Assessing disease progression and therapeutic intervention in Metachromatic Leukodystrophy

• Applicant: Professor Dr. Samuel Gröschel
• Subject Area: Pediatric and Adolescent Medicine
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 421769743

Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by a deficiency of the arylsulfatase A (ARSA). Therefore, sulfatides accumulate throughout the body, primarily in the nervous system and ultimately lead to progressive demyelination. Patients with MLD subsequently exhibit a deterioration in cognitive and motor function. With evolving therapeutic options such as gene therapy and hematopoietic stem cell transplantation (HSCT), there is an increasing need to identify biomarkers and quantify disease progression so to assess treatment efficacy and monitor outcome. The prediction of disease onset becomes crucial for paving the way for newborn screening in MLD and guiding treatment decisions, especially for pre-symptomatic individuals. During the past DFG funding period, we successfully established our database as a national registry for untreated and treated patients with MLD in Germany, collecting and investigating clinical, MRI, biosamples, and genetic data from over 150 patients. We were able to quantify disease progression using new parameters from MRI, clinical assessment, and biomarkers. Moreover, we acquired biosamples and follow-up data after HSCT and the recently approved ex vivo lentiviral gene therapy for MLD, as well as identified patients in a newborn screening pilot study. The objective of this renewal study is to comprehensively analyze this data in three work packages: 1. MLD brain microstructure as assessed by an advanced myelin-specific MRI protocol will be comparatively investigated in untreated and treated (HSCT and gene therapy) patients to identify biologically and clinically meaningful MRI biomarkers for quantifying disease progression in the brain. In addition, KI-based quantification of cerebral demyelination will be applied. 2. After having established a new nerve ultrasound methodology and reference parameters for the demyelination in the peripheral nervous system in children, the influence of neuropathy on the disease course in children with MLD will be investigated. 3. In a multi-omics approach, biosamples will be further investigated to predict and quantify disease progression. This will become especially important when predicting disease onset in patients identified by newborn screening. We will expand the previous OMICs studies and analyze the data in a combined approach. The analyzes include transcriptome and proteome data sets of MLD patients before and after therapeutic interventions and will be compared to other lysosomal disorders to characterize MLD specific changes. Our data will reveal new insights into the disease course, helping to harmonize treatment recommendations and give meaningful biomarkers for the prediction of disease course and evaluation of therapy.

• DFG Programme: Research Grants