RARE DISEASE
Metachromatic leukodystrophy
Metachromatic leukodystrophy
Metachromatic leukodystrophy
Synonyms: Arylsulfatase A deficiency, MLD
Synonyms: Arylsulfatase A deficiency, MLD
Synonyms: Arylsulfatase A deficiency, MLD
Drug discovery
9
drugs
With orphan designations
Overview
Metachromatic Leukodystrophy (MLD) is an autosomal recessive lysosomal storage disorder caused by deficient ARSA or PSAP gene activity, leading to sulfatide accumulation and progressive demyelination. Clinically, it manifests as neurodegeneration with motor decline, cognitive impairment, and psychiatric symptoms, classified into late infantile (most severe), juvenile, and adult-onset forms. Diagnosis relies on reduced arylsulfatase A activity, genetic testing, and MRI findings of white matter changes. No cure exists, but emerging therapies include gene therapy and hematopoietic stem cell transplantation (HSCT) for select patients [1][2][12].
Burden
High morbidity: Progressive loss of motor/cognitive function; 34% mortality in pediatric cohorts, with late infantile forms often fatal by age 5–8 [4][7].
Caregiver impact: Significant psychological/financial strain due to 24/7 care needs and ~$22,579/year/patient medical costs [4][15].
Diagnostic delays: >50% of leukodystrophy cases remain undiagnosed, complicating timely intervention [4][10].
Therapies
Supportive care: Physical/occupational therapy, seizure management, and nutritional support [6][14].
Disease-modifying: FDA-approved gene therapy (Lenmeldy®) for pre-symptomatic late infantile/juvenile MLD; HSCT for early-stage cases [12][16].
Experimental: Intrathecal enzyme replacement therapy (ERT), substrate reduction therapy, and pharmacological chaperones [3][8].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders, rare transplant-related disorders
Research Papers
334 drug discovery papers about Metachromatic leukodystrophy, with 2 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
334 drug discovery papers about Metachromatic leukodystrophy, with 2 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2024-11-27 | Emerging Role of Ubiquitin Proteasome System and Autophagy in Pediatric Demyelinating Leukodystrophies and Therapeutic Opportunity.
Leukodystrophies represent a heterogeneous group of disorders characterized by specific genetic mutations, metabolic abnormalities, and degeneration of white matter in the central nervous system. These disorders are classified into several categories, with X-linked adrenoleukodystrophy (X-ALD), metachromatic leukodystrophy (MLD), and globoid cell leukodystrophy (GLD) being the most prevalent demyelinating leukodystrophies in pediatric populations. Maintaining proteostasis, which is critical for normal cellular function, relies fundamentally on the ubiquitin-proteasome system (UPS) and autophagy for the degradation of misfolded and damaged proteins. Compelling evidence has highlighted the critical roles of UPS and autophagy dysfunction in the pathogenesis of neurodegenerative diseases. Given the complex and poorly understood pathomechanisms underlying demyelinating leukodystrophies, coupled with the pressing need for effective therapeutic strategies, this review aims to systemically analyze the molecular and pathological evidence linking UPS and autophagy dysfunction to demyelinating leukodystrophies, specifically X-ALD and GLD. Furthermore, we will assess the therapeutic potential of autophagy modulators in the management of X-ALD and GLD, with the objective to inspire further research into therapeutic approaches that target autophagy and UPS pathways. Novel therapies that enhance autophagy and UPS function hold promise as complementary regimens in combination therapies aimed at achieving comprehensive correction of the pathogenic mechanisms in demyelinating leukodystrophies.
2024-10-25 | Exploration of phytoconstituents of Medhya Rasayana herbs to identify potential inhibitors for cerebroside sulfotransferase through high-throughput screening.
Cerebroside sulfotransferase (CST) is a key enzyme in sulfatide biosynthesis and regulation of the myelin sheath in the nervous system. To counter sulfatide accumulation with the deficiency of aryl sulfatase A, CST is considered a target protein in substrate reduction therapy in metachromatic leukodystrophy. In this study, 461 phytoconstituents from four herbs of Medhya Rasayana were screened using multi-pronged virtual screening methods including molecular docking, molecular dynamics (MD) simulation, and reverse pharmacophore analysis. The initial screening of the top 15 hits was based on the binding affinity of the compounds toward the CST substrate-binding site using the lowest free energy of a binding score cutoff of ≤ -7.5 kcal/mol, with the number of conformations in the largest cluster more than 75. The absorption, distribution, metabolism, and excretion (ADME) and toxicity-based pharmacokinetic analysis delivered the top four hits: 18alpha-glycyrrhetinic acid, lupeol, alpha carotene, and beta-carotene, with high blood-brain barrier permeability and negligible toxicity. Furthermore, a 100-ns simulation of protein-ligand complexes with a trajectory analysis of structural deviation, compactness, intramolecular interactions, principal component analysis, free energy landscape, and dynamic cross-correlation analysis showed the binding potential and positioning of the four hits in the binding pocket. Thus, an in-depth analysis of protein-ligand interactions from pre- and post-molecular dynamics simulation, along with reverse pharmacophore mapping, suggests that 18alpha-glycyrrhetinic acid is the most potent and specific CST inhibitor, while beta-carotene could be considered the second most potent compound for CST inhibition as it also exhibited overall stability throughout the simulation. Therefore, the computational drug screening approach applied in this study may contribute to the development of oral drugs as a therapeutic option for metachromatic leukodystrophy.
2024-10-25 | Screening of phytoconstituents from Bacopa monnieri (L.) Pennell and Mucuna pruriens (L.) DC. to identify potential inhibitors against Cerebroside sulfotransferase.
Cerebroside sulfotransferase (CST) is considered a target protein in developing substrate reduction therapy for metachromatic leukodystrophy. This study employed a multistep virtual screening approach for getting a specific and potent inhibitor against CST from 35 phytoconstituents of Bacopa monnieri (L.) Pennell and 31 phytoconstituents of Mucuna pruriens (L.) DC. from the IMPPAT 2.0 database. Using a binding score cutoff of -8.0 kcal/mol with ADME and toxicity screening, four phytoconstituents IMPHY009537 (Stigmastenol), IMPHY004141 (alpha-Amyrenyl acetate), IMPHY014836 (beta-Sitosterol), and IMPHY001534 (jujubogenin) were considered for in-depth analysis. In the binding pocket of CST, the major amino acid residues that decide the orientation and interaction of compounds are Lys85, His84, His141, Phe170, Tyr176, and Phe177. The molecular dynamics simulation with a 100ns time span further validated the stability and rigidity of the docked complexes of the four hits by exploring the structural deviation and compactness, hydrogen bond interaction, solvent accessible surface area, principal component analysis, and free energy landscape analysis. Stigmastenol from Bacopa monnieri with no potential cross targets was found to be the most potent and selective CST inhibitor followed by alpha-Amyrenyl acetate from Mucuna pruriens as the second-best performing inhibitor against CST. Our computational drug screening approach may contribute to the development of oral drugs against metachromatic leukodystrophy.
2024-10-24 | Phytoconstituents of Withania somnifera (L.) Dunal (Ashwagandha) unveiled potential cerebroside sulfotransferase inhibitors: insight through virtual screening, molecular dynamics, toxicity, and reverse pharmacophore analysis.
