This is a Phase 1/2, open-label, multiple-dose, dose-escalating study to evaluate the safety, tolerability, and plasma and CSF concentrations of GTX-102 in pediatric patients participants with AS.

The study includes screening, baseline, treatment, and safety follow-up periods. Eligible patients who meet all of the inclusion criteria and none of the exclusion criteria and who successfully complete all screening and baseline assessments will be assigned to one of 5 sequential dose cohorts. GTX-102 will be administered by intrathecal (IT) injection via lumbar puncture (LP) at Baseline followed by 3 subsequent IT injections on study Days 30, 58 and 86. The procedure for IT administration of GTX-102 will performed by a clinician with experience in LP and anesthetic care will be directed by experienced anesthesiologists with a focus on patient safety and comfort. The total duration of study for each patient is anticipated to be approximately 6 months. An open-label extension (OLE) study will be conducted under a separate protocol where patients can receive continued treatment with GTX-102. The study includes a Loading phase followed by a Maintenance phase. Participants may continue on GTX-102 during the Maintenance phase of the study until GTX-102 is commercially available, intolerable toxicity occurs, the parent/legal guardian withdraws consent, the participant enrolls in another experimental study, or this study is terminated.

This study was previously posted by GeneTX Biotherapeutics, LLC and was transferred to Ultragenyx in July 2022.

Inclusion Criteria:

• Signed informed consent from parent(s) or legal guardian(s)
• Documented genetic confirmation of full maternal UBE3A gene deletion causing AS (e.g. DNA methylation testing with either a chromosomal microarray or FISH) in the region of 15q11.2-q13 including class I, II or III ).
• Age ≥ 4 to ≤ 17 years at screening
• Stable seizure control (defined as clinically stable with no changes in antiepileptic medications over the prior 1 month before the screening visit, other than weight associated dose adjustments)
• Able to ambulate independently, or with an assistive device (note, a child whose primary means of mobility is by wheelchair is excluded from the study)
• Platelet count, prothrombin time (PT) / international normalized ratio (INR) ratio, and partial thromboplastin time (PTT) within 1.2 x the normal limits
• Normal renal function with serum creatinine and spot urine protein within ≤ 1.4 x the upper limit of normal limits (ULN)
• Normal hepatic function with total bilirubin, aspartate aminotransferase (AST),alanine aminotransferase (ALT) and alkaline phosphatase within normal limits Normal hepatic function with total bilirubin, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase ≤ 1.4 x ULN. Exception: levels ≤ 2 × ULN are acceptable if due to anti-epileptic drugs (AEDs) or Gilbert syndrome
• Willing and able to comply with scheduled visits, drug administration plan, laboratory tests, study restrictions, and all study procedures LP. procedures, including LP procedure
• Able to tolerate the anesthetic regimen regimen, if required for LP procedure
• A female patient is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: Female of non-childbearing potential (ie, pre-menarche), Female of childbearing potential who agrees to remain abstinent (refrain from heterosexual intercourse) or use acceptable contraceptive methods during the treatment period and for at least 3 months after the final dose of GTX-102
• A male patient is eligible to participate if he agrees to remain abstinent (refrain from heterosexual intercourse) or use acceptable contraceptive methods during the treatment period and for at least 3 months after the final dose of GTX-102

Exclusion Criteria:

• Any change in medications (excluding antiepileptic drugs AEDs) or diet diet/supplements intended to treat symptoms of AS ( e.g. eg, sleeping aids, supplements, dietary change including ketogenic or low-glycemic index diet, other) over the prior 3 months 1 month before screening .
• Inability to ambulate independently or with an assistive device or caregiver hand-hold
• Any bleeding or platelet disorder
• Any clinically significant (CS) cardiovascular, endocrine, hepatic, renal, pulmonary, gastrointestinal, neurologic neurological, malignant, metabolic, psychiatric, or other condition that, in the judgment of the Investigator, will pose a safety risk, will make the patient unsuitable for participation in, and/or unable to complete the study procedures .
• Any laboratory abnormality, that, in the Investigator's opinion, could adversely affect the safety of the patient, make it unlikely that the course of treatment or follow up would be completed, or impair the assessment of study result
• Known positive for hepatitis B virus, hepatitis C virus, or human immunodeficiency virus
• Any active infection
• Bone, spine, bleeding, or other disorder that exposes the patient to risk of injury or unsuccessful lumbar puncture
• Drugs that increase the risk of bleeding ( e.g. eg, heparin, low molecular weight heparin, platelet inhibitors) .
• Use of any investigational oligonucleotide in the past 6 months
• Any prior use of gene therapy
• Use of any investigational drugs in the past 6 months Use of any investigational drugs in the past 6 months or within 5 half-lives, whichever period is greater (with the exception of prior GTX 102)
• Known hypersensitivity to any oligonucleotide, as demonstrated by an immune mediated reaction (eg, pneumonitis, hepatitis, nephritis, neuritis, or other system inflammation), or a systemic allergic reaction such as signs and symptoms of anaphylaxis, urticaria, clinically significant rash
• Patient is pregnant or lactating
• Any medical condition that would require intubation for the anesthesia procedure
• Any medical condition that would require intubation for the anesthesia procedure