Restoring Activity of NAGLU Enzyme Corrected Metabolic Abnormalities in Sanfilippo, Mouse Study Finds

Restoring the activity of the alpha-N-acetylglucosaminidase (NAGLU) enzyme using an artificial viral vector successfully corrected metabolic abnormalities in a mouse model of Mucopolysaccharidosis IIIB (MPS IIIB), also known as Sanfilippo syndrome, a new study using mice shows.

The study, “Near-Complete Correction of Profound Metabolomic Impairments Corresponding to Functional Benefit in MPS IIIB Mice after IV rAAV9-hNAGLU Gene Delivery,” was published in Molecular Therapy.

MPS IIIB is a lysosomal disorder caused by mutations in the NAGLU gene that encodes for the NAGLU  enzyme. This enzyme usually is found in lysosomes, which are small compartments within cells that digest and recycle several molecules. It is essential to break down long complex sugar molecules called heparan sulfate glycosaminoglycans (HS-GAGs).

When genetic mutations reduce the activity of NAGLU, the HS-GAGs start to accumulate inside lysosomes, leading to broad metabolic impairments, inflammation and degeneration of the central nervous system. As research progressed and more therapies for MPS IIIB were being investigated, it became clear there was a  lack of accessible biomarkers necessary to facilitate patients’ assessments’ for therapies.

Researchers performed a global metabolic screen, using a technique called mass spectrometry, on the serum of mice with MPS IIIB and in healthy control animals to analyze the metabolic changes as the disease progressed.

From the 361 serum metabolites analyzed by mass spectrometry, 225 were reduced significantly — including eight essential amino acids, vitamins C, E, B2 and B6, and several neurotransmitters (serotonin, glutamate, aspartate, tryptophan, and N-acetyltyrosine) — while six were abnormally high in samples from MPS IIIB mice in comparison to healthy animals.

Moreover, these metabolic abnormalities appeared during the early stages of disease (before animals were two months old) and affected all major metabolism signaling cascades of amino acids, which are the building blocks of proteins, peptides, carbohydrates, lipids, nucleotides, vitamins and energy.

To evaluate the biomarker potential of serum metabolic profiling for MPS IIIB, researchers injected MPS IIIB animals with an artificial viral vector (called rAAV9-hNAGLU) designed to restore the activity of NAGLU. They then compared the effects to non-treated MPS IIIB mice and healthy controls.

Viruses have evolved specialized molecular mechanisms that allow them to efficiently transport their genes inside the cells they infect. Some viruses can integrate (blend) into the cell’s own DNA, facilitating stable gene expression, making them suitable vehicles for use in gene therapies.

Gene therapies have focused on the development of adeno-associated virus (AAV)-mediated gene therapies that target the brain. AAV gene therapy uses an inactive viral vector, which is similar to an empty shell, to deliver the gene-of-interest to a targeted location.

By restoring the activity of NAGLU with an intravenous injection of the artifical rAAV9-hNAGLU viral vector, researchers nearly corrected all the metabolic abnormalities previously reported (87 percent were corrected to normal levels and 13 percent were over-corrected).

Treated MPS IIIB mice also performed better at behavioral tasks and even survived for a longer period of time compared to non-treated animals, suggesting an improvement in neurological function.

“We also strongly believe that serum metabolomic profiles may provide a powerful tool for studying disease mechanisms and identifying specific potential biomarkers for assessing disease
progression, severity, and therapeutic outcome for MPS IIIB,” the authors wrote.

“Furthermore, this biomarker potential of serum metabolomic profiling observed may be applicable to humans, given the resemblance of the MPS IIIB mouse model to the human disease,” they added.

Taken together, the study authors contend, these findings demonstrate that reduced NAGLU activity plays a major role on the metabolic abnormalities triggered in the course of MPS IIIB. Furthermore, these metabolic anomalies can be corrected using a systemic rAAV9-hNAGLU gene delivery, which supports the use of serum metabolic profiling as a biomarker for MPS IIIB.