Cerebroside sulfotransferase (CST) is considered as therapeutic target for substrate reduction therapy (SRT) for metachromatic leukodystrophy (MLD). The present study evaluates the therapeutic potential of 57 phytoconstituents of Withania somnifera against CST. Using binding score cutoff ≤-7.0 kcal/mol, top 10 compounds were screened and after ADME and toxicity-based screening, Withasomidienone, 2,4-methylene-cholesterol, and 2,3-Didehydrosomnifericin were identified as safe and potent drug candidates for CST inhibition. Key substrate binding site residues involved in interaction were LYS82, LYS85, SER89, TYR176, PHE170, PHE177. Four steroidal Lactone-based withanolide backbone of these compounds played a critical role in stabilizing their position in the active site pocket. 100 ns molecular dynamics simulation and subsequent trajectory analysis through structural deviation and compactness, principal components, free energy landscape and correlation matrix confirmed the stability of CST-2,3-Didehydrosomnifericin complex throughout the simulation and therefore is considered as the most potent drug candidate for CST inhibition and Withasomidienone as the second most potent drug candidate. The reverse pharmacophore analysis further confirmed the specificity of these two compounds towards CST as no major cross targets were identified. Thus, identified compounds in this study strongly present their candidature for oral drug and provide route for further development of more specific CST inhibitors.
2024-05-06 | Higher precision, first tier newborn screening for metachromatic leukodystrophy using 16:1-OH-sulfatide.
Newborn screening (NBS) for metachromatic leukodystrophy (MLD) is based on first-tier measurement of sulfatides in dried blood spots (DBS) followed by second-tier measurement of arylsulfatase A in the same DBS. This approach is very precise with 0-1 false positives per ∼30,000 newborns tested. Recent data reported here shows that the sulfatide molecular species with an α-hydroxyl, 16‑carbon, mono-unsaturated fatty acyl group (16:1-OH-sulfatide) is superior to the original biomarker 16:0-sulfatide in reducing the number of first-tier false positives. This result is consistent across 4 MLD NBS centers. By measuring 16:1-OH-sulfatide alone or together with 16:0-sulfatide, the estimated false positive rate is 0.048% and is reduced essentially to zero with second-tier arylsulfatase A activity assay. The false negative rate is predicted to be extremely low based on the demonstration that 40 out of 40 newborn DBS from clinically-confirmed MLD patients are detected with these methods. The work shows that NBS for MLD is extremely precise and ready for deployment. Furthermore, it can be multiplexed with several other inborn errors of metabolism already tested in NBS centers worldwide.
cell therapies
2025-12-24 | Effectiveness and Safety of Intravenous Administration of Mesenchymal Stem Cells Overexpressing Arylsulfatase A for the Treatment of Metachromatic Leukodystrophy in a Pig Model
This study evaluated intravenous administration of allogeneic mesenchymal stem cells (MSCs) transduced with AAV9-ARSA to pigs. The MSCs were modified to overexpress human arylsulfatase A (ARSA). Thirty-five days after treatment, ARSA activity significantly increased in CNS tissues. No hepatotoxicity or systemic inflammation was observed. The results confirm the safety and efficacy of this MSC-based gene therapy for metachromatic leukodystrophy (MLD).
2025-10-14 | Encapsulated cells as an enzyme replacement therapy for metachromatic leukodystrophy.
Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by an inherited deficiency of arylsulfatase A (ARSA) and characterized by accumulation of sulfatides in both glial cells and neurons resulting in myelin degeneration in the central and peripheral nervous systems, neuronal degeneration and neuroinflammation. Currently, no effective treatment is available for patients once symptoms are already present. Libmeldy©, an Ex vivo gene therapy, is the gold standard for pre-symptomatic patients with late-infantile and early juvenile MLD, and early symptomatic patients with early-juvenile MLD. Here, we investigated an innovative approach to deliver the recombinant ARSA enzyme by encapsulated-cell therapy. A cell-based device is capable of continuously delivering human ARSA compared to weekly intrathecal delivery of recombinant ARSA, which is under clinical evaluation in a phase II-III clinical trial. Two constructs of genetically engineered cells have been tested to determine which one could target more efficiently the central nervous system. Importantly, a dose response evaluation has been done with 2 doses (cells number loaded) to evaluate the best therapeutic effect. MLD mice were implanted at 6 months of age once disease is well established. The device biocompatibility as well as the therapeutic efficacy have been evaluated 3 months after implantation. The device was well tolerated in animals. Moreover, we demonstrate a correction of sulfatide storage and significant improvement of neuroinflammation in the CNS of all treated mice. All these data establish a strong rational to propose cell-based device therapy in symptomatic MLD patients.
2024-09-26 | Hematopoietic stem cell transplantation in leukodystrophies.
More than 50 leukodystrophies have been described. This group of inherited disorders affects myelin development and/or maintenance and can manifest from birth to adulthood. Neuroinflammation is a hallmark of some leukodystrophies, explaining in part the therapeutic benefit of hematopoietic stem cell transplantation (HSCT). Indeed, in addition to supplying the CNS with myelomonocyte donor cells expressing the deficient protein or enzyme, HSCT allows the restoration of normal microglia function, which may act on neuroinflammation. In this chapter, we explore the rationale, indication, and outcome of HSCT in Cerebral Adrenoleukodystrophy (CALD), Metachromatic Leukodystrophy (MLD), Krabbe Disease (KD), and Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP), which are among the most frequent leukodystrophies. For these leukodystrophies, HSCT may modify notably the natural history and improve CNS-related deficits, provided that the procedure is performed early into the disease course. In addition, we discuss the recent development of ex vivo gene therapy for CALD and MLD as a promising alternative to allograft.
2024-02-07 | Inventory of current practices regarding hematopoietic stem cell transplantation in metachromatic leukodystrophy in Europe and neighboring countries
Abstract Background For decades, early allogeneic stem cell transplantation (HSCT) has been used to slow neurological decline in metachromatic leukodystrophy (MLD). There is lack of consensus regarding who may benefit, and guidelines are lacking. Clinical practice relies on limited literature and expert opinions. The European Reference Network for Rare Neurological Diseases (ERN-RND) and the MLD initiative facilitate expert panels for treatment advice, but some countries are underrepresented. This study explores organizational and clinical HSCT practices for MLD in Europe and neighboring countries to enhance optimization and harmonization of cross-border MLD care. Methods A web-based EUSurvey was distributed through the ERN-RND and the European Society for Blood and Marrow Transplantation Inborn Errors Working Party. Personal invitations were sent to 89 physicians (43 countries) with neurological/metabolic/hematological expertise. The results were analyzed and visualized using Microsoft Excel and IBM SPSS statistics. Results Of the 30 countries represented by 42 respondents, 23 countries offer HSCT for MLD. The treatment is usually available in 1–3 centers per country (18/23, 78%). Most countries have no or very few MLD patients transplanted during the past 1–5 years. The eligibility criteria regarding MLD subtype, motor function, IQ, and MRI largely differ across countries. Conclusion HSCT for MLD is available in most European countries, but uncertainties exist in Eastern and South-Eastern Europe. Applied eligibility criteria and management vary and may not align with the latest scientific insights, indicating physicians’ struggle in providing evidence-based care. Interaction between local physicians and international experts is crucial for adequate treatment decision-making and cross-border care in the rapidly changing MLD field.
2023-12-05 | Gene therapy for neurodegenerative disorders in children: dreams and realities.
