Sanfilippo B Enzyme Replacement Therapy M041 Can Get Into Cells

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Brain-in-a-Dish models | Sanfilippo Syndrome News | illustration of cells in petri dishes

M041, an enzyme replacement therapy M6P Therapeutics (M6PT) is developing for Sanfilippo syndrome type B, can effectively be transported into cells, proof-of-concept preclinical data show.

With data showing such “increased efficiency … M041 is a potential novel recombinant enzyme therapy for Sanfilippo B syndrome,” M6PT said in a press release.

The results were presented at the 16th Annual International Symposium of MPS and Related Diseases (MPS 2021), in a poster titled “Recombinant human NAGLU with improved mannose 6-phosphorylation for Sanfilippo B syndrome.”

Sanfilippo B is caused by mutations in the gene NAGLU, which provides instructions for making an enzyme called alpha-N-acetylglucosaminidase. Normally, this enzyme is present in the lysosomes — a cell’s “recycling centers” — where it helps to break down a complex sugar molecule called heparan sulfate.

Mutations in NAGLU that cause Sanfilippo B lead to a functional lack of the enzyme, allowing the sugar molecule to accumulate to toxic levels in the body. Such buildup causes systemwide damage to the body, especially to brain tissue.

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“There are currently no approved therapies for Sanfilippo B syndrome, also known as MPS IIIB,” said Patricia Dickson, MD, chief of the division of genetics and genomic medicine at Washington University of St. Louis, in Missouri.

M041 uses a lysosomal enzyme “as the key to developing a potentially effective therapy to treat this rare pediatric disorder,” said Dickson, a co-author of the poster. She served as its presenter at the recent virtual MPS 2021 conference.

“I anticipate that M6PT’s platform technology will lead to advancements in therapies for other LSDs [lysosomal storage diseases],” Dixon added.

The overall goal of enzyme replacement therapy, or ERT, is exactly what the name suggests: to administer a “replacement” version of a missing enzyme. In this case, M041 would allow the body to break down heparan sulfate.

However, getting the therapy into the body’s cells is no easy feat — and the NAGLU enzyme specifically needs to be in lysosomes in order to function.

The way enzymes are trafficked around inside cells is extremely complex, and governed by a multitude of biochemical processes. In simple terms, one strategy used to regulate intracellular traffic is by attaching small molecular “tags” to proteins that are meant to go to a particular destination.

One such tag is a small sugar molecule called mannose 6-phosphate, which is attached to molecules bound for the lysosome. M041 is a version of the NAGLU enzyme that is engineered to have increased amounts of mannose 6-phosphate.

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In the MPS 2021 poster, researchers described the production of the “tagged” enzyme. This involves genetically engineering cells in a dish so that they produce the NAGLU enzyme, and also make a modified, more efficient version of an enzyme called GlcNAc-1-phosphotransferase, which is able to add the mannose 6-phosphate tag to other proteins.

Through a series of biochemical tests, the researchers demonstrated that the NAGLU enzyme produced in this manner did indeed have increased amounts of the lysosome-targeting molecular tag. They also showed that the added tag did not change the enzyme’s stability.

Finally, the team demonstrated that the NAGLU enzyme with the additional mannose 6-phosphate was able to more effectively get into cells. Once in the cells, the tagged version was active, implying that it effectively got to the lysosome. Notably, blocking mannose 6-phosphate receptors (by adding excessive amounts of the molecular tag) inhibited the tagged enzyme’s ability to get into cells and be active.

The researchers concluded that their system “is an effective way to improve the mannose 6-phosphate content of [the NAGLU enzyme], making it more suitable for use as enzyme replacement therapy.”