Central Nervous System Diseases

Enzymes are proteins that help break down or metabolize substances in the body. If certain enzymes are not present, the body will not be able to metabolize a substance. If the substance remains in the body, it may accumulate. This can lead to serious health complications. For example, metachromatic leukodystrophy (MLD) occurs when an enzyme called arylsulfatase A (ARSA) is not present in the body.

MLD is an autosomal recessive disorder and is a common lysosomal disease. Its pathogenesis is due to ARSA deficiency, which blocks brain sulfolipid hydrolysis in the lysosome. Therefore MLD is also known as ARSA deficiency. There are three forms of MLD, including late infantile MLD (found in children 6 to 24 months of age), adolescent MLD (found in children 3 to 16 years of age), and adult MLD (found in adolescents or adults of any age). Each form produces similar symptoms and is identified by the age at which they appear.

It has been reported to occur in 1 in 40,000 to 160,000 people worldwide. The disease is characterized by progressive central and peripheral demyelination, leading to severe neurological deterioration. The most prominent signs and symptoms are ataxia, spasticity, cognitive decline, behavioral disturbances, and peripheral neuropathy. This eventually leads to a severe state of disability with epilepsy, painful spasticity, loss of motor and communication skills, and premature death.

Figure 1. Expression of GFP and ARSA in the brains of treated MLD mice. (Miyake, N., et al., 2021)

Over 110 mutations in the ARSA gene that cause MLD have been identified. These mutations greatly reduce ARSA activity. Severe disruption of ARSA activity interferes with the catabolism of sulfatide. This leads to the accumulation of fatty substances (lipids) in cells (especially in the brain, spinal cord, and peripheral nerves) to toxic levels. This causes lesions in the white matter of the brain, peripheral nerves, and other visceral tissues, leading to demyelinating neurodegenerative diseases that produce severe metabolic abnormalities.

There is no cure for MLD. The presence of the blood-brain barrier (BBB) hinders the development of enzyme replacement therapies (ERT) and gene therapy for MLD, which impede the delivery of therapeutic products to the brain. Depending on the form and age of onset, early diagnosis and treatment can only manage some of the signs and symptoms and mitigate the progression of the disease.

Creative BioMart provides ARSA protein products to customers in the field of CNS disease research to advance ARSA mutation research and MLD therapeutic research. Please feel free to contact us if you have any needs for our products. You can also place your order online. We look forward to working with you in the field of neurocentral system diseases.

Reference:

1. Miyake, N., et al., (2021). "Treatment of adult metachromatic leukodystrophy model mice using intrathecal administration of type 9 AAV vector encoding arylsulfatase A." Scientific Reports, 11, 20513.