Gene therapy encompasses the administration of biological medicinal products containing recombinant nucleic acids, mainly DNA, with the aim of treating or curing diseases. This represents a unique therapeutic strategy to reach the brain, in order to prevent or halt a neurodegenerative process. During the past decade, active multidisciplinary research has started to solve many issues for gene therapy in neurodegenerative disorders in terms of vectors, modes of administration, and expression of the therapeutic DNA. The engineering of hematopoietic stem cells (HSC) with lentivirus vectors for ex vivo gene therapy has demonstrated efficiency in reaching the brain through their transformation into microglial/macrophages cells with a long-term gene expression of the therapeutic vector as an alternative to autologous HSC transplants. Two drugs based on this strategy have been approved to date. The first is for metachromatic leukodystrophy (MLD), a severe lysosomal storage disease, and provides high levels of the deficient enzyme; the second one is for cerebral forms of X-linked adrenoleukodystrophy (X-ALD), and works by halting the neuroinflammation process. However, due to the long-lasting effect of the procedure, the therapy is applicable only to pre- or pauci/oligo-symptomatic patients. In vivo gene therapy via direct injection into the brain or the cerebrospinal fluid, but also by intravenous injection, represents a more efficient approach; however, many challenges remain to be solved despite the approval of two drugs: one for the early infantile form of spinal muscular atrophy (SMA), in which the gene product injected intravenously is able to prevent spinal motoneuron neurodegeneration. The second one, for aromatic L-amino acid decarboxylase (AADC) deficiency, provides the defective enzyme to the basal ganglia via intraparenchymal injection. The production of vectors able to reach the brain target cells with a sufficiently high expression remains a major bottleneck. In parallel, efforts must continue in order to better define (i) the natural history and clinical outcomes of many neurodegenerative disorders with childhood onset, and (ii) the mechanisms involved in the neurodegenerative process. © 2023 Published by Elsevier Masson SAS on behalf of French Society of Pediatrics.
proteins
2026-02-03 | Prosaposin in CNS health and disease, metabolic stress and exercise adaptation.
Prosaposin (PSAP), a highly conserved lysosomal protein and precursor of saposins A-D, has emerged as a key regulator of cellular and central nervous system (CNS) homeostasis. Disrupted PSAP trafficking may lead to amyloid protein aggregation with implications for neurodegenerative diseases. In Alzheimer's disease (AD) and Parkinson's disease (PD), PSAP shows altered expression patterns and pathological co-localization with amyloid aggregates. PSAP variants are linked to multiple neurodegenerative diseases, including synucleinopathies, Gaucher's disease, and metachromatic leukodystrophy. Its levels are elevated in blood and cerebrospinal fluid in some individuals with AD or PD and are upregulated by stress conditions such as nerve injury and cold adaptation, but not by exercise. Prosaptides, short peptides derived from PSAP, show protective effects in models of oxidative stress, CNS injury, and metabolic disorders. Pharmacological stabilization of PSAP interactions with progranulin has shown promise in neurodegenerative disease models. These findings suggest PSAP plays an important role in maintaining brain health and may hold therapeutic potential. Here, we provide a comprehensive overview of PSAP's role in CNS health and disease, metabolic stress, and exercise adaptation.
2024-08-09 | Seed-competent α-synuclein pathology in metachromatic leukodystrophy: the expanding spectrum of α-synucleinopathy in sphingolipidoses
ABSTRACT Metachromatic leukodystrophy (MLD) is a rare - typically paediatric - sphingolipid storage disorder resulting from bi-allelic pathogenic variants in the ARSA gene, encoding the lysosomal arylsulphatase A (ASA). Heterozygous variants in ARSA are associated with risk of Lewy body diseases (LBD), a group of age-associated neurodegenerative disorders characterised by the accumulation of the protein α-synuclein; however, no study has yet determined whether α-synuclein with putative pathological features is observed in MLD brain tissue. We examined post-mortem brain tissue from MLD cases (N=5, age 2-33) compared to matched control cases using histological approaches and α-synuclein seeding amplification assay (SAA). Juvenile-onset MLD cases exhibited granular α-synuclein deposits in neurons of regions prone to neuronal pathology in MLD, and seed-competent conformers that generated atypical short, twisted fibrils on SAA. In contrast, infantile-onset MLD cases gave only variably positive reactions on SAA. In summary, this study suggests MLD cases manifest α-synuclein pathology reminiscent of that observed in LBD, even in juvenile populations, further expanding the spectrum of sphingolipid storage disorders associated with the aggregation of α-synuclein. These findings have important implications for understanding the disease process of both LBD and MLD, potentially highlighting novel pathways for therapeutic interventions in both conditions.
2021-12-10 | Recent Advancements in the Diagnosis and Treatment of Leukodystrophies.
Leukodystrophies and genetic leukoencephalopathies comprise a growing group of inherited white matter disorders. Diagnostic rates have improved with increased utilization of next generation sequencing. As treatment options continue to advance for leukodystrophies, so will candidacy for inclusion in the United States' newborn Recommended Universal Screening Panel as was achieved for X-linked adrenoleukodystrophy. Stem cell therapies have become standard of care for selected leukodystrophies. However, transplantation-related risks remain high and outcomes are not fully satisfactory. Transduction of autologous hematopoietic stem cells with lentiviral vectors, referred to as ex vivo gene therapy, circumvents some, but not all, of the risks of traditional transplantation and has recently been demonstrated to be safe and efficective in clinical studies of X-linked adrenoleukodystrophy and metachromatic leukodystrophy. Gene therapy, through direct infusion of adeno-associated virus vectors, has emerged as a safer alternative for many monogenetic pediatric neurological disorders. Numerous preclinical studies have shown safety and efficacy of adeno-associated virus gene therapy in leukodystrophies allowing expanded access treatment for Canavan disease prior to initiation of a clinical trial. For inherited white matter disorders resulting from overexpression of a protein, such as Pelizaeus-Merzbacher disease, emerging RNA therapies have shown success in preclinical studies and promise for rapid translation to the clinic. Lastly, small molecule and protein therapies remain a long-term treatment option for a number of leukodystrophies, including intrathecal enzyme replacement therapy for metachromatic leukodystrophy. Herein we review recent advances in diagnosis and treatment of inherited white matter disorders.
2013-08-01 | Toward the successful delivery of lysosomal enzymes across the blood–brain barrier
Abstract The development of enzyme replacement therapy ( ERT ) has been one of the most remarkable successes of translational studies, bridging laboratory discoveries to clinical settings. Although ERT is very effective in clearing peripheral tissue storage in many lysosomal storage diseases ( LSD ), negotiating the blood‐brain barrier ( BBB ) remains a key challenge in delivering corrective lysosomal enzymes into the brain. In recent years, brain delivery of lysosomal enzymes has been vigorously pursued for treating neurodegenerative LSD . Delivery strategies include high‐dose and long‐term treatment regimens, manipulation of receptor‐mediated transport, biochemical engineering of enzymes, use of transport vectors, and enzyme administration by alternative routes. Most studies have investigated biochemical or histological improvements in central nervous system ( CNS ) storage after treatment. Few studies, however, have directly focused on the mechanisms of lysosomal enzyme transport across the BBB . In previous studies, we discovered that the luminally expressed mannose 6‐phosphate/insulin‐like growth factor‐ II receptor is a universal transporter of lysosomal enzymes. We and others have also successfully manipulated receptor‐mediated transport by using endogenous characteristics of the BBB . Interestingly, accumulating evidence indicates that some lysosomal enzymes employ multiple mechanisms for their transport across the BBB . This review provides a detailed discussion of the kinetics of lysosomal enzyme transport across the BBB , and the manipulation of transport characteristics based on studies of the transport of β‐glucuronidase, sulfamidase, arylsulfatase A and acid α‐glucosidase. Furthermore, recent achievements in treating abnormalities in CNS storage and their contribution to developing new therapeutic approaches are also discussed.
