTand/or alkaline phosphatase ≥ 2 × upper limit of normal (ULN) and/or totalbilirubin > 1.5 × ULN

• Anemia (hemoglobin < 10 g/dL)

• Leukopenia or leukocytosis (total WBC count < 3,000/mm3 and > 15,000/mm3respectively)

• Abnormal absolute neutrophil count (ANC) of < 1000/mm3

• Platelet count < 100,000/mm3

• Coagulopathy (international normalized ratio [INR] > 1.5) or aPTT > 40 seconds

• Renal impairment, defined as estimated glomerular filtration rate (eGFR) belowthe lower limit of normal (age and sex appropriate) based on Bedside Schwartzequation

• Female of childbearing potential who is pregnant or demonstrates a positive urine orbhCG result at screening assessment (if applicable)

• Cohorts 1-3: Any vaccination with viral attenuated vaccines less than 30 days priorto the scheduled date of treatment (and use of prednisolone)

• Previous treatment by Hematopoietic Stem Cell transplantation

• Previous participation in a gene/cell therapy or enzyme replacement therapy (ERT)clinical trial

Cohort 4 only:

• Known hypersensitivity, that in the judgment of the PI, places the subject atincreased risk for adverse effects.

• Willing to avoid consumption of grapefruit juice and the use of strong inhibitors ofCYP3A4 and/or P-gp (eg, ketoconazole, voriconazole, itraconazole, erythromycin,telithromycin, or clarithromycin), strong inducers of CYP3A4 and/or P-gp (eg,rifampin, rifabutin, phenobarbital, carbamazepine, or phenytoin), or St. John's Wort 30 days prior to Screening and until completion of the sirolimus regimen, due topotential interaction with sirolimus.