A Safety and Efficacy Study of Cryopreserved OTL-200 for Treatment of Metachromatic Leukodystrophy (MLD)

OTL-200 is autologous CD34+ cells transduced with lentiviral vector containing human arylsulfatase A (ARSA) complementary deoxyribonucleic acid (cDNA) used for the treatment of MLD. MLD is an autosomal recessive lysosomal storage disorder (LSD) characterized by severe and progressive demyelination affecting the central and peripheral nervous system. This study will assess safety and efficacy of treatment using cryopreserved formulation of OTL-200 in pediatric subjects with pre-symptomatic Early Onset MLD (Late Infantile (LI) to Early Juvenile (EJ) MLD) and early symptomatic EJ MLD.


Eligibility Criteria:
Inclusion Criteria:

* Documented biochemical and molecular diagnosis of MLD, based on ARSA activity below the normal range and identification of two disease-causing ARSA alleles, either known or novel mutations. Novel mutations will be analyzed with in silico prediction tools and excluded from being known common polymorphisms. In the case of a novel mutation(s), a 24-hour urine collection must show elevated sulfatide levels.
* Eligible subjects must have EITHER

  1. an older sibling affected by MLD (index case), whose age of symptom onset was \<=6 years of age (i.e., had not celebrated 7th birthday). Subjects will be classified as LI, EJ or intermediate LI/EJ based on age of symptom onset in the index case and their ARSA genotype; LI: symptom onset in index case \<=30 months of age and genotype typically 0/0; EJ: symptom onset in index case \>30 months and \<= 6 years of age with genotype typically 0/R; Intermediate LI/EJ: symptom onset in index case \<= 6 years of age but unable to unambiguously characterize index case as LI or EJ OR
  2. if MLD is diagnosed in a pre-symptomatic child without an older affected sibling, (e.g.) incidentally or via newborn screening) and the totality of the data available to the investigator strongly suggest that the subject has an early onset variant of MLD likely to benefit from gene therapy, and the subject is \<=6 years of age (i.e., has not celebrated 7th birthday), the subject may be considered eligible after discussion and approval by the Orchard medical monitor.
* Parental/guardian signed and dated informed consent.

Exclusion Criteria:

* If LI MLD variant, clinical manifestations of the disease defined as EITHER of the following:

  * delay in expected achievement of independent standing or independent walking, together with abnormal signs at neurological evaluation
  * Or documented neurological signs and symptoms of MLD associated with cognitive, motor, or behavioural functional impairment or regression (substantiated by neurological examination and/or neuropsychological tests appropriate for age).

If EJ MLD variant, symptoms of MLD resulting in the loss of capacity of walking independently as defined by a GMFC level ≥2 or symptoms consistent with cognitive impairment as defined by an IQ\<85 using age-appropriate neurocognitive instruments.

NOTE: The following will not be exclusionary if present alone:

* Seizures
* Signs of the disease revealed at instrumental evaluations (Electroneurography \[ENG\] and brain MR)

  * Documented HIV infection (positive HIV RNA and/or anti-p24 antibodies).
  * Malignant neoplasia (except local skin cancer) or a documented history of hereditary cancer syndrome. Subjects with a prior successfully treated malignancy and a sufficient follow-up to exclude recurrence (based on oncologist opinion) can be included after discussion and approval by the Medical monitor.
  * Myelodysplasia, cytogenetic alterations characteristic of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), or other serious hematological disorders.
  * Subjects currently enrolled in other interventional trials.
  * Has previously undergone allogeneic hematopoietic stem cell transplantation and has evidence of residual cells of donor origin.
  * Previous gene therapy.
  * Has symptomatic herpes zoster, not responsive to specific treatment. Subjects with a recent history of herpes zoster may be included in the study. In such cases, inclusion, additional monitoring and treatment of the condition must be discussed and approved by the medical monitor.
  * Evidence of active tuberculosis (TB) based upon medical examination, chest imaging and TB testing i.e. QuantiFERON-TB Gold test and microbiological evidence. Subjects with latent tuberculosis, as documented by medical history and/or TB testing may be included in the study if receiving antibiotic prophylaxis (e.g. isoniazid). Inclusion, monitoring and treatment of TB in such subjects must be discussed and approved by the medical monitor.
  * Acute or chronic stable Hepatitis B as evidenced by positive Hepatitis B surface antigen (HBsAg) test result at screening or within 3 months prior to onset of conditioning and/or positive hepatitis B virus (HBV) DNA. Subjects with positive Hepatitis B core antibody due to prior resolved disease may be enrolled, only if a confirmatory negative Hepatitis B surface antigen and negative Hepatitis B DNA test are obtained. Inclusion, monitoring and treatment of hepatitis in such subjects must be discussed and approved by the medical monitor.
  * Presence of positive Hepatitis C RNA test result at screening; subjects who have previously tested positive for antibodies against hepatitis C can be treated, provided they demonstrate absence of ongoing infection using a nucleic acid test with a limit of quantification of \<=15 international units/milliliter (IU/mL). Negative test results are 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 more than 3 days prior to cell harvest. Inclusion, monitoring and treatment of hepatitis in such subjects must be discussed and approved by the medical monitor.
  * End-organ dysfunction, severe active infection not responsive to treatment, or other severe disease or clinical condition which, in the judgment of the investigator, would make the subject inappropriate for entry into this study. In addition to the potential infections the PI should consider testing for other transmissible infectious agents listed in the European Union (EU) Cell and Tissue Directive as clinically appropriate and results discussed with the medical monitor prior to cell harvest.
  * Subjects with alanine transferase (ALT) \>2x upper limit of normal (ULN) or total bilirubin \>1.5xULN may be included only after discussed and agreed with the medical monitor and considered in the context of the criterion for excluding subjects with other severe disease.
  * Isolated elevation of total bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35 percent of total.