gene therapies
2026-08-11 | A study on the quality of life and burden of informal caregivers of children with metachromatic leukodystrophy in Poland
Abstract Background Metachromatic leukodystrophy (MLD) is a rare, inherited lysosomal storage disorder caused by a deficiency in arylsulfatase A (ARSA), leading to sulfatide accumulation, demyelination, and progressive neurological decline. Without treatment, patients – particularly those with early-onset forms – typically lose the ability to walk or communicate within months of symptom onset, and life expectancy is markedly reduced, often below 10 years. Although MLD is likely underdiagnosed in Poland, prevalence may be higher than average. Early diagnosis and prompt intervention with gene therapy (arsa-cel) are critical, as neuronal damage is irreversible. This exploratory study aimed to characterise the clinical course of MLD in Poland and assess the quality of life and financial well-being of caregivers. Results The study included 13 MLD patients and 28 caregivers. The most common forms were late-infantile (46.2%) and early-juvenile (38.5%). Most patients were classified as GMFC-MLD stage 6 (53.8%) and ELFC-MLD stage 4 (69.2%). Common symptoms included spasticity (84.6%), walking difficulties (84.6%), and speech disorders (69.2%). The mean age at diagnosis was 4.8 years, with 69.2% of caregivers reporting that delayed diagnosis adversely impacted the child’s health. Caregivers were predominantly female (67.9%) and reported high caregiving demands (mean = 35.7 h/week). WHOQOL-BREF scores exceeded medians for caregivers of people with rare diseases across all domains. Financial well-being was strongly correlated with physical health ( r = 0.636, p < 0.001) and psychological health ( r = 0.717, p < 0.001). Only 14.3% of MLD caregivers received psychological counselling at diagnosis, though 92.3% received financial support. Gene therapy was reported in 15.4% of cases; most patients received multiple forms of rehabilitative therapy. Conclusion MLD in Poland is characterised by early-onset, rapidly progressing forms that lead to severe disability and impose significant burdens on families. Delayed diagnosis was commonly reported in this cohort, with many caregivers indicating that it had negatively affected the child’s health and limited timely access to potentially disease-modifying treatments. Despite intensive caregiving responsibilities, many caregivers report a relatively preserved quality of life, especially when financial support is available. While these exploratory findings should be interpreted with caution, they support the need for improved early detection and coordinated care for individuals with MLD. Within this broader context, systematic newborn screening in Poland may facilitate earlier diagnosis and timely access to gene therapy, potentially improving patient outcomes and reducing the long-term burden on families and the healthcare system. Clinical trial number Not applicable
2026-08-03 | Gene therapy for rare diseases marks a new era in precision medicine: Insights from clinical trials
Gene therapy represents an important advance in the treatment of rare diseases, offering precise and transformative therapeutic strategies. As many rare diseases are associated with well-defined genetic variants, they represent ideal candidates for targeted genetic interventions. The substantial unmet medical need associated with rare diseases has driven growing interest in gene therapy, with more than 300 clinical trials reported to date. The aim of this study was to evaluate the current evidence on gene therapy for rare diseases by examining therapeutic strategies, target diseases, clinical progress, clinical outcomes, and emerging research trends. Several approved therapies, including those for hemophilia B, spinal muscular atrophy, metachromatic leukodystrophy, and Wiskott–Aldrich syndrome, have demonstrated the clinical potential of gene therapy. Clinical evidence suggests that gene-based therapies in the management of rare diseases can achieve sustained functional benefits, reduce disease-related complications, and lessen dependence on long-term replacement or supportive treatments. However, challenges in ethical considerations, regulatory requirements, manufacturing complexity, treatment costs, and limited patient access remain. Continued clinical evaluation is essential to further establish long-term safety and effectiveness. Advances in gene therapy technologies and clinical applications continue to expand therapeutic opportunities for rare diseases while supporting the broader development of precision medicine.
2026-07-22 | Design and application of prime editing to target ARSA P426L mutation in a metachromatic leukodystrophy patient
Metachromatic leukodystrophy (MLD) is a rare inherited lysosomal storage disease caused primarily by mutations in the Arylsulfatase A (ARSA) gene. Loss of functional ARSA leads to sulfatide accumulation, causing demyelination in the peripheral and central nervous system. MLD presents in different clinical forms, which all eventually result in severe neurological decline and death. Currently available treatment options are limited. Enzyme replacement therapy (ERT) and allogeneic hematopoietic stem cell transplantation (allo-HSCT) may slow disease progression but do not offer a cure. Libmeldy was recently approved by the European Medicines Agency (EMA) as the first gene therapy for early-onset forms of MLD. However, the potential long-term risk of insertional mutagenesis remains a concern and requires ongoing evaluation. In this project we targeted the ARSA P426L mutation, one of the most common MLD-causing mutations in Europe. We used prime editing, a CRISPR-Cas9 based mechanism, which allows to introduce precise changes into the genome. The experiments were carried out in K562 cells and hematopoietic stem and progenitor cells (HSPCs). If the ARSA P426L mutation could be corrected ex vivo in patient-derived HSPCs prior to transplantation, this approach could offer a potentially curative treatment for patients who are currently lacking effective therapeutic options. Such a strategy would eliminate the need to find a matching donor for allogeneic HSCT, evade its side effects and avoid the risk of insertional mutagenesis associated with Libmeldy. Instead, it would restore physiological ARSA expression by precisely correcting the mutation at its endogenous locus. In K562 cells, we successfully introduced the ARSA P426L mutation using prime editing, achieving mean editing efficiencies of 1.88% with PE2 and 10.20% with PE3. However, no editing was detected in HSPCs of healthy donors. As a result, this study did not progress to target patient-derived HSPCs. Further investigations are needed to focus on optimizing the prime editing mechanism as well as related components in order to achieve higher editing efficiency. Also research about target site specific limitations for prime editing should be closely monitored and taken into account when planning for future projects. Although editing of the ARSA P426L locus was not successful, the high efficiency to induce the IL2RG c.458T>C mutation in HSPCs, which was used as a proof of concept, supports the general feasibility of prime editing based gene therapy approaches.
2025-08-10 | Gene therapy for lysosomal storage diseases.
Lysosomal storage diseases (LSDs) are metabolic disorders caused by the dysfunction of enzymes and other substances localized in lysosomes, known as intracellular organelles. There are many types of LSDs, with a wide range of clinical manifestations. LSDs are highly amenable to gene therapy due to various reasons, including the fact that they are essentially monogenic diseases and existence of cross-correction mechanisms. The only gene therapy product currently approved for lysosomal diseases is one for metachromatic leukodystrophy, but several have progressed to phase III clinical trials such as the products for Mucopolysaccharidosis or Fabry disease. However, serious adverse events have been reported even with gene therapy methods that have been considered safe. Therefore, research on the safety of gene therapy is becoming increasingly important.
2025-05-28 | Newborn screening for metachromatic leukodystrophy: Preparation of reagents and methodology for measurement of sulfatides and arylsulfatase A enzymatic activity in dried blood spots.
Ex vivo gene therapy combined with haemapoietic stem cell transplant has recently been approved in Europe and the USA for treatment of metachromatic leukodystrophy (MLD). Since treatment is only efficacious if carried out in the pre-symptomatic or minimally-symptomatic phases, newborn screening (NBS) for MLD is warranted. MLD NBS is being developed worldwide through the International MLD Newborn Screening Alliance. Screening is carried out by measurement of the elevation of two sulfatide molecular species, 16: 0- and 16:1-OH-sulfatide in dried blood spots (DBS) followed by second-tier measurement of arylsulfatase A (ARSA) enzymatic activity in the same DBS. After 2-3 years of NBS assay development including pilot studies, members of the International MLD Newborn Screening Alliance arrived at a consensus set of assay protocols. In this article, we provide these protocols with full details so that the methods can be readily adopted by additional NBS laboratories. We also provide the full details of preparation of the required reagents.
small molecules
2024-11-27 | Emerging Role of Ubiquitin Proteasome System and Autophagy in Pediatric Demyelinating Leukodystrophies and Therapeutic Opportunity.
