Drug Repurposing To Tackle Multiple Sulfatase Deficiency

Drug repurposing has emerged as a critical strategy for accelerating therapeutic development in rare diseases, where traditional pipelines often stall due to limited patient numbers, high costs, and disease heterogeneity.  

Multiple sulfatase deficiency is an ultra-rare lysosomal storage disorder with no approved curative treatment. At the Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Annika Wittich is working to identify existing drug candidates that might treat MSD. 

Ahead of her talk at the Society for Laboratory Automation and Screening (SLAS) Europe Conference 2026, Technology Networks spoke with Wittich to discuss the biology of MSD, the rationale behind drug repurposing, and how a high‑throughput screening approach is uncovering promising therapeutic leads. 

The biology and clinical burden of MSD 

MSD is an extremely rare inherited lysosomal storage disorder that affects fewer than 1 in 500,000 people.  

“It is caused by mutations in the SUMF1 gene, which encodes the formylglycine-generating enzyme (FGE),” explained Wittich. “FGE's function is essential for the post-translational activation of all 17 cellular human sulfatases, most of which are localized in the lysosome.”

 

Sulfatases are essential for degrading glycosaminoglycans and sulfatides. When they become dysfunctional due to FGE impairment, these biomolecules accumulate in the lysosomes, which causes tissue and organ damage, eventually leading to organ failure.

Symptoms, including developmental delays, liver and bone problems, vision loss, epilepsy, and loss of motor and cognitive abilities, emerge in early childhood. The average life expectancy for a child with MSD is around 13 years. 

“No curative treatment options are currently available for MSD,” said Wittich. 

What do we know about MSD? 

• Pathogenic mutations to the SUMF1 gene disrupt the function of FGE, preventing the proper activation of all 17 human sulfatases. 

• MSD affects multiple organ systems and presents with variable symptoms and severity. 

• There is currently no cure for MSD; instead, treatment focuses on symptom management. 

Why drug repurposing offers a strategic advantage for MSD 

Like many other rare diseases, drug discovery for MSD faces challenges throughout the pipeline. 

“The small patient population and associated economic constraints by big pharma make it difficult to justify large, de novo drug development efforts,” explained Wittich. “This makes repurposing existing compounds an attractive strategy.” 

As data on the pharmacokinetics, pharmacodynamics, and safety of existing compounds is already available, drug repurposing could reduce the timeline and associated costs of drug development for rare diseases. 

However, “the limited number of patients can complicate the design and execution of clinical studies, creating challenges for efficacy testing and regulatory approval of identified repurposable compounds,” noted Wittich. 

 

“MSD poses the unique challenge, but also opportunity, to restore FGE function in order to reactivate the entire sulfatase system,” she continued. 

Beyond restoring FGE, compounds that alleviate secondary pathologies—such as substrate accumulation, impaired autophagy, mitochondrial dysfunction, or disrupted signaling—may offer complementary therapeutic benefit. 

Strategic considerations for repurposing in MSD: 

• Repurposing leverages existing safety and pharmacokinetics and pharmacodynamics data to accelerate development. 

• Ultra‑rare disease populations make traditional drug pipelines economically challenging. 

• Restoring FGE could reactivate the entire sulfatase network, and targeting secondary pathologies may provide additional clinical benefit. 

High‑throughput screening to identify repurposable compounds 

For the drug repurposing screen, Wittich and her colleagues focused on arylsulfatase A (ARSA) activity in response to a small molecule library of 5,632 compounds, including preclinical and clinical candidates, marketed, and withdrawn drugs. 

“ARSA is one of the 17 sulfatases that are dysfunctional in MSD and is described as the major driver of severity and neurological decline of MSD patients,” explained Wittich. 

The team treated immortalized fibroblasts from an MSD patient with compounds from the repurposing library, followed by cell lysis. By adding an ARSA-specific substrate to the lysate that is cleaved into a product that increases optical density, they could measure the activity of ARSA—after it is activated by FGE—with a microplate reader. 

“Focusing on ARSA for the primary screen enabled us to develop a robust, relatively fast, and automation-compatible high-throughput screening assay, as the chemical substrate worked well in biochemical assays,” said Wittich. “Hit confirmation using additional sulfatase activity assays is also crucial for validating compound effects on FGE and to confirm that we do not just increase ARSA activity alone, but broadly restore sulfatase function.” 

From the repurposing screen, “several initial hits converged on shared targets that were not fully anticipated, making them particularly interesting for follow-up,” noted Wittich. “We observed common structural features across active compounds, suggesting a coherent shared mechanism of action.” 

“One of the most potent candidates stood out despite not yet being in the clinical stage, highlighting it as a promising lead for further development,” she said. 

Insights from the repurposing screen: 

• A 5,632‑compound library enabled broad exploration of repurposable candidates. 

• ARSA activity served as a robust, FGE‑dependent functional readout. 

• Multiple hits shared structural and mechanistic features. 

Prioritizing hits for preclinical development 

From the initial hits, Wittich and her colleagues ranked the top candidates based on potency, toxicity, target class predictions, and blood–brain barrier (BBB) permeability. 

“Compounds that already show a strong effect size with minimal toxicity at expected doses are far more likely to succeed in preclinical and early clinical studies,” said Wittich. 

“Target class prediction plays a central role in understanding the mechanism of action,” she continued. “Without a clear biological target, it is difficult to interpret results, optimize compound delivery, or design meaningful follow-up experiments.” 

 

By understanding the compound's primary target, the pathway  underlying the drug response can be validated through further experiments, and potential side effects or drug interactions can be anticipated. 

For MSD in particular, prioritizing hits based on their ability to penetrate the BBB is essential, given its neurological manifestations. “If a compound cannot effectively cross the BBB, it is unlikely to reach its site of action at sufficient concentrations, regardless of how potent it is in vitro,” explained Wittich. “We developed a model of the BBB using induced pluripotent stem cells, which will be used to assess BBB permeability of selected prioritized hits in cells derived from an MSD patient as well as in a gene-corrected control.”

“Patients and families facing MSD have limited time and currently lack effective treatment options. By rigorously selecting compounds using these early filters, the next steps are designed to move as efficiently as possible toward compounds that have the potential to make it into clinical trials.” – Annika Wittich. 

The prioritized compounds will need to undergo validation in primary cells derived from MSD patients and in in vivo animal studies. Further mechanistic studies will also characterize their mechanism of action and confirm their efficacy.  

This work will be conducted by the CHAMPION consortium, which is funded by the first Joint Transnational Call of the European Rare Disease Research Alliance and brings together international experts in drug development and MSD, alongside a patient organization. 

Criteria guiding lead optimization: 

• Potency and low toxicity determine feasibility for preclinical progression. 

• Target class prediction informs mechanism‑of‑action studies and safety considerations. 

• BBB permeability is essential for treating MSD’s neurological symptoms. 

Translating repurposing success to MSD: Insights ahead of SLAS Europe

At SLAS Europe 2026, Wittich will highlight these efforts toward finding a small molecule-based treatment option for MSD.  

“I will also briefly showcase a successful drug repurposing approach that was recently published in Cell,” she told Technology Networks. “Using patient-derived cells and new approach methodologies, we identified the phosphodiesterase 5 inhibitor sildenafil as a clinical candidate for another rare, neurometabolic disease called Leigh syndrome.” 

Based on these data, sildenafil was granted Orphan Drug Designation for the treatment of Leigh Syndrome by the European Medicines Agency, and a clinical trial is being planned. 

“My hope is that the drug repurposing strategy proven successful in Leigh syndrome can be similarly translated to MSD, ultimately offering new treatment options for patients,” concluded Wittich. 

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