Overview

OTL-200 is a cryopreserved dispersion for infusion containing autologous CD34+ cell enriched population that contains haematopoietic stem and progenitor cells (HSPC) transduced ex vivo using a lentiviral vector encoding the human arylsulfatase A (ARSA) gene. MLD is an autosomal recessive lysosomal storage disorder (LSD) characterized by severe and progressive demyelination affecting the central and peripheral nervous system. The aim of this clinical study is to assess the pharmacodynamic effect and long-term clinical efficacy and safety of OTL-200 in Late Juvenile MLD patients.

Eligibility

Inclusion Criteria:

All the following criteria need to be met:

• Documented biochemical and molecular diagnosis of MLD, based on ARSA activity below the normal range and identification of two disease-causing ARSA alleles.
• 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. before their 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 of late-juvenile MLD variant 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 IQ85 on age appropriate cognitive scales.
• a) If the participant is <7 years (i.e. before their 7th birthday): normal motor milestones achievement, normal gross motor function according to chronological age and 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 mild gross motor function impairment, defined by a GMFC-MLD 0 or 1 (i.e. patient is able to walk independently).
• If applicable, participant willing and capable of compliance with contraceptive use requirements.
• Participant (or if applicable, parent/legal guardian) providing signed informed consent

Exclusion Criteria:

• Documented HIV infection (positive HIV RNA and/or anti-p24 antibodies).
• Malignant neoplasia (except localised skin cancer) or a documented history of hereditary cancer syndrome
• 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 of residual cells of donor origin.
• Previous gene therapy.
• Has symptomatic herpes zoster, not responsive to specific treatment.
• Evidence of active tuberculosis (TB) based upon medical examination, chest imaging and TB testing
• Acute or chronic stable Hepatitis B (HBV) 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 HBV DNA
• Presence of positive Hepatitis C RNA test result at screening
• 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 participant inappropriate for entry into this study.
• In addition to the potential infections tested per protocol, 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 must be discussed with the Orchard medical monitor prior to stem cell harvest.
• Participants 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 Orchard medical monitor and considered in the context of the criterion for excluding participants with other severe disease. Isolated elevation of total bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35% of total.