Metachromatic leukodystrophy (MLD) is a rare lysosomal storage disease caused by deficient activity of arylsulfatase A (ASA). Treatment options for patients are limited; gene therapy based on haematopoietic stem cell transplantation is the only approved treatment for some subtypes of MLD. Any therapeutic benefit of treatments must be meaningful for patients and their families. We evaluated the clinical meaningfulness of slowing the decline in gross motor function as measured by the Gross Motor Function Classification in MLD (GMFC-MLD) from the caregiver perspective via semi-structured telephone interviews with caregivers of children with late-infantile MLD. We also evaluated the perceived significance of declines in communication abilities measured by the Expressive Language Function Classification in MLD (ELFC-MLD). This work could help to inform the endpoints of a phase 2 clinical trial (NCT03771898) assessing the efficacy of intrathecal recombinant human ASA in MLD.
Twelve caregivers were recruited, reporting on 12 children with MLD. Children had a mean age of 6.1 years; mean age at symptom onset was 17.6 months. Most children (10/12) progressed from walking without support (categories 0-1) to a loss of locomotion (categories 5-6) in ≤ 2 years. Caregivers felt that GMFC-MLD and ELFC-MLD accurately described motor and language declines in their children, respectively. Most caregivers (10/12) reported that the idea of delaying disease progression would be meaningful. Further, a slowing of motor function decline in GMFC-MLD, from category 1 to category 3 or from category 2 to category 4 over 2 years, was seen as meaningful by all caregivers asked; however, only 3/12 caregivers reported that delayed decline would be meaningful if baseline category was ≥ 3. Caregivers also reported that delaying expressive language decline at any level that did not indicate a complete loss of expressive language (indicated by categories 1-3) would be meaningful.
Caregivers of children with MLD felt that a delayed decline in gross motor function, as assessed by the GMFC-MLD, would be meaningful, supporting the selection of primary and secondary endpoints for the phase 2 clinical trial. Communication abilities were another area of significance for consideration in future clinical trial design.

UNASSIGNED: Cardiac surgery associated AKI (CSA-AKI) complicates recovery and may be associated with a greater risk of developing chronic kidney disease and mortality. The aim of this study was to assess long-term clinical consequences of transient increased activity of urinary enzymes after cardiac surgery (CS).
UNASSIGNED: An observational study was conducted in a group of 88 adult patients undergoing planned coronary artery bypass grafting (CABG), but all samples were obtained from 79 patients. The activity of urinary enzymes: N-acetyl-beta-glucosaminidase (NAG), arylsulfatase A (ASA) and beta-glucuronidase was evaluated in sequential urine samples. A comparative analysis of biochemical parameters was performed regarding the occurrence of acute kidney injury (AKI) defined by KIDGO at 24 hours, at day 30 and 5-years after the operation.
UNASSIGNED: During the first 24 hours after CS AKI was diagnosed in 13 patients. A comparison of the activity of urinary enzymes in pre-defined time-points showed significant differences for ASA and NAG (post OP-sample p < 0.028 and p < 0.022; POD 1 sample p < 0.004 and p < 0.001 respectively). No patient had any biochemical or clinical features of kidney failure at day 30. In the AKI group kidney failure was diagnosed in 36% of patients within 5 years of follow-up as opposed to 5% in the no AKI group. The activities of tubular enzymes in urine reflect a general injury of kidney tubules during and after the operation. However, they are not ideal biomarkers for prediction of the degree of kidney injury and further poor prognosis of CS-AKI.

Metachromatic leukodystrophy (MLD) is an autosomal recessive disorder caused by deficient arylsulfatase A (ASA) activity and characterized by neurological involvement that results in severe disability and premature death. We examined the safety and tolerability of intrathecally delivered recombinant human ASA (rhASA; SHP611, now TAK-611) in children with MLD (NCT01510028). Secondary endpoints included change in cerebrospinal fluid (CSF) sulfatide and lysosulfatide levels, and motor function (assessed by Gross Motor Function Measure-88 total score).
Twenty-four children with MLD who experienced symptom onset aged ≤ 30 months were enrolled. Patients received rhASA every other week (EOW) for 38 weeks at 10, 30, or 100 mg (cohorts 1-3; n = 6 per cohort), or 100 mg manufactured using a revised process (cohort 4; n = 6).
No rhASA-related serious adverse events (SAEs) were observed; 25% of patients experienced an SAE related to the intrathecal device or drug delivery method. Mean CSF sulfatide and lysosulfatide levels fell to within normal ranges in both 100 mg cohorts following treatment. Although there was a general decline in motor function over time, there was a tendency towards a less pronounced decline in patients receiving 100 mg.
Intrathecal rhASA was generally well tolerated at doses up to 100 mg EOW. These preliminary data support further development of rhASA as a therapy for patients with MLD.