Using different cellular models of Sanfilippo syndrome type B, researchers have found that exposure time and dose significantly affect the cellular uptake of BMN 250, an investigational enzyme replacement therapy, and the clearance of sugar molecules called heparan sulfate.
Sanfilippo syndrome type B, also known as mucopolysaccharidosis type IIIB (MPS IIIB), is a rare genetic lisosomal storage disorder (LSD) caused by mutations in the NAGLU gene, which provides instructions to make the alpha-N-acetylglucosaminidase (NAGLU) enzyme.
This enzyme, usually found in lysosomes — small, specialized cell compartments that digest and recycle different types of molecules — is essential for breaking down heparan sulfate, which are long complex sugar molecules. When genetic mutations reduce the activity of NAGLU, heparan sulfate starts to accumulate inside the lysosomes, causing brain atrophy (shrinkage) and gradual cognitive decline.
Although there are no approved treatments for MPS IIIB, enzyme replacement therapy (ERT) — a technique in which a faulty enzyme is replaced by a healthy one — has shown promise.
BMN 250 (NAGLU-IGF2) is an investigational ERT currently being evaluated in a Phase 1/2 clinical trial (NCT02754076). That trial is testing the therapy’s safety and tolerability, and its impact on cognitive function in people with MPS IIIB.
It is a lab-made version of NAGLU, in which the enzyme is fused together with the insulin-like growth factor 2 (IGF2), a small peptide that promotes the association of NAGLU to lysosomes.
Researchers from Biomarin Pharmaceuticals, the company developing this ERT, now tested the ability of BMN 250 to decrease the amount of heparan sulfate in different cellular models of disease, compared with a normal version of the enzyme.
To do so, they first created three different primary cellular models of MPS IIIB in which heparan sulfate accumulated inside lysosomes. One model was composed by MPS IIIB human fibroblasts, another by MPS IIIB mouse neurons, and a third by MPS IIIB mouse astrocytes.
A primary cell line is one that has been established by cells isolated directly from a tissue source, and then placed in a lab dish, without being maintained in the lab for long periods of time. Fibroblasts are cells from the connective tissue, while astrocytes are star-shaped nerve cells thought to provide support to neurons.
NAGLU uptake and heparan sulfate clearance occurred similarly in cells treated with BMN 250 or regular NAGLU, if constantly exposed to either compound.
However, when cells were exposed to the compounds for shorter periods of time, BMN 250 was uptaken faster than normal NAGLU by all cell types, reducing the levels of heparan sulfate in a more efficient way.
“In comparing the differential uptake and cellular activity of NAGLU-IGF2 [BMN 250] and unmodified NAGLU, we discovered that both exposure time and dose significantly affects cellular uptake of recombinant NAGLU and the subsequent clearance of lysosomal [heparan sulfate],” the researchers said.
“Our cellular models incorporating short exposure times are potentially more physiologically relevant than models using sustained exposure. Since in these models, NAGLU-IGF2 has a lower effective concentration and is more rapidly taken up compared to unmodified NAGLU, it would be interesting to compare the two in vivo [in the body] to see if these distinctions hold and which might have the highest clinical benefit,” they added.
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