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 ≥ 60 (n = up to 6). Up to 2 additional subjects > 2 years and ≤ 5years of age with a BSITD-III Cognitive DQ < 60 may also be enrolled. •Subjectsmust be ≥ 6 months of age before UX111 administration. However, subjects may beconsented and initiate relevant Screening Procedures and IM treatment < 6months of age. Refer to Section 8.2 for relevant screening procedures •Forchildren ≤ 24 months chronological age who were born prematurely, defined asborn at < 36 weeks gestational age, the corrected gestational age must be usedfor determining inclusion •The BSITD-III Cognitive DQ is assessed during theonsite Screening visit, for subjects who require it •The age of the child onthe date of the Screening BSITD-III assessment is used to determine therequirement for the BSITD-III Cognitive DQ score.

• Cohort 4 only: Vaccination status based on age according to country-specificguidelines that is up to date 30 days prior to Enrollment 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 or conditionalmarketing authorization of coronavirus disease (COVID) vaccines is included unlessthere is an accepted medical exemption.

Exclusion Criteria:

• Inability to participate in the clinical evaluation as determined by PI

• Cohorts 1 to 3 only: Identification of two nonsense or null variants on genetictesting of the SGSH gene (based upon review of documented results from a qualifiedlaboratory, and with confirmation 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 to 3 only: Subjects with total anti-AAV9 antibody titers ≥ 1:100equivalent to a positive screen as determined by ELISA binding assay in serum,Cohort 4 only: Subjects testing positive for total anti-AAV9 antibody titers inserum as determined at Screening

• Cohorts 1-3 only: Subjects with a positive response for the enzyme-linkedimmunosorbent spot assay (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 that 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 aminotransferase (ALT), GGT, and/oralkaline phosphatase ≥ 2 × upper limit of normal (ULN) and/or total bilirubin > 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.

• Unwilling to avoid consumption of grapefruit juice and the use of strong inhibitorsof CYP3A4 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), and St. John'sWort from 30 days prior to Screening through completion of the IM regimen.