Gene therapy hope for rare brain disease in children

Copied word for word from the study's registry entry, so the wording is the study team's rather than ours.

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. 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. * 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 IQ≥85 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). 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 use requirements. * Participant (or if applicable, parent/legal guardian) providing signed informed consent 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 of hereditary cancer syndrome. Participants 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 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. NOTE: Participants 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. Participants 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 participants must be discussed and approved by the Medical Monitor. * 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. NOTE: Participants with positive Hepatitis B core antibody due to prior resolved disease may be enrolled, only if a confirmatory negative HBsAg and negative Hepatitis B DNA test are obtained. Inclusion, monitoring and treatment of hepatitis in such participants must be discussed and approved by the Medical Monitor. * Presence of positive Hepatitis C RNA test result at screening. NOTE: Patients who have previously tested positive for antibodies to 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/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 participants 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 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.