Enzyme Replacement Therapy for Sanfilippo A Shows Promise
Tests in mouse models showed brain levels of disease biomarkers were reduced
A novel enzyme replacement therapy developed by BioMarin Pharmaceutical for Sanfilippo syndrome type A showed promising effects in a mouse model of the disease, a study showed.
Researchers were also able to identify a previously unknown receptor protein that lets the enzyme enter cells.
The study, “Intracerebroventricular dosing of N-sulfoglucosamine sulfohydrolase in mucopolysaccharidosis IIIA mice reduces markers of brain lysosomal dysfunction,” was published in the Journal of Biological Chemistry.
Sanfilippo type A, the most common and severe form, is caused by mutations that impair the production of the N-sulfoglucosamine sulfohydrolase (SGSH) enzyme. Like other forms of Sanfilippo, it is caused by the toxic accumulation of heparan sulfate, a long complex sugar molecule, inside cells.
Enzyme replacement therapy, or ERT, is a therapeutic strategy that basically aims to deliver a working version of the missing SGSH enzyme to a patient’s cells. While some investigational ERTs for Sanfilippo A have entered clinical trials, results have generally been disappointing.
One potential explanation for the poor results may be that not enough of the delivered enzyme is reaching cells, since it needs to physically enter cells to do its job.
“In order to properly interpret ERT biodistribution and [heparan sulfate] clearance results, a thorough understanding of cellular uptake mechanisms is necessary,” the researchers wrote.
SGSH is known to enter cells through a receptor protein called CI-MPR, since blocking these receptors reduces the amount of the enzyme that can enter cells. However, cells without CI-MPR can still take up SGSH, implying that another receptor may be involved in the enzyme’s uptake. The identity of this receptor has not been known.
SGSH enzyme as potential ERT
Now, BioMarin developed a lab-made version of a highly soluble and fully active SGSH enzyme as a potential ERT for Sanfilippo type A.
As part of the therapy’s characterization process, the researchers evaluated its uptake in lab-grown structural cells called fibroblasts from a Sanfilippo A patient. They performed a series of experiments in these fibroblasts and in mouse fibroblasts to evaluate how well the cells could take up the enzyme when different receptor proteins were blocked.
Results showed that blocking a protein receptor called LRP1 reduced the uptake of SGSH into cells. Simultaneously blocking both LRP1 and CI-MPR completely prevented the enzyme from entering into the cells.
“Thus, both LRP1 and CI-MPR mediate [the ERT] cellular uptake in fibroblasts,” the researchers wrote.
The team then tested the therapy, administered through intracerebroventricular (ICV) injections, in a mouse model of Sanfilippo type A.
Intracerebroventricular administration means the treatment was injected directly into the cerebrospinal fluid (the fluid surrounding the brain and spinal cord) of the cerebral ventricles, the four fluid-filled interconnected cavities in the brain.
Results showed that a single dose of the therapy led to a widespread distribution of the delivered enzyme throughout the brain. Also, therapy levels were reduced by half after about nine days, and levels of heparan sulfate and the disease-specific form of heparan sulfate showed the lowest levels after two years.
Two months of weekly treatment at a dose of 148 micrograms significantly reduced levels of heparan sulfate and disease-specific heparan sulfate in cells by over 95%. While total heparan sulfate levels remained significantly higher than what’s seen in healthy mice, those of the disease-specific form were found to be normalized in seven of the eight treated mice.
The brain levels of biomarkers of disease mechanisms were also significantly reduced.
These findings highlighted that “ICV delivery of a sufficient amount of [this ERT], higher than previously tested in humans, should be expected to eliminate [heparan sulfate] accumulation in [Sanfilippo type A] patients,” the researchers wrote.
Additional pilot tests suggested that comparable effects might be possible with lower and/or less frequent doses. Further studies “could evaluate these hypotheses and may help define the optimal dose and treatment regimen,” the team wrote.
Notably, the team noted that these findings are comparable to those previously reported for tralesinidase alfa (formerly known as BMN 250), a potential ERT for Sanfilippo type B, in a mouse model of the disease.
Originally developed by BioMarin and now owned by Allievex, tralesinidase alfa has also showed promising results in children with Sanfilippo type B in a Phase 1/2 clinical trial (NCT02754076).