Multiple sulfatase deficiency (MSD) is an ultra-rare, fatal neurodegenerative disorder with emerging therapeutic options, including an AAV9 gene therapy and drug repurposing. With several investigational drug candidates undergoing clinical planning, there is an urgent unmet need to identify optimal patient-centric clinical endpoints.

Our prior work defined distinct phenotypes of MSD (severe and attenuated), which correlate with genotype and a novel biomarker, glucosaminoglycan non-reducing ends (GAG-NREs). Despite its rarity, we have enrolled more than 40 individuals in our ongoing natural history study, which represents a large proportion of the known global population. This ongoing study includes collection of historical medical records, longitudinal administration of clinical outcome assessments (COA) in parallel with the collection of biospecimens. This work leverages the resources of the Rare Disease Clinical Research Network (RDCRN)-funded Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN), which supports the regulatory infrastructure of the MSD natural history study. The disease severity and complexity of MSD requires a patient-centric approaches for clinical trial design, utilizing concepts of interest most meaningful to patients and families.

We report an ex‑vivo lentiviral gene therapy approach for multiple sulfatase deficiency (MSD) using autologous hematopoietic stem/progenitor cells engineered to express formylglycine generating enzyme (FGE). Transduced cells showed stable vector integration and correction of biochemical markers of disease.  In relevant cellular assays, restored sulfatase activities reduced substrate storage and improved lysosomal markers. In vivo, treated animals demonstrated durable engraftment and biochemical correction in hematopoietic and neural tissues. We are exploring microglia–neuron interactions in vitro to optimize vector design and dosing for clinical translation efforts.

Formylglycine generating enzyme (FGE) is an essential catalyst in the post translational activation of sulfatases, and its loss of function underlies the pathology of multiple sulfatase deficiency (MSD). Pharmacological chaperones capable of stabilising misfolded or destabilised FGE represent a promising therapeutic strategy to restore residual enzymatic activity in vivo. Building on our recent fragment based screening campaign, we will present an update on our ongoing efforts to discover and optimise small molecule FGE stabilisers. We will highlight new structural biology insights that define ligandable pockets; computer aided drug design guiding fragment elaboration and scaffold selection; synthetic chemistry achievements to explore an emerging structure–activity relationship; and in vitro biophysical and biochemical data demonstrating the stabilising potential of our latest compounds.

Together, these results outline a developing and increasingly coherent discovery programme aimed at establishing the foundations for future pharmacological chaperones targeting MSD.

Multiple sulfatase deficiency (MSD, OMIM 272200) is an ultra-rare, multisystemic neurogenerative disorder caused by the loss of formylglycine generating enzyme (FGE) which is crucial for the activation of all cellular sulfatases. These includes sulfatases that are defective in five mucopolysaccharidosis (MPS) subtypes (i.e., MPS II, IIIA, IIID, IVA, VI), metachromatic leukodystrophy (MLD), and Steroid sulfatase (STS) deficiency. Based on the age of symptom onset, organs involved and extent of psychomotor development, MSD can be characterized into a clinical spectrum from severe to attenuated forms. Although genotype–phenotype correlations have been reported, they remain incompletely defined, highlighting the need for integrated biochemical characterization to support disease severity stratification. In addition, disease-modifying therapies for MSD are currently under development. Therefore, comprehensive biochemical profiling will be critical not only for improving disease characterization and understanding of pathophysiology, but also for identifying biomarkers capable of monitoring disease progression and therapeutic response. 

The biochemical hallmark of MSD is the accumulation of substrates associated with the impaired sulfatases, including glycosaminoglycans (GAGs), endogenous non-reducing end (NRE) GAG biomarkers, sulfatides, and cholesterol sulfate (CS), in biofluids and tissues. Because MSD results in the combined deficiency of multiple sulfatases, comprehensive biochemical profiling across multiple substrate classes is particularly important to capture the full spectrum of metabolic derangements associated with the disease. To address this, we profiled endogenous NRE GAG biomarkers, sulfatides, and CS in urine, plasma, and CSF from 19 MSD patients and 10 obligate carriers using liquid chromatography–tandem mass spectrometry. These disease-specific biomarkers directly reflect the underlying enzyme deficiencies and therefore serve as powerful probes for investigating the biochemical abnormalities associated with MSD.

Our preliminary results demonstrated that urinary endogenous NRE GAG biomarker profiles are highly characteristic of MSD. Among these, the MPS IIID-specific biomarker emerged as the most sensitive biomarker for MSD detection. Furthermore, the levels and patterns of sulfatase-relevant biomarkers, including NRE GAG biomarkers, sulfatides, and CS, differed between patients with severe and attenuated disease phenotypes, supporting a relationship between biochemical abnormalities and clinical severity. Future analyses integrating biochemical and clinical data will further evaluate the utility of these biomarkers for disease stratification and therapeutic monitoring in MSD.

Good nutrition is important for all children, but it can be especially important for children who may experience unique challenges related to eating, feeding, growth, and nutrition. Children may have sensory sensitivities, oral-motor difficulties, food selectivity, or challenges with mealtime routines. Collaboration with healthcare providers, dietitians, speech-language pathologists, occupational therapists, and other members of the care team can help address feeding concerns and support individualized strategies.

This presentation will review the basics of good nutrition for children, including meeting nutritional needs through foods, complete formulas, or a combination of both. We will discuss the key nutrients that support growth, development, and overall health.

