RGX-121-3102 Gene Therapy in Participants With MPS II (Hunter Syndrome)

Inclusion Criteria:

• The participant's legal guardian(s) is (are) willing and able to provide written,signed informed consent after the nature of the study has been explained, and priorto any study-related procedures being performed.

• Is a male ≥ 4 months to < 5 years of age on Day 1.

• Has a documented diagnosis of MPS II, with a confirmed neuronopathic phenotype.

• Has a BSID-III Cognitive Composite score at or below -1SD (85) from the normativemean.

• Has 2 consecutive neurodevelopment assessments that support a decline on MSEL VisualReception, Expressive Language, or Fine Motor, or BSID-III Cognitive, ExpressiveCommunication, or Fine Motor of ≥ 1 SD on serial neurodevelopment testingadministered between 3 to 36 months apart. Evidence for neurodevelopmental declinecan be provided from historical medical records.

• Has a relative clinically diagnosed with neuronopathic MPS II who has the same IDSvariant(s) as the participant AND the participant, in the opinion of a geneticist,has inherited a neuronopathic form of MPS II. Evidence for support of a relativewith neuronopathic MPS II should be provided through medical record documentation ofneurodevelopmental function at or below -2 SD from the normative mean. If standardscores are unavailable to document SD from the normative mean, a developmentalquotient (AEq/chronological age × 100) of ≤ 60 can be used to document neuronopathicMPS II.

• Has documented variant(s) in IDS known to result in a neuronopathic phenotype. Theparticipant's neuronopathic phenotype will be confirmed by an independent geneticreview, with documented supporting evidence from previously reported cases of thesame variant(s).

• Has sufficient auditory and visual capacity, with or without aids, to complete therequired protocol testing, and be compliant with wearing the aid, if applicable, ontesting days.

• Able to ambulate 100 meters independently without use of assistive devices, if theparticipant is, based on the judgement of the investigator, of a chronological ageat screening at which independent ambulation would typically be expected in a childwith neuronopathic MPS II.

• Provision of signed and dated informed consent form (ICF) and willingness to complywith all study procedures and availability for the duration of the study.

Exclusion Criteria:

• Has a contraindication for an intracisternal (IC) and intraventricular (IVR)infusion, including any of the following:

• Review of baseline MRI testing by the team of neuroradiologist/neurosurgeonsparticipating in study shows a contradiction for an IC and IVR infusion.

• History of prior head/neck surgery, which resulted in a contraindication to both ICand IVR infusion, based on review of available information by the team ofneuroradiologists/neurosurgeons participating in the study.

• Has any contradiction to computed tomography or general anesthesia.

• Has any contradiction to MRI or gadolinium.

• Has renal insufficiency as determined by an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2, based on creatinine. If the laboratory determines thatcreatinine is less than the lower limit of assay validation or detection, then thelowest limit cutoff value will be used to estimate eGFR.

• Has previously experienced a clinically significant intracranial bleed that, in theopinion of the investigator and team of neuroradiologists/neurosurgeons, is acontraindication to IC and IVR infusion.

• Has an elevated intracranial pressure (≥ 30 cm H2O).

• Has any neurocognitive deficit not attributable to MPS II or diagnosis of aneuropsychiatric condition that may, in the opinion of the investigator, confoundinterpretation of study results.

• Has any contraindication to lumbar puncture.

• Has a (cerebral) ventricular shunt that in the opinion of the site neuroradiologist/neurosurgeon and through discussion with the Medical Monitor, may impact theadministration and proper dosing of the participant.

• Has had prior treatment with AAV-based gene therapy product.

• Has undergone HSCT.

• Is receiving idursulfase (ELAPRASE) via IT administration, or a blood brainbarrier-crossing ERT. Participants receiving IT ELAPRASE or a blood brainbarrier-crossing ERT may enroll if they agree to discontinue these therapiesstarting at least 3 months prior to dosing with RGX-121, and for the duration offollow-up.

• Has received idursulfase (ELAPRASE) IV and experienced a serious hypersensitivityreaction, including anaphylaxis, deemed related to IV idursulfase (ELAPRASE)administration. If the participant has experienced a severe hypersensitivityreaction, they may enroll in the trial if the hypersensitivity has been treated andthe investigator, Medical Monitor, and Sponsor agree that it no longer poses asafety or efficacy risk.

• Has received any Investigational Product within 30 days of Day 1 or 5 half-livesbefore signing of the ICF, whichever is longer.

• Has any history of lymphoma or history of another cancer, other than squamous cellor basal cell carcinoma of the skin, that has not been in full remission for atleast 1 year before Screening.

• Has a history of human immunodeficiency virus (HIV) or hepatitis B or hepatitis Cvirus (HCV) infection, or positive screening tests for hepatitis B surface antigenor hepatitis B core antibody, or hepatitis C (either hepatitis C antibody or HCVRNA) or HIV antibodies.

• Has a clinically significant ECG abnormality that, in the opinion of theinvestigator, would compromise the participant's safety.

• Has a serious or unstable medical or psychological condition that, in the opinion ofthe investigator, would compromise the participant's safety or successfulparticipation in the study or interpretation of study results.

• Has uncontrolled seizures that in opinion of the investigator would put theparticipant at undue risk.

• Has uncontrolled hypertension despite medical treatment, defined for children ≤ 17years of age to be systolic blood pressure (SBP) or diastolic blood pressure (DBP) > 99th percentile plus 5mmHg based on normative standards for age, sex, and height.

• Has a platelet count < 100,000 per µL.

• Has ALT or AST > 3 × ULN or total bilirubin > 1.5 × ULN at Screening unless theparticipant has a previously known history of Gilbert's syndrome.

• Is a first-degree family member of a clinical site employee or of any otherindividual involved with the conduct of the study.

• REGENXBIO staff involved in the planning and/or conduct of the study.

• Employees of the study site or any other individuals involved with the conduct ofthe study or immediate family members of such individuals.

• Has any condition that would contraindicate treatment with methylprednisolone,prednisone, tacrolimus, or sirolimus.

• Has a history of a hypersensitivity reaction to methylprednisolone, tacrolimus,sirolimus, or prednisone.

• Has a history of a primary immunodeficiency (eg, common variable immunodeficiencysyndrome), splenectomy, or any underlying condition that predisposes the participantto infection.

• Has herpes zoster (varicella zoster virus [VZV]), CMV, or EBV infection that has notcompletely resolved at least 12 weeks prior to Screening.

• Has any infection requiring hospitalization or treatment with parenteralanti-infectives not resolved at least 8 weeks prior to Day -2.

• Has any active infection requiring oral anti-infectives (including antivirals)within 10 days prior to Day -2.

• Has a history of active tuberculosis (TB) or a positive Quantiferon-TB Gold testduring Screening.

• Has any live, replication-competent vaccine within 6 weeks prior to Day-2.

• Had major surgery within 8 weeks before signing the ICF or major surgery plannedduring the study period.

• Anticipates the need for adenoidectomy or tonsillectomy within 6 months ofenrollment. If adenoidectomy or tonsillectomy is anticipated, it should be performedprior to Screening.

• Has an absolute neutrophil count (ANC) < 1.0 × 103/µL.

• Has any condition or laboratory abnormality that the investigator believes would notbe appropriate for immunosuppressive therapy.