Metachromatic Leukodystrophy (MLD)
Metachromatic leukodystrophy (MLD) is a rare hereditary white matter disease caused by mutations in the arylsulfatase A (ARSA) gene. Almost all individuals ultimately experience complete loss of motor and cognitive functions. At our company, we've assembled a team of seasoned professionals with a wealth of experience in navigating drug and therapy development challenges specific to metachromatic leukodystrophy.
Introduction to Metachromatic Leukodystrophy
Metachromatic leukodystrophy is a rare genetic condition characterized by the accumulation of fatty substances, specifically sulfatides, within cells, especially affecting the brain, spinal cord, and peripheral nerves. This accumulation occurs due to a deficiency in the enzyme arylsulfatase A, which is responsible for breaking down sulfatides. As a result, the protective myelin sheath covering nerve cells becomes damaged, leading to a progressive decline in brain and nervous system functions. The global incidence of MLD ranges from 1 in 40,000 to 1 in 160,000 births.
Fig. 1 Two main mutations responsible for MLD and gentotype-phenotype correlation. (Gieselmann, V. and Krageloh-Mann, I., 2010)Pathogenesis of Metachromatic Leukodystrophy
Metachromatic leukodystrophy is caused by a deficiency in the lysosomal enzyme arylsulfatase A (ARSA) or its activator protein SapB, leading to the accumulation of sulfatides that damage the myelin sheath covering nerve fibers. This deficiency results from mutations in the ARSA and PSAP genes, with disease severity influenced by the type of mutation and residual ARSA activity. The accumulation of sulfatides disrupts cellular homeostasis and induces inflammation, causing progressive motor and cognitive impairments.
Fig. 2 Main pathophysiological mechanisms in argininosuccinic aciduria. (Shaimardanova, A.A., et al., 2020)Therapeutics Development of Metachromatic Leukodystrophy
Table. 1 Therapeutic approaches for MLD therapy undergoing in vivo animal studies.
| Therapeutic agent | Model | Therapeutic regimen | Therapy results |
|---|---|---|---|
| Cell therapy | |||
| MGTA-456 (population of CD34+CD90+ cells) | Immunodeficient NSG mice | NA | Microglia engraftment efficiency increased by 10 times |
| ERT | |||
| Recombinant ARSA enzyme | ARSA knockout mice | Continuous administration of the enzyme into the right lateral ventricle of the brain for 4 weeks | Sulfatide storage in the infused hemisphere decreased by 51–56%, while the enzyme had a short CSF half-life of 10 minutes |
| Chimeric ARSA protein crosslinked with mouse IgG domain of transferrin receptor | ARSA knockout mice | Intraperitoneal or subcutaneous administration of 5 mg/kg of protein three times a week for 5 weeks | The safety of recombinant protein was confirmed |
| Gene therapy | |||
| AAV5-ARSA | ARSA-deficient mice | Injection of 3×109 vg of the virus into the cerebellar vermis and the left and right internal capsules | Sustained expression of recombinant ARSA in the brain (3–15 months) to prevent neuropathological and neuromotor disorders |
| AVV9-ARSA | Newborn ARSA knockout mice | Injection of 2×1012 vg of the drug into the jugular vein of newborn mice | Long-term enzyme expression (up to 15 weeks) primarily in muscles and heart, with moderate CNS expression |
| Gene-cell therapy | |||
| HSCs genetically modified to overexpress ARSA | ARSA knockout mice | BMT | Enzyme levels rose to 33% of normal in the CNS, 100% in the kidneys, and 800% in the spleen and bone marrow. Sulfatide levels decreased, and neurophysiological disorders were normalized. |
Our Services
Our company adopts a collaborative approach, partnering closely with clients to create tailored and innovative therapy strategies for Metachromatic Leukodystrophy. Our focus on customized strategies ensures that we meet your individual needs with the highest level of support and guidance.
Platforms of Metachromatic Leukodystrophy Therapy Development
Animal Models of Metachromatic Leukodystrophy
We have considerable expertise in developing and employing animal models that accurately replicate the disease characteristics and therapeutic responses seen in Metachromatic Leukodystrophy. These models are instrumental in investigating the underlying mechanisms and assessing the safety and effectiveness of prospective therapies with precision.
Non-Genetically Engineering Models
They are biological systems used in research that do not involve the manipulation or alteration of an organism's genetic material.
Optional Models: Hyperammonemia Induction Model; Amino Acid Restriction Model; Urease Injection Model
Genetically Engineering Models
Genetically engineering models involve the manipulation of genetic material to study specific disease mechanisms and therapeutic interventions.
Optional Models: ARSA Knockout Mice Mode; Saposin B (SapB) Deficient Mice Model; Transgenic Models with Human ARSA Mutations
Moreover, we provide a variety of detailed animal model services focused on particular signaling pathways and molecular targets.
If you are interested in our services, please don't hesitate to contact us.
References
- Gieselmann, V. and Krageloh-Mann, I., "Metachromatic leukodystrophy--an update." Neuropediatrics, (2010). 41(1): p. 1-6.
- Shaimardanova, A.A., et al., "Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches." Front Med (Lausanne), (2020). 7: p. 576221.
All of our services and products are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.