Leukodystrophies represent a heterogeneous group of disorders characterized by specific genetic mutations, metabolic abnormalities, and degeneration of white matter in the central nervous system. These disorders are classified into several categories, with X-linked adrenoleukodystrophy (X-ALD), metachromatic leukodystrophy (MLD), and globoid cell leukodystrophy (GLD) being the most prevalent demyelinating leukodystrophies in pediatric populations. Maintaining proteostasis, which is critical for normal cellular function, relies fundamentally on the ubiquitin-proteasome system (UPS) and autophagy for the degradation of misfolded and damaged proteins. Compelling evidence has highlighted the critical roles of UPS and autophagy dysfunction in the pathogenesis of neurodegenerative diseases. Given the complex and poorly understood pathomechanisms underlying demyelinating leukodystrophies, coupled with the pressing need for effective therapeutic strategies, this review aims to systemically analyze the molecular and pathological evidence linking UPS and autophagy dysfunction to demyelinating leukodystrophies, specifically X-ALD and GLD. Furthermore, we will assess the therapeutic potential of autophagy modulators in the management of X-ALD and GLD, with the objective to inspire further research into therapeutic approaches that target autophagy and UPS pathways. Novel therapies that enhance autophagy and UPS function hold promise as complementary regimens in combination therapies aimed at achieving comprehensive correction of the pathogenic mechanisms in demyelinating leukodystrophies.
2024-10-25 | Exploration of phytoconstituents of Medhya Rasayana herbs to identify potential inhibitors for cerebroside sulfotransferase through high-throughput screening.
Cerebroside sulfotransferase (CST) is a key enzyme in sulfatide biosynthesis and regulation of the myelin sheath in the nervous system. To counter sulfatide accumulation with the deficiency of aryl sulfatase A, CST is considered a target protein in substrate reduction therapy in metachromatic leukodystrophy. In this study, 461 phytoconstituents from four herbs of Medhya Rasayana were screened using multi-pronged virtual screening methods including molecular docking, molecular dynamics (MD) simulation, and reverse pharmacophore analysis. The initial screening of the top 15 hits was based on the binding affinity of the compounds toward the CST substrate-binding site using the lowest free energy of a binding score cutoff of ≤ -7.5 kcal/mol, with the number of conformations in the largest cluster more than 75. The absorption, distribution, metabolism, and excretion (ADME) and toxicity-based pharmacokinetic analysis delivered the top four hits: 18alpha-glycyrrhetinic acid, lupeol, alpha carotene, and beta-carotene, with high blood-brain barrier permeability and negligible toxicity. Furthermore, a 100-ns simulation of protein-ligand complexes with a trajectory analysis of structural deviation, compactness, intramolecular interactions, principal component analysis, free energy landscape, and dynamic cross-correlation analysis showed the binding potential and positioning of the four hits in the binding pocket. Thus, an in-depth analysis of protein-ligand interactions from pre- and post-molecular dynamics simulation, along with reverse pharmacophore mapping, suggests that 18alpha-glycyrrhetinic acid is the most potent and specific CST inhibitor, while beta-carotene could be considered the second most potent compound for CST inhibition as it also exhibited overall stability throughout the simulation. Therefore, the computational drug screening approach applied in this study may contribute to the development of oral drugs as a therapeutic option for metachromatic leukodystrophy.
2024-10-25 | Screening of phytoconstituents from Bacopa monnieri (L.) Pennell and Mucuna pruriens (L.) DC. to identify potential inhibitors against Cerebroside sulfotransferase.
Cerebroside sulfotransferase (CST) is considered a target protein in developing substrate reduction therapy for metachromatic leukodystrophy. This study employed a multistep virtual screening approach for getting a specific and potent inhibitor against CST from 35 phytoconstituents of Bacopa monnieri (L.) Pennell and 31 phytoconstituents of Mucuna pruriens (L.) DC. from the IMPPAT 2.0 database. Using a binding score cutoff of -8.0 kcal/mol with ADME and toxicity screening, four phytoconstituents IMPHY009537 (Stigmastenol), IMPHY004141 (alpha-Amyrenyl acetate), IMPHY014836 (beta-Sitosterol), and IMPHY001534 (jujubogenin) were considered for in-depth analysis. In the binding pocket of CST, the major amino acid residues that decide the orientation and interaction of compounds are Lys85, His84, His141, Phe170, Tyr176, and Phe177. The molecular dynamics simulation with a 100ns time span further validated the stability and rigidity of the docked complexes of the four hits by exploring the structural deviation and compactness, hydrogen bond interaction, solvent accessible surface area, principal component analysis, and free energy landscape analysis. Stigmastenol from Bacopa monnieri with no potential cross targets was found to be the most potent and selective CST inhibitor followed by alpha-Amyrenyl acetate from Mucuna pruriens as the second-best performing inhibitor against CST. Our computational drug screening approach may contribute to the development of oral drugs against metachromatic leukodystrophy.
2024-10-24 | Phytoconstituents of Withania somnifera (L.) Dunal (Ashwagandha) unveiled potential cerebroside sulfotransferase inhibitors: insight through virtual screening, molecular dynamics, toxicity, and reverse pharmacophore analysis.
Cerebroside sulfotransferase (CST) is considered as therapeutic target for substrate reduction therapy (SRT) for metachromatic leukodystrophy (MLD). The present study evaluates the therapeutic potential of 57 phytoconstituents of Withania somnifera against CST. Using binding score cutoff ≤-7.0 kcal/mol, top 10 compounds were screened and after ADME and toxicity-based screening, Withasomidienone, 2,4-methylene-cholesterol, and 2,3-Didehydrosomnifericin were identified as safe and potent drug candidates for CST inhibition. Key substrate binding site residues involved in interaction were LYS82, LYS85, SER89, TYR176, PHE170, PHE177. Four steroidal Lactone-based withanolide backbone of these compounds played a critical role in stabilizing their position in the active site pocket. 100 ns molecular dynamics simulation and subsequent trajectory analysis through structural deviation and compactness, principal components, free energy landscape and correlation matrix confirmed the stability of CST-2,3-Didehydrosomnifericin complex throughout the simulation and therefore is considered as the most potent drug candidate for CST inhibition and Withasomidienone as the second most potent drug candidate. The reverse pharmacophore analysis further confirmed the specificity of these two compounds towards CST as no major cross targets were identified. Thus, identified compounds in this study strongly present their candidature for oral drug and provide route for further development of more specific CST inhibitors.
2024-05-06 | Higher precision, first tier newborn screening for metachromatic leukodystrophy using 16:1-OH-sulfatide.