MSD is classically associated with severe, early-onset multisystem disease. In this talk, I will present three individuals with biallelic SUMF1 variants and an attenuated clinical phenotype. Two adult patients first presented to the eye clinic with retinal dystrophy as their sole or predominant complaint, with no prior diagnosis of MSD; in one of these, no extra-ocular features have been identified to date. In all three, biochemical testing confirmed reduced but not absent sulfatase enzyme activity, consistent with hypomorphic SUMF1genotypes. These cases expand the phenotypic spectrum of MSD to include retinal-predominant and isolated retinal disease, and highlight the importance of including SUMF1 in inherited retinal disease gene panels to ensure timely and accurate diagnosis.

Background

The key defect in Multiple Sulfatase Deficiency (MSD) is the loss of function of formylglycine-generating enzyme (FGE). Mutations in the gene coding for FGE compromise FGE’s function, often due to incorrect protein folding and low intracellular protein stability. We want to develop pharmacological chaperones, i.e. small molecules that stabilize FGE in cells and thereby rescue its function. Pharmacological chaperones have become a treatment option for other lysosomal storage diseases. For example, Migalastat was approved for treatment of Fabry’s disease.

Results

We performed a crystallographic screen to test more around 1200 fragments and found more than 80 fragments that bind to FGE. Fragments are smaller than usual drugs and their binding to FGE is generally not strong enough to result in sufficient stabilization of FGE. Therefore, fragments serve as starting point for optimization into larger and tighter-binding drug-like molecules. Our collaborator Matthias Baud performs this optimization. For efficient optimization, structural information about the interaction between the fragments and FGE from X-ray crystallography is essential. Our data show eight binding sites on FGE with most fragments binding to site 1 (=active site), site 2 or site 3. Fragments that bind to sites different from the active site are expected not to impair FGE’s normal function, i.e. the activation of its sulfatase substrates. Our results suggest that FGE should be druggable, i.e. the development of pharmacological chaperones should be possible in principle. The almost 90 fragments that we found to bind to FGE and the detailed visualization of their binding mode will help medicinal chemists to rationally design larger optimized molecules that will eventually be tested for their therapeutic effect in cell culture or in animal models for MSD.

Multiple sulfatase deficiency (MSD; MIM #272200) is a devastating lysosomal disorder with no approved disease-modifying therapy and a major unmet medical need. To accelerate therapeutic development, we pursued a drug-repurposing strategy based on biochemical sulfatase activity screening in patient-derived disease models.

In an initial high-throughput screen, we identified the third-generation retinoid tazarotene as a compound capable of reversing key features of MSD cellular pathology in vitro. Tazarotene was subsequently advanced within the EU-funded REMEDI4ALL initiative. Through target product profiling, gap analysis, pediatric reformulation, and access to existing preclinical and clinical data via industry collaboration, this program has generated a translational roadmap toward the first clinical trial in MSD patients, currently planned for early 2027.

Given the known safety concerns of retinoids, particularly in children, we established a parallel backup strategy to identify additional repurposing candidates. To this end, we developed an automation-compatible screening platform by miniaturizing an Arylsulfatase A-based assay, one of the sulfatases that is dysfunctional in MSD patients, and applied it to a library of 5,632 marketed, clinical, mature preclinical and withdrawn compounds. The campaign identified 56 confirmed hits with reproducible activity across independent experiments. 

These candidates are now being advanced in CHAMPION (Compound Hit Analysis for MSD Patients to Investigate and Optimize Novel Therapies), a newly funded multinational European Rare Disease Research Alliance (ERDERA) consortium. CHAMPION will systematically rank and validate the most promising compounds through in vitro and in vivo studies, including mode-of-action analysis, early safety assessment, and PK/PD profiling. Together, these efforts establish a translational pipeline from drug screening to clinical development in MSD and may provide a broader framework for repurposing-based therapy development in rare lysosomal diseases.

Multiple sulfatase deficiency (MSD) is associated with neurological signs and symptoms resulting from central nervous system involvement and peripheral neuropathy. Brain pathology is reflected by characteristic abnormalities on cerebral magnetic resonance imaging (MRI). To date, descriptions of MRI patterns in MSD have largely been limited to monographs and case reports, often lacking standardized imaging protocols and prospective assessment.

To comprehensively characterize cerebral MRI findings in MSD, we analyzed 60 MRI datasets from 22 patients with MSD. Of these, 55 datasets were obtained from longitudinal assessments in 17 patients, whereas 5 represented single time-point examinations. Qualitative image analysis facilitated identification of pathological features, of which leukodystrophy and atrophy were the most frequent. Volumetric analysis demonstrated a progressive loss of brain volume over time. Magnetic resonance spectroscopy data were available for 11 patients.

To our knowledge, these data represent the largest cohort and the most comprehensive analysis of cerebral MRI findings in MSD to date. Ongoing analyses aim to further define the temporal evolution of MRI changes in MSD and to assess potential correlations with clinical manifestations, particularly motor function.

Professor and researcher Alia Crum is famous for saying and then proving in her studies that “the effect you expect is the effect you get.” Our minds are remarkable in their ability to find evidence that supports their premise.  I think this is true in caregiving.  If we believe that burnout is a certainty and unavoidable, we will find enough evidence to support that belief until we end up there.

But what if it doesn’t have to be that way?  Before you write me off as a nut or as someone who doesn’t get the reality of your life, I know your life is hard.  To some degree, I live it. But what if the way we see our life and the person we care for has as much to do with thriving or burning out as the job itself?

When you think about providing the best life possible for your child, does it energize or drain you? When you think about the smile on their face that your actions produce, does it make you want to do it again or run away?  Showing compassion and doing good for your child actually produces energy not fatigue.

In this session, we’re going to talk about how to be intentional in creating a mindset toward caregiving that brings life, not despair.