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

The main objective of this study is to evaluate the efficacy and safety of UX111 for the treatment of MPS IIIA.

Open-label, single dose, dose-escalation clinical trial of UX111 (scAAV9.U1a.hSGSH) injected intravenously through a peripheral limb vein. A limited course of prophylactic immunomodulatory (IM) therapy will be administered. At approved sites adjuvant IM therapy may be administered to selected participants. The Principal Investigator and/or caregiver, in consultation with the medical monitor, will determine whether to initiate adjuvant IM therapy. Not all participants may receive adjuvant IM therapy.

This study was previously posted by Abeona Therapeutics, Inc and was transferred to Ultragenyx in August 2022.

Eligibility Criteria:
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 (based upon review of documented results from a qualified laboratory, and with confirmation with Medical Monitor)
* Age:

  * For Cohort 1-3: From birth (participating sites in USA and Australia) OR 6 months (participating sites in Spain) to 2 years of age with no BSITD-III Cognitive Development Quotient (DQ) requirement, or older than 2 years with a BSITD-III Cognitive DQ of 60 or above (participating sites globally).
  * For Cohort 4 (participating sites in Spain): 3 months to ≤ 2 years of age with no BSITD-III Cognitive DQ requirement, or \> 2 years of age with a BSITD-III Cognitive 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 Screening Visit 1 may be enrolled to characterize the optimized prophylactic IM therapy in this more advanced disease patient population.
* Cohort 4 only: Vaccination status based on age according to country-specific guidelines that is up to date 30 days prior to Screening as verified by documentation from the subject's primary care physician, and willing to defer vaccines through 6 months after completion of the subject's IM medication, or longer per Principal Investigator (PI) judgment. Emergency use authorization of coronavirus disease (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 with confirmation with Medical Monitor)
* At least one S298P mutation in the SGSH gene (based upon review of documented results 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 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
* Cohorts 1-3 only: Subjects with total anti-AAV9 antibody titers ≥ 1:100 equivalent to a positive screen as determined by ELISA in serum, Cohort 4: Subjects testing positive for total anti-AAV9 antibodies as determined at Screening
* Cohorts 1-3 only: Subjects with a positive response for the enzyme-linked immunosorbent 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 systemic treatment including, but not limited to, HIV; hepatitis A, B, or C; varicella zosters virus; human T-cell lymphotropic virus type 1 \[HTLV-1\]; tuberculosis; or COVID-19) that would interfere with participation in the study.
* 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, hearing, or other impairment sufficient to preclude cooperation with neurodevelopmental testing
* Uncontrolled seizure disorder
* Any item (braces, etc.) or circumstance 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
* Cohorts 1-3: Abnormal laboratory values Grade 2 or higher as defined in common terminology 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 screening assessment:

  * Aspartate aminotransferase (AST), alanine aminotransaminase (ALT), and/or GGT and/or alkaline 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/mm3 respectively)
  * 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) below the lower limit of normal (age and sex appropriate) based on Bedside Schwartz equation
* Female of childbearing potential who is pregnant or demonstrates a positive urine or bhCG result at screening assessment (if applicable)
* Cohorts 1-3: Any vaccination with viral attenuated vaccines less than 30 days prior to 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 at increased risk for adverse effects.
* Willing to avoid consumption of grapefruit juice and the use of strong inhibitors of 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), or St. John's Wort 30 days prior to Screening and until completion of the sirolimus regimen, due to potential interaction with sirolimus.