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 ofMLD.

• 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.before their 17th birthday) AND must have a sibling with a diagnosis oflate-juvenile MLD variant based on age at disease onset (≥7 and <17 years of agei.e. before sibling's 17th birthday), with biochemical and molecular diagnosis.

• Normal cognitive function as defined by an IQ≥85 on age appropriate cognitivescales.

• a) If the participant is <7 years (i.e. before their 7th birthday): normal motormilestones achievement, normal gross motor function according to chronological ageand normal 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 ableto walk independently).

NOTE: The following will not be exclusionary if present alone: 1.) Seizures 2.) Signs of the 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 treatedmalignancy and a sufficient follow-up to exclude recurrence (based on oncologistopinion) can be included 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 imagingand TB testing. Participants with latent tuberculosis, as documented by medicalhistory and/or TB testing may be included in the study if receiving antibioticprophylaxis (e.g. isoniazid). Inclusion, monitoring and treatment of TB in suchparticipants must be discussed and approved by the Medical Monitor.

• Acute or chronic stable Hepatitis B (HBV) as evidenced by positive Hepatitis Bsurface antigen (HBsAg) test result at screening or within 3 months prior to onsetof conditioning and/or positive HBV DNA. NOTE: Participants with positive HepatitisB core antibody due to prior resolved disease may be enrolled, only if aconfirmatory negative HBsAg and negative Hepatitis B DNA test are obtained.Inclusion, monitoring and treatment of hepatitis in such participants must bediscussed and approved by the Medical Monitor.

• Presence of positive Hepatitis C RNA test result at screening. NOTE: Patients whohave previously tested positive for antibodies to hepatitis C can be treated,provided they demonstrate absence of ongoing infection using a nucleic acid testwith a limit of quantification of ≤15 international units/ml. Negative test resultsare required on at least 3 sequential occasions over a period of at least 4 weeks,after completion of treatment for Hepatitis C, with the final test conducted no morethan 3 days prior to cell harvest. Inclusion, monitoring and treatment of hepatitisin such participants must 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,would make 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 discussedwith the 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 >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35% oftotal.