Inclusion Criteria: 1. A male or female ≥ 4 months of age. 2. Willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to any study-related procedures. If the participant is unable to provide informed consent, then informed assent will be obtained, and informed consent must be provided by the participant's legal guardian. 3. Having previously documented diagnosis of MPS I confirmed by molecular genetic testing, or IDUA deficiency in leucocytes or fibroblasts. 4. Has documented evidence of CNS involvement due to MPS I based on one of the following criteria, if not explainable by any other neurologic or psychiatric factors: 1. A score of ≥ 1 standard deviation below mean on neurodevelopmental testing or in 1 domain of neuropsychological function. 2. A decline of \> 1 standard deviation on sequential neurodevelopmental testing or in 1 domain of neuropsychological function administered between 3 to 36 months apart. 3. Has a documented diagnosis of severe MPS I confirmed by biallelic mutations predictive of the severe phenotype or has a relative clinically diagnosed with severe MPS I and the same IDUA mutations. This participant is not required to have documented evidence of neurocognitive deficit. 5. Participants who have had HSCT may be enrolled in the study if the investigator, Medical Monitor, and Sponsor agree that he/she can safely and successfully participate in the study. 6. Has sufficient auditory and visual capacity, with or without aids, to complete the required protocol testing and willing to be compliant with wearing the aid, if applicable, on testing days. 7. Females of childbearing potential must have negative serum pregnancy test at the screening visit, have negative results on Day 1, and be willing to have additional pregnancy tests during the study. 8. Sexually active male participants must be willing to use a medically accepted method of barrier contraception (eg, condom or female diaphragm) from the screening visit until 24 weeks after vector administration. Cessation of birth control after this point should be discussed with the participant's physician. 9. Sexually active females must be willing to use an effective method of birth control from the screening visit until 12 weeks after the last dose of sirolimus or tacrolimus, whichever is later. Cessation of birth control after this point should be discussed with the participant's physician. Effective methods of birth control include a double barrier method (eg, male condom plus a diaphragm), an intrauterine device, or hormonal contraception. Sustained abstinence is an acceptable practice; however, periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. Exclusion Criteria: 1. Has any contradiction to MRI, contrast or to general anesthesia 1. Has any contradiction to gadolinium 2. 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 that the creatinine level is less than the lower limit of assay validation or detection, then the lowest limit cutoff value will be used for the eGFR. 2. Has a contradiction for an IC and IVR infusion, including any of the following: 1. Review of baseline MRI testing by the team of neuroradiologists/neurosurgeons participating in the study (1 per site) shows a contraindication for an IC and an IVR infusion. 2. History of prior head/neck surgery, which resulted in a contraindication to IC and IVR infusion, based on review of available information by the team of neuroradiologists/neurosurgeons participating in the study. 3. Has previously experienced a clinically significant intracranial bleed that, in the opinion of the investigator and team of neuroradiologists/neurosurgeons, is a contraindication to IC and IVR infusion. 3. Has any neurocognitive deficit not attributable to MPS I or has a diagnosis of a neuropsychiatric condition that may, in the opinion of the investigator, confound interpretation of study results. 4. Has any contradiction to lumbar puncture. 5. Has received IT laronidase at any time and experienced a significant AE considered related to IT administration that, in the opinion of the investigator, would put the participant at undue risk. 6. Has received IV laronidase at any time and experienced a significant AE considered related to IV administration that, in the opinion of the investigator, would put the participant at undue risk. 7. Has imminent plans to receive HSCT within the next year. 8. Has any history of lymphoma or history of another cancer other than squamous cell or basal cell carcinoma of the skin that has not been in full remission for at least 3 months before screening. 9. Has uncontrolled hypertension (systolic BP \> 180 mmHg, diastolic BP \> 100 mmHg) despite maximal medical treatment. 10. Has alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> 3 × ULN or total bilirubin \> 1.5 × ULN at screening, unless the participant has a previously known history of Gilbert's syndrome and a fractionated bilirubin that shows conjugated bilirubin \< 35% of total bilirubin. 11. Has a history of human immunodeficiency virus (HIV) or hepatitis B or hepatitis C virus infection, or positive screening tests for hepatitis B surface antigen or hepatitis B core antibody, or hepatitis C or HIV antibodies. 12. Received any IP within 30 days or 5 half-lives before signing of the Informed consent form (ICF), whichever is longer. 13. Is a first-degree family member of a clinical site employee or any other individual involved in the conduct of the study, or is a clinical site employee or any other individual involved in the conduct of the study. 14. Is pregnant, \< 6 weeks postpartum, breastfeeding at screening, or planning to become pregnant (self or partner) at any time from signing of informed consent through Week 52. Plans to become pregnant after Week 52 should be discussed with the participant's physician. 15. Has history of alcohol or substance abuse within 1 year before screening. 16. Has a clinically significant ECG or transthoracic echocardiogram abnormality that, in the opinion of the investigator, would compromise the participant's safety. 17. Has a serious or unstable medical or psychological condition that, in the opinion of the investigator, would compromise the participant's safety or successful participation in the study or interpretation of study results. Exclusion criteria related to immunosuppressive therapy: 18. A history of a hypersensitivity reaction to tacrolimus, sirolimus, or prednisone. 19. A history of a severe immunodeficiency (eg, common variable immunodeficiency syndrome), splenectomy, or any underlying condition that predisposes the participant to infection. 20. Varicella zoster virus (VZV), herpes zoster (shingles), CMV, or EBV infection that has not completely resolved at least 12 weeks prior to screening. 21. Any infection requiring hospitalization or treatment with parenteral anti-infectives not resolved at least 8 weeks prior to Visit 2. 22. Any active infection requiring oral anti-infectives (including antivirals) within 10 days prior to Visit 2. 23. History of active tuberculosis (TB) or a positive QuantiFERON-TB Gold test during screening. 24. Any live vaccine within 4 weeks prior to Day -2. 25. Major surgery within 8 weeks before signing the ICF or major surgery planned during the study period. 26. Absolute neutrophil count \< 1.3 × 103/µL. 27. Any condition or laboratory abnormality that the investigator believes would not be appropriate for immunosuppressive therapy.