OTL-200 in Patients With Late Juvenile Metachromatic Leukodystrophy (MLD)

Inclusion Criteria: All the following criteria need to be met:

• Documented biochemical and molecular diagnosis of MLD, based on ARSA activity belowthe normal range and identification of two disease-causing ARSA alleles. Novelmutations will be analyzed with in silico prediction tools and excluded from beingknown common polymorphisms. In the case of a novel mutation(s), a 24-hour urinecollection must show elevated sulfatide levels.
• 0/R or R/R genotype or a genotype recognized as associated with the LJ variant of MLD.
• a) If symptomatic: age at disease onset between ≥7 and <17 years of age (i.e. beforetheir 17th birthday). OR
• b) If pre-symptomatic: participant must be <17 years of age at treatment (i.e. beforetheir 17th birthday) AND must have a sibling with a diagnosis of late-juvenile MLDvariant based on age at disease onset (≥7 and <17 years of age i.e. before sibling's 17th birthday), with biochemical and molecular diagnosis.
• Normal cognitive function as defined by an IQ≥85 on age appropriate cognitive scales.
• a) If the participant is <7 years (i.e. before their 7th birthday): normal motormilestones achievement, normal gross motor function according to chronological age andnormal neurological examination (if applicable based on the age of the subject,GMFC-MLD = 0) OR b) If participant is ≥7 years: normal gross motor function or mildgross motor function impairment, defined by a GMFC-MLD 0 or 1 (i.e. patient is able towalk independently). NOTE: The following will not be exclusionary if present alone: 1.) Seizures 2.) Signs ofthe disease revealed at instrumental evaluations (Electroneurography [ENG] and brain MR)
• If applicable, participant willing and capable of compliance with contraceptive userequirements.
• Participant (or if applicable, parent/legal guardian) providing signed informedconsent or assent as applicable

Exclusion Criteria:

• Documented HIV infection (positive HIV RNA and/or anti-p24 antibodies).
• Malignant neoplasia (except localised skin cancer) or a documented history ofhereditary cancer syndrome. Participants with a prior successfully treated malignancyand a sufficient follow-up to exclude recurrence (based on oncologist opinion) can beincluded after discussion and approval by the Medical Monitor.
• Myelodysplasia, cytogenetic alterations characteristic of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) or other serious haematological disorders.
• Patients currently enrolled in other interventional trials
• Has previously undergone allogeneic HSPC gene therapy (HSPC-GT) and has evidence ofresidual cells of donor origin.
• Previous gene therapy.
• Has symptomatic herpes zoster, not responsive to specific treatment. NOTE:Participants with a recent history of herpes zoster may be included in the study. Insuch cases, inclusion, additional monitoring and treatment of the condition must bediscussed and approved by the Medical Monitor.
• Evidence of active tuberculosis (TB) based upon medical examination, chest imaging andTB testing. Participants with latent tuberculosis, as documented by medical historyand/or TB testing may be included in the study if receiving antibiotic prophylaxis (e.g. isoniazid). Inclusion, monitoring and treatment of TB in such participants mustbe discussed and approved by the Medical Monitor.
• Acute or chronic stable Hepatitis B (HBV) as evidenced by positive Hepatitis B surfaceantigen (HBsAg) test result at screening or within 3 months prior to onset ofconditioning and/or positive HBV DNA. NOTE: Participants with positive Hepatitis Bcore antibody due to prior resolved disease may be enrolled, only if a confirmatorynegative HBsAg and negative Hepatitis B DNA test are obtained. Inclusion, monitoringand treatment of hepatitis in such participants must be discussed and approved by theMedical Monitor.
• Presence of positive Hepatitis C RNA test result at screening. NOTE: Patients who havepreviously tested positive for antibodies to hepatitis C can be treated, provided theydemonstrate absence of ongoing infection using a nucleic acid test with a limit ofquantification of ≤15 international units/ml. Negative test results are required on atleast 3 sequential occasions over a period of at least 4 weeks, after completion oftreatment for Hepatitis C, with the final test conducted no more than 3 days prior tocell harvest. Inclusion, monitoring and treatment of hepatitis in such participantsmust be discussed and approved by the Medical Monitor.
• End-organ dysfunction, severe active infection not responsive to treatment, or othersevere disease or clinical condition which, in the judgment of the investigator, wouldmake the participant inappropriate for entry into this study.
• In addition to the potential infections tested per protocol, the PI should considertesting for other transmissible infectious agents listed in the European Union (EU)Cell and Tissue Directive as clinically appropriate and results must be discussed withthe Orchard medical monitor prior to stem cell harvest.
• Participants with alanine transferase (ALT) >2x upper limit of normal (ULN) or totalbilirubin >1.5xULN may be included only after discussed and agreed with the Orchardmedical monitor and considered in the context of the criterion for excludingparticipants with other severe disease. Isolated elevation of total bilirubin >1.5xULNis acceptable if bilirubin is fractionated and direct bilirubin <35% of total.