Newborn screening (NBS) for metachromatic leukodystrophy (MLD) is based on first-tier measurement of sulfatides in dried blood spots (DBS) followed by second-tier measurement of arylsulfatase A in the same DBS. This approach is very precise with 0-1 false positives per ∼30,000 newborns tested. Recent data reported here shows that the sulfatide molecular species with an α-hydroxyl, 16‑carbon, mono-unsaturated fatty acyl group (16:1-OH-sulfatide) is superior to the original biomarker 16:0-sulfatide in reducing the number of first-tier false positives. This result is consistent across 4 MLD NBS centers. By measuring 16:1-OH-sulfatide alone or together with 16:0-sulfatide, the estimated false positive rate is 0.048% and is reduced essentially to zero with second-tier arylsulfatase A activity assay. The false negative rate is predicted to be extremely low based on the demonstration that 40 out of 40 newborn DBS from clinically-confirmed MLD patients are detected with these methods. The work shows that NBS for MLD is extremely precise and ready for deployment. Furthermore, it can be multiplexed with several other inborn errors of metabolism already tested in NBS centers worldwide.
cell therapies
2025-12-24 | Effectiveness and Safety of Intravenous Administration of Mesenchymal Stem Cells Overexpressing Arylsulfatase A for the Treatment of Metachromatic Leukodystrophy in a Pig Model
This study evaluated intravenous administration of allogeneic mesenchymal stem cells (MSCs) transduced with AAV9-ARSA to pigs. The MSCs were modified to overexpress human arylsulfatase A (ARSA). Thirty-five days after treatment, ARSA activity significantly increased in CNS tissues. No hepatotoxicity or systemic inflammation was observed. The results confirm the safety and efficacy of this MSC-based gene therapy for metachromatic leukodystrophy (MLD).
2025-10-14 | Encapsulated cells as an enzyme replacement therapy for metachromatic leukodystrophy.
Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by an inherited deficiency of arylsulfatase A (ARSA) and characterized by accumulation of sulfatides in both glial cells and neurons resulting in myelin degeneration in the central and peripheral nervous systems, neuronal degeneration and neuroinflammation. Currently, no effective treatment is available for patients once symptoms are already present. Libmeldy©, an Ex vivo gene therapy, is the gold standard for pre-symptomatic patients with late-infantile and early juvenile MLD, and early symptomatic patients with early-juvenile MLD. Here, we investigated an innovative approach to deliver the recombinant ARSA enzyme by encapsulated-cell therapy. A cell-based device is capable of continuously delivering human ARSA compared to weekly intrathecal delivery of recombinant ARSA, which is under clinical evaluation in a phase II-III clinical trial. Two constructs of genetically engineered cells have been tested to determine which one could target more efficiently the central nervous system. Importantly, a dose response evaluation has been done with 2 doses (cells number loaded) to evaluate the best therapeutic effect. MLD mice were implanted at 6 months of age once disease is well established. The device biocompatibility as well as the therapeutic efficacy have been evaluated 3 months after implantation. The device was well tolerated in animals. Moreover, we demonstrate a correction of sulfatide storage and significant improvement of neuroinflammation in the CNS of all treated mice. All these data establish a strong rational to propose cell-based device therapy in symptomatic MLD patients.
2024-09-26 | Hematopoietic stem cell transplantation in leukodystrophies.
More than 50 leukodystrophies have been described. This group of inherited disorders affects myelin development and/or maintenance and can manifest from birth to adulthood. Neuroinflammation is a hallmark of some leukodystrophies, explaining in part the therapeutic benefit of hematopoietic stem cell transplantation (HSCT). Indeed, in addition to supplying the CNS with myelomonocyte donor cells expressing the deficient protein or enzyme, HSCT allows the restoration of normal microglia function, which may act on neuroinflammation. In this chapter, we explore the rationale, indication, and outcome of HSCT in Cerebral Adrenoleukodystrophy (CALD), Metachromatic Leukodystrophy (MLD), Krabbe Disease (KD), and Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP), which are among the most frequent leukodystrophies. For these leukodystrophies, HSCT may modify notably the natural history and improve CNS-related deficits, provided that the procedure is performed early into the disease course. In addition, we discuss the recent development of ex vivo gene therapy for CALD and MLD as a promising alternative to allograft.
2024-02-07 | Inventory of current practices regarding hematopoietic stem cell transplantation in metachromatic leukodystrophy in Europe and neighboring countries
Abstract Background For decades, early allogeneic stem cell transplantation (HSCT) has been used to slow neurological decline in metachromatic leukodystrophy (MLD). There is lack of consensus regarding who may benefit, and guidelines are lacking. Clinical practice relies on limited literature and expert opinions. The European Reference Network for Rare Neurological Diseases (ERN-RND) and the MLD initiative facilitate expert panels for treatment advice, but some countries are underrepresented. This study explores organizational and clinical HSCT practices for MLD in Europe and neighboring countries to enhance optimization and harmonization of cross-border MLD care. Methods A web-based EUSurvey was distributed through the ERN-RND and the European Society for Blood and Marrow Transplantation Inborn Errors Working Party. Personal invitations were sent to 89 physicians (43 countries) with neurological/metabolic/hematological expertise. The results were analyzed and visualized using Microsoft Excel and IBM SPSS statistics. Results Of the 30 countries represented by 42 respondents, 23 countries offer HSCT for MLD. The treatment is usually available in 1–3 centers per country (18/23, 78%). Most countries have no or very few MLD patients transplanted during the past 1–5 years. The eligibility criteria regarding MLD subtype, motor function, IQ, and MRI largely differ across countries. Conclusion HSCT for MLD is available in most European countries, but uncertainties exist in Eastern and South-Eastern Europe. Applied eligibility criteria and management vary and may not align with the latest scientific insights, indicating physicians’ struggle in providing evidence-based care. Interaction between local physicians and international experts is crucial for adequate treatment decision-making and cross-border care in the rapidly changing MLD field.
2023-12-05 | Gene therapy for neurodegenerative disorders in children: dreams and realities.
Gene therapy encompasses the administration of biological medicinal products containing recombinant nucleic acids, mainly DNA, with the aim of treating or curing diseases. This represents a unique therapeutic strategy to reach the brain, in order to prevent or halt a neurodegenerative process. During the past decade, active multidisciplinary research has started to solve many issues for gene therapy in neurodegenerative disorders in terms of vectors, modes of administration, and expression of the therapeutic DNA. The engineering of hematopoietic stem cells (HSC) with lentivirus vectors for ex vivo gene therapy has demonstrated efficiency in reaching the brain through their transformation into microglial/macrophages cells with a long-term gene expression of the therapeutic vector as an alternative to autologous HSC transplants. Two drugs based on this strategy have been approved to date. The first is for metachromatic leukodystrophy (MLD), a severe lysosomal storage disease, and provides high levels of the deficient enzyme; the second one is for cerebral forms of X-linked adrenoleukodystrophy (X-ALD), and works by halting the neuroinflammation process. However, due to the long-lasting effect of the procedure, the therapy is applicable only to pre- or pauci/oligo-symptomatic patients. In vivo gene therapy via direct injection into the brain or the cerebrospinal fluid, but also by intravenous injection, represents a more efficient approach; however, many challenges remain to be solved despite the approval of two drugs: one for the early infantile form of spinal muscular atrophy (SMA), in which the gene product injected intravenously is able to prevent spinal motoneuron neurodegeneration. The second one, for aromatic L-amino acid decarboxylase (AADC) deficiency, provides the defective enzyme to the basal ganglia via intraparenchymal injection. The production of vectors able to reach the brain target cells with a sufficiently high expression remains a major bottleneck. In parallel, efforts must continue in order to better define (i) the natural history and clinical outcomes of many neurodegenerative disorders with childhood onset, and (ii) the mechanisms involved in the neurodegenerative process. © 2023 Published by Elsevier Masson SAS on behalf of French Society of Pediatrics.
proteins
2026-02-03 | Prosaposin in CNS health and disease, metabolic stress and exercise adaptation.
