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 ABO-102 for the treatment of MPS IIIA.

Open-label, single dose, dose-escalation clinical trial of ABO-102 (scAAV9.U1a.hSGSH) injected intravenously through a peripheral limb vein. A tapering course of prophylactic enteral prednisone or prednisolone will be administered for a period of at least three months. At approved sites immunosuppression (IS) 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 IS therapy. Not all participants may receive IS therapy. This study was previously posted by Abeona Therapeutics, Inc and was transferred to Ultragenyx in August 2022.

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.

The Principal Investigator and/or caregiver, in consultation with the medical monitor, will determine whether to initiate adjuvant IS therapy. Not all participants may receive IS therapy.

Change from Baseline in Cognitive Domain Bayley Scales of Infant and Toddler Development Raw Scores-Third edition (BSID-III)

If Applicable, According to the Appropriate Developmental Age, Non-verbal Index Raw Scores for Kaufman Assessment Battery for Children-Second Edition (KABC-II)

Number of Participants with Adverse Events, Treatment-emergent Adverse Events, and Serious Adverse Events

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 (DQ) 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 Principal Investigator (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 equivalent to a positive screen as determined by ELISA in serum Subjects with a positive response for the enzyme-linked immunosorbent spot (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 Hematopoietic Stem Cell transplantation Previous participation in a gene/cell therapy or enzyme replacement therapy (ERT) clinical trial

Fu H, Cataldi MP, Ware TA, Zaraspe K, Meadows AS, Murrey DA, McCarty DM. Functional correction of neurological and somatic disorders at later stages of disease in MPS IIIA mice by systemic scAAV9-hSGSH gene delivery. Mol Ther Methods Clin Dev. 2016 Jun 8;3:16036. doi: 10.1038/mtm.2016.36. eCollection 2016.

Fu H, Meadows AS, Pineda RJ, Kunkler KL, Truxal KV, McBride KL, Flanigan KM, McCarty DM. Differential Prevalence of Antibodies Against Adeno-Associated Virus in Healthy Children and Patients with Mucopolysaccharidosis III: Perspective for AAV-Mediated Gene Therapy. Hum Gene Ther Clin Dev. 2017 Dec;28(4):187-196. doi: 10.1089/humc.2017.109. Epub 2017 Oct 24.

McCurdy VJ, Johnson AK, Gray-Edwards HL, Randle AN, Bradbury AM, Morrison NE, Hwang M, Baker HJ, Cox NR, Sena-Esteves M, Martin DR. Therapeutic benefit after intracranial gene therapy delivered during the symptomatic stage in a feline model of Sandhoff disease. Gene Ther. 2021 Apr;28(3-4):142-154. doi: 10.1038/s41434-020-00190-1. Epub 2020 Sep 3.