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Metachromatic Leukodystrophy (MLD)

The primary therapeutic challenge in metachromatic leukodystrophy (MLD) lies in delivering effective treatments across the blood-brain barrier to halt rapid neurodegeneration before irreversible damage occurs. With our deep expertise in MLD therapy development, Protheragen is well positioned to provide tailored solutions and comprehensive support to facilitate your journey from MLD therapy research to commercialization.

Introduction to Metachromatic Leukodystrophy (MLD)

Metachromatic leukodystrophy (MLD) is a rare, fatal lysosomal storage disorder (LSD) characterized by progressive demyelination of the central and peripheral nervous systems. The disease results from impaired sulfatide metabolism due to arylsulfatase A (ARSA) deficiency (95% of cases) or, rarely, saposin B deficiency. With an estimated incidence of 1 in 40,000 to 160,000 live births, MLD presents in three primary clinical forms:

Subtypes	Onset Age	Progression	Initial Symptoms	Common Mutations
Late-Infantile MLD	6–24 months	Rapid (death in 5–10 years)	Motor regression (crawling/walking loss)	c.459+1G>A, p.P426L
Juvenile MLD	3–10 years	Moderate (survived into teenage or twenties)	Academic/behavioral decline, ataxia	p.I179S, p.D255H
Adult MLD	Adolescence to adulthood	Slow (decades-long decline)	Psychiatric (dementia, personality changes)	p.G86D, p.T274M

Pathogenesis of Metachromatic Leukodystrophy (MLD)

Metachromatic leukodystrophy (MLD) is caused by deficient arylsulfatase A (ARSA) or saposin B activity, leading to toxic sulfatide accumulation in nervous system cells. This primarily affects myelin-producing oligodendrocytes and Schwann cells, triggering progressive demyelination in both central and peripheral nervous systems. The resulting neurodegeneration manifests as severe motor and cognitive decline, with symptom severity inversely correlating with residual enzyme activity.

Schematic diagram of the sulfatide metabolic pathway. Fig.1 Sulfatide metabolic pathway. (Shaimardanova A A, et al., 2020)

Therapeutic Development for Metachromatic Leukodystrophy (MLD)

Drug Names	Mechanism of Action	Targets	NCT Number	Research Phase
HGT-1110	Recombinant enzyme replacement that crosses the blood-brain barrier via receptor-mediated uptake to degrade accumulated sulfatides	Lysosomal sulfatides	NCT01510028	Phase I/II
Metazym	Engineered human arylsulfatase A enzyme supplement to restore sulfatide breakdown in lysosomes	ARSA enzyme	NCT00418561	Phase I
Warfarin	Indirect sulfatide reduction by blocking vitamin K-dependent glycosphingolipid synthesis pathways	Vitamin K epoxide reductase	NCT00683189	Phase I/II
SHP611	Lentiviral gene therapy inserting functional ARSA gene into patient's hematopoietic stem cells to enable enzyme production	ARSA gene	NCT03771898	Phase II/III

Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.

Our Services

Specializing in comprehensive solutions for metachromatic leukodystrophy (MLD), Protheragen integrates diagnostic development with cutting-edge in vitro diagnostic (IVD) kits for early disease identification. Our therapeutic development pipeline leverages exclusive disease models, such as physiologically representative blood-brain barrier (BBB) models, to expedite the exploration and authentication of central nervous system (CNS) targeted treatments.

Therapeutic Development Services

By Molecule Types

By Mechanism of Action

Disease Model Development Services

In Vitro Model Development
Patient-Derived Cell Model Development Neuronal Cell Model Development Glial Cell Model Development	Co-Culture Model Development Brain Organoid Development Spinal Cord Organoid Development
Microfluidic Model Development
Neurovascular Unit (NVU) Model Development Axon Degeneration Model Development Neuromuscular Junction (NMJ) Model Development	Neuroinflammation Model Development Synaptic Plasticity Model Development Organoid-on-a-Chip Model Development
Animal Model Development
ARSA Knockout Mice: These mice are created by disrupting the ARSA gene, leading to a deficiency in the enzyme responsible for breaking down sulfatides, a hallmark of metachromatic leukodystrophy (MLD). SapB Deficient Mice: These models have a mutation in the prosaposin gene, affecting the production of saposin B, which is also involved in sulfatide metabolism.

Specializing in comprehensive preclinical assessment, Protheragen offers professional pharmacodynamic (PD), pharmacokinetic (PK) and toxicology research services to accelerate the therapeutic development of metachromatic leukodystrophy (MLD). If you are interested in our services, please feel free to contact us for more details and quotation information of related services.

Reference

Shaimardanova A A, Chulpanova D S, Solovyeva V V, et al. Metachromatic leukodystrophy: diagnosis, modeling, and treatment approaches[J]. Frontiers in medicine, 2020, 7: 576221.

For research use only. Not intended for any clinical use.