Prosaposin (PSAP), a highly conserved lysosomal protein and precursor of saposins A-D, has emerged as a key regulator of cellular and central nervous system (CNS) homeostasis. Disrupted PSAP trafficking may lead to amyloid protein aggregation with implications for neurodegenerative diseases. In Alzheimer's disease (AD) and Parkinson's disease (PD), PSAP shows altered expression patterns and pathological co-localization with amyloid aggregates. PSAP variants are linked to multiple neurodegenerative diseases, including synucleinopathies, Gaucher's disease, and metachromatic leukodystrophy. Its levels are elevated in blood and cerebrospinal fluid in some individuals with AD or PD and are upregulated by stress conditions such as nerve injury and cold adaptation, but not by exercise. Prosaptides, short peptides derived from PSAP, show protective effects in models of oxidative stress, CNS injury, and metabolic disorders. Pharmacological stabilization of PSAP interactions with progranulin has shown promise in neurodegenerative disease models. These findings suggest PSAP plays an important role in maintaining brain health and may hold therapeutic potential. Here, we provide a comprehensive overview of PSAP's role in CNS health and disease, metabolic stress, and exercise adaptation.
2024-08-09 | Seed-competent α-synuclein pathology in metachromatic leukodystrophy: the expanding spectrum of α-synucleinopathy in sphingolipidoses
ABSTRACT Metachromatic leukodystrophy (MLD) is a rare - typically paediatric - sphingolipid storage disorder resulting from bi-allelic pathogenic variants in the ARSA gene, encoding the lysosomal arylsulphatase A (ASA). Heterozygous variants in ARSA are associated with risk of Lewy body diseases (LBD), a group of age-associated neurodegenerative disorders characterised by the accumulation of the protein α-synuclein; however, no study has yet determined whether α-synuclein with putative pathological features is observed in MLD brain tissue. We examined post-mortem brain tissue from MLD cases (N=5, age 2-33) compared to matched control cases using histological approaches and α-synuclein seeding amplification assay (SAA). Juvenile-onset MLD cases exhibited granular α-synuclein deposits in neurons of regions prone to neuronal pathology in MLD, and seed-competent conformers that generated atypical short, twisted fibrils on SAA. In contrast, infantile-onset MLD cases gave only variably positive reactions on SAA. In summary, this study suggests MLD cases manifest α-synuclein pathology reminiscent of that observed in LBD, even in juvenile populations, further expanding the spectrum of sphingolipid storage disorders associated with the aggregation of α-synuclein. These findings have important implications for understanding the disease process of both LBD and MLD, potentially highlighting novel pathways for therapeutic interventions in both conditions.
2021-12-10 | Recent Advancements in the Diagnosis and Treatment of Leukodystrophies.
Leukodystrophies and genetic leukoencephalopathies comprise a growing group of inherited white matter disorders. Diagnostic rates have improved with increased utilization of next generation sequencing. As treatment options continue to advance for leukodystrophies, so will candidacy for inclusion in the United States' newborn Recommended Universal Screening Panel as was achieved for X-linked adrenoleukodystrophy. Stem cell therapies have become standard of care for selected leukodystrophies. However, transplantation-related risks remain high and outcomes are not fully satisfactory. Transduction of autologous hematopoietic stem cells with lentiviral vectors, referred to as ex vivo gene therapy, circumvents some, but not all, of the risks of traditional transplantation and has recently been demonstrated to be safe and efficective in clinical studies of X-linked adrenoleukodystrophy and metachromatic leukodystrophy. Gene therapy, through direct infusion of adeno-associated virus vectors, has emerged as a safer alternative for many monogenetic pediatric neurological disorders. Numerous preclinical studies have shown safety and efficacy of adeno-associated virus gene therapy in leukodystrophies allowing expanded access treatment for Canavan disease prior to initiation of a clinical trial. For inherited white matter disorders resulting from overexpression of a protein, such as Pelizaeus-Merzbacher disease, emerging RNA therapies have shown success in preclinical studies and promise for rapid translation to the clinic. Lastly, small molecule and protein therapies remain a long-term treatment option for a number of leukodystrophies, including intrathecal enzyme replacement therapy for metachromatic leukodystrophy. Herein we review recent advances in diagnosis and treatment of inherited white matter disorders.
2013-08-01 | Toward the successful delivery of lysosomal enzymes across the blood–brain barrier
Abstract The development of enzyme replacement therapy ( ERT ) has been one of the most remarkable successes of translational studies, bridging laboratory discoveries to clinical settings. Although ERT is very effective in clearing peripheral tissue storage in many lysosomal storage diseases ( LSD ), negotiating the blood‐brain barrier ( BBB ) remains a key challenge in delivering corrective lysosomal enzymes into the brain. In recent years, brain delivery of lysosomal enzymes has been vigorously pursued for treating neurodegenerative LSD . Delivery strategies include high‐dose and long‐term treatment regimens, manipulation of receptor‐mediated transport, biochemical engineering of enzymes, use of transport vectors, and enzyme administration by alternative routes. Most studies have investigated biochemical or histological improvements in central nervous system ( CNS ) storage after treatment. Few studies, however, have directly focused on the mechanisms of lysosomal enzyme transport across the BBB . In previous studies, we discovered that the luminally expressed mannose 6‐phosphate/insulin‐like growth factor‐ II receptor is a universal transporter of lysosomal enzymes. We and others have also successfully manipulated receptor‐mediated transport by using endogenous characteristics of the BBB . Interestingly, accumulating evidence indicates that some lysosomal enzymes employ multiple mechanisms for their transport across the BBB . This review provides a detailed discussion of the kinetics of lysosomal enzyme transport across the BBB , and the manipulation of transport characteristics based on studies of the transport of β‐glucuronidase, sulfamidase, arylsulfatase A and acid α‐glucosidase. Furthermore, recent achievements in treating abnormalities in CNS storage and their contribution to developing new therapeutic approaches are also discussed.
gene therapies
2026-08-11 | A study on the quality of life and burden of informal caregivers of children with metachromatic leukodystrophy in Poland
Abstract Background Metachromatic leukodystrophy (MLD) is a rare, inherited lysosomal storage disorder caused by a deficiency in arylsulfatase A (ARSA), leading to sulfatide accumulation, demyelination, and progressive neurological decline. Without treatment, patients – particularly those with early-onset forms – typically lose the ability to walk or communicate within months of symptom onset, and life expectancy is markedly reduced, often below 10 years. Although MLD is likely underdiagnosed in Poland, prevalence may be higher than average. Early diagnosis and prompt intervention with gene therapy (arsa-cel) are critical, as neuronal damage is irreversible. This exploratory study aimed to characterise the clinical course of MLD in Poland and assess the quality of life and financial well-being of caregivers. Results The study included 13 MLD patients and 28 caregivers. The most common forms were late-infantile (46.2%) and early-juvenile (38.5%). Most patients were classified as GMFC-MLD stage 6 (53.8%) and ELFC-MLD stage 4 (69.2%). Common symptoms included spasticity (84.6%), walking difficulties (84.6%), and speech disorders (69.2%). The mean age at diagnosis was 4.8 years, with 69.2% of caregivers reporting that delayed diagnosis adversely impacted the child’s health. Caregivers were predominantly female (67.9%) and reported high caregiving demands (mean = 35.7 h/week). WHOQOL-BREF scores exceeded medians for caregivers of people with rare diseases across all domains. Financial well-being was strongly correlated with physical health ( r = 0.636, p < 0.001) and psychological health ( r = 0.717, p < 0.001). Only 14.3% of MLD caregivers received psychological counselling at diagnosis, though 92.3% received financial support. Gene therapy was reported in 15.4% of cases; most patients received multiple forms of rehabilitative therapy. Conclusion MLD in Poland is characterised by early-onset, rapidly progressing forms that lead to severe disability and impose significant burdens on families. Delayed diagnosis was commonly reported in this cohort, with many caregivers indicating that it had negatively affected the child’s health and limited timely access to potentially disease-modifying treatments. Despite intensive caregiving responsibilities, many caregivers report a relatively preserved quality of life, especially when financial support is available. While these exploratory findings should be interpreted with caution, they support the need for improved early detection and coordinated care for individuals with MLD. Within this broader context, systematic newborn screening in Poland may facilitate earlier diagnosis and timely access to gene therapy, potentially improving patient outcomes and reducing the long-term burden on families and the healthcare system. Clinical trial number Not applicable
2026-08-03 | Gene therapy for rare diseases marks a new era in precision medicine: Insights from clinical trials
Gene therapy represents an important advance in the treatment of rare diseases, offering precise and transformative therapeutic strategies. As many rare diseases are associated with well-defined genetic variants, they represent ideal candidates for targeted genetic interventions. The substantial unmet medical need associated with rare diseases has driven growing interest in gene therapy, with more than 300 clinical trials reported to date. The aim of this study was to evaluate the current evidence on gene therapy for rare diseases by examining therapeutic strategies, target diseases, clinical progress, clinical outcomes, and emerging research trends. Several approved therapies, including those for hemophilia B, spinal muscular atrophy, metachromatic leukodystrophy, and Wiskott–Aldrich syndrome, have demonstrated the clinical potential of gene therapy. Clinical evidence suggests that gene-based therapies in the management of rare diseases can achieve sustained functional benefits, reduce disease-related complications, and lessen dependence on long-term replacement or supportive treatments. However, challenges in ethical considerations, regulatory requirements, manufacturing complexity, treatment costs, and limited patient access remain. Continued clinical evaluation is essential to further establish long-term safety and effectiveness. Advances in gene therapy technologies and clinical applications continue to expand therapeutic opportunities for rare diseases while supporting the broader development of precision medicine.
