Enzyme replacement therapy (ERT) has been explored as a potential therapeutic option for mucopolysaccharidosis type III A (MPS III-A or Sanfilippo syndrome type A). However, these solutions have not performed well in clinical studies. Some believe that this is because the enzyme is not adequately reaching or entering cells. Since there is no effective treatment option for MPS III-A, overcoming these obstacles is urgent and needed.
Researching ERT Solutions
According to an article in Sanfilippo News, BioMarin Pharmaceutical (“BioMarin”) is currently working on developing a novel ERT designed for MPS III-A. This ERT delivers a lab-made, highly soluble, and fully active N-sulfoglucosamine sulfohydrolase (SGSH) enzyme via the LRP1 receptor.
SGSH enters into cells through the CI-MPR receptor. But even when this receptor is blocked, SGSH can still enter into certain cells. Researchers discovered that this is due to the LRP1 receptor; this was not previously known. In a study published in the Journal of Biological Chemistry, a research team found that blocking both of these receptors stopped SGSH from entering cells. However, they wondered whether leveraging the LRP1 receptor could improve ERT efficacy.
To test this, the research team administered SGSH ERT intracerebroventricularly to mice models of MPS III-A. They found that the drug was effectively delivered throughout the brain, even with a single dose. With a weekly treatment, the ERT significantly reduced heparan sulfate levels, stopped heparan sulfate from accumulating, and lowered MPS III-A related biomarkers.
More research is needed on dosages, safety, and whether this may be effective in humans and not just mice models. However, it does suggest that a potential treatment for MPS III-A could be on the horizon.
About MPS III-A (and Other Forms of MPS III)
Mucopolysaccharidosis type III is also known as Sanfilippo syndrome. This rare disorder primarily affects the central nervous syndrome (CNS). MPS III occurs when the body has an enzyme deficiency which prevents the breakdown of long chains of sugar molecules called heparan sulfate.
There are four main types of MPS III. The first type, MPS III-A, is the most common and most severe form; these individuals lack a normal heparan N-sulfatase enzyme. Next, those with MPS III-B are missing alpha-N-acetylglucosaminidase or have deficient levels. Then, in MPS III-C, people are missing or deficient in acetyl-CoAlpha-glucosaminide acetyltransferase. Finally, MPS III-D is characterized by missing or deficient N-acetylglucosamine 6-sulfatase.
Many children born with Sanfilippo syndrome show no signs at birth but develop symptoms in early childhood (between 2-5 years old). Symptoms can, but do not always, include:
- Frequent ear or throat infections
- Persistent diarrhea
- Developmental delays or regression
- Delayed speech
- Behavioral issues such as hyperactivity, impulsivity, or irritability
- “Coarse” facial features
- Stiff joints that do not extend fully
- Sleep difficulties or disruptions
- Excess hair growth
- Enlarged liver and/or spleen
- Cardiomyopathy
- Seizures