2026-07-22 | Design and application of prime editing to target ARSA P426L mutation in a metachromatic leukodystrophy patient
Metachromatic leukodystrophy (MLD) is a rare inherited lysosomal storage disease caused primarily by mutations in the Arylsulfatase A (ARSA) gene. Loss of functional ARSA leads to sulfatide accumulation, causing demyelination in the peripheral and central nervous system. MLD presents in different clinical forms, which all eventually result in severe neurological decline and death. Currently available treatment options are limited. Enzyme replacement therapy (ERT) and allogeneic hematopoietic stem cell transplantation (allo-HSCT) may slow disease progression but do not offer a cure. Libmeldy was recently approved by the European Medicines Agency (EMA) as the first gene therapy for early-onset forms of MLD. However, the potential long-term risk of insertional mutagenesis remains a concern and requires ongoing evaluation. In this project we targeted the ARSA P426L mutation, one of the most common MLD-causing mutations in Europe. We used prime editing, a CRISPR-Cas9 based mechanism, which allows to introduce precise changes into the genome. The experiments were carried out in K562 cells and hematopoietic stem and progenitor cells (HSPCs). If the ARSA P426L mutation could be corrected ex vivo in patient-derived HSPCs prior to transplantation, this approach could offer a potentially curative treatment for patients who are currently lacking effective therapeutic options. Such a strategy would eliminate the need to find a matching donor for allogeneic HSCT, evade its side effects and avoid the risk of insertional mutagenesis associated with Libmeldy. Instead, it would restore physiological ARSA expression by precisely correcting the mutation at its endogenous locus. In K562 cells, we successfully introduced the ARSA P426L mutation using prime editing, achieving mean editing efficiencies of 1.88% with PE2 and 10.20% with PE3. However, no editing was detected in HSPCs of healthy donors. As a result, this study did not progress to target patient-derived HSPCs. Further investigations are needed to focus on optimizing the prime editing mechanism as well as related components in order to achieve higher editing efficiency. Also research about target site specific limitations for prime editing should be closely monitored and taken into account when planning for future projects. Although editing of the ARSA P426L locus was not successful, the high efficiency to induce the IL2RG c.458T>C mutation in HSPCs, which was used as a proof of concept, supports the general feasibility of prime editing based gene therapy approaches.
2025-08-10 | Gene therapy for lysosomal storage diseases.
Lysosomal storage diseases (LSDs) are metabolic disorders caused by the dysfunction of enzymes and other substances localized in lysosomes, known as intracellular organelles. There are many types of LSDs, with a wide range of clinical manifestations. LSDs are highly amenable to gene therapy due to various reasons, including the fact that they are essentially monogenic diseases and existence of cross-correction mechanisms. The only gene therapy product currently approved for lysosomal diseases is one for metachromatic leukodystrophy, but several have progressed to phase III clinical trials such as the products for Mucopolysaccharidosis or Fabry disease. However, serious adverse events have been reported even with gene therapy methods that have been considered safe. Therefore, research on the safety of gene therapy is becoming increasingly important.
2025-05-28 | Newborn screening for metachromatic leukodystrophy: Preparation of reagents and methodology for measurement of sulfatides and arylsulfatase A enzymatic activity in dried blood spots.
Ex vivo gene therapy combined with haemapoietic stem cell transplant has recently been approved in Europe and the USA for treatment of metachromatic leukodystrophy (MLD). Since treatment is only efficacious if carried out in the pre-symptomatic or minimally-symptomatic phases, newborn screening (NBS) for MLD is warranted. MLD NBS is being developed worldwide through the International MLD Newborn Screening Alliance. Screening is carried out by measurement of the elevation of two sulfatide molecular species, 16: 0- and 16:1-OH-sulfatide in dried blood spots (DBS) followed by second-tier measurement of arylsulfatase A (ARSA) enzymatic activity in the same DBS. After 2-3 years of NBS assay development including pilot studies, members of the International MLD Newborn Screening Alliance arrived at a consensus set of assay protocols. In this article, we provide these protocols with full details so that the methods can be readily adopted by additional NBS laboratories. We also provide the full details of preparation of the required reagents.
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Drug Discovery Landscape
9 orphan drug designations for Metachromatic leukodystrophy, including 2 approved therapies.
9 orphan drug designations for Metachromatic leukodystrophy, including 2 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
recombinant fusion protein composed of a recombinant human arylsulfatase A (rhARSA) fused with a variable domain of the heavy chain of heavy chain-only antibody fragment targeting human transferrin | proteins | FDA | 2023-12-15 | — | Linno Pharmaceuticals, Inc. |
Adeno-associated virus serotype HSC15 expressing human arylsulfatase A | gene therapies | FDA | 2020-08-11 | — | Homology Medicines, Inc. |
Adeno-associated virus serotype HSC15 expressing human arylsulfatase A gene | gene therapies | EMA | 2020-06-26 | — | Propharma Group The Netherlands B.V. |
atidarsagene autotemcel [Lenmeldy] | cell therapies | FDA | 2018-03-08 | 2024-03-18 | Orchard Therapeutics Ltd. |
Recombinant human arylsulfatase A | proteins | EMA | 2010-11-26 | — | Takeda Pharmaceuticals International AG Ireland Branch |
recombinant human arylsulphatase A | proteins | FDA | 2008-04-11 | — | Shire Human Genetic Therapies |
arylsulfatase A (rhASA) | proteins | FDA | 2008-02-27 | — | Takeda Development Center Americas, Inc. |
Autologous CD34+ cells transfected with lentiviral vector containing the human arylsulfatase A cDNA [Libmeldy] | cell therapies | EMA | 2007-04-13 | 2020-12-18 | Orchard Therapeutics (Netherlands) B.V. |
Cebsulfase alfa | gene therapies | EMA | 2003-07-09 | — | Shire Pharmaceuticals Ireland Limited |
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