Treating Sanfilippo syndrome type A (SSA) may be possible with a fusion protein that effectively reaches the brain, according to lab research with mice.
The study, “Reduction in Brain Heparan Sulfate with Systemic Administration of an IgG Trojan Horse-Sulfamindase Fusion Protein in the Mucopolysaccharidosis Type IIIA Mouse,” appeared in the journal Molecular Pharmaceutics.
Sanfilippo syndrome type A is caused by mutations in the gene that provides instructions to make the enzyme SGSH, also known as sulfamidase, or heparan N-sulfatase.
A deficiency in SGSH results in the accumulation of aggregates made of large sugar chains called heparan sulfate. These molecules can create deposits in brain lysosomes — the cellular organelles responsible for the breakdown of storage material — leading to dysfunctions in the central nervous system.
Because SGSH is not able to cross the blood-brain barrier, enzyme replacement therapy with intravenous administration of SGSH has not been possible.
A possible alternative would be intrathecal — via the spinal canal — infusion, but chronic treatment by this route is not possible in humans, and researchers are unsure if this approach would enable proper distribution of the enzyme in the brain.
To overcome this limitation, researchers engineered SGSH by fusing it with an antibody domain (IgG) against the mouse transferrin receptor (called cTfRMAb). The antibody domain acts as a molecular Trojan horse to enable SGSH delivery into the brain.
The fusion protein was able to bind to the mouse transferrin receptor with high affinity and retained high SGSH activity in the brain — similar to the human SGSH.
The usual dose (5 mg/kg body weight) of the fusion protein “is expected to produce a therapeutic level of SGSH enzyme activity in the brains of mice,” the team wrote.
Researchers treated a mouse model of Sanfilippo syndrome type A, which completely lacks SGSH, with 5 mg/kg of the cTfRMAb-SGSH fusion protein.
This led to a 70% reduction in brain heparan sulfate, and an 85% reduction in liver heparan sulfate. Treatment was administered to the mice over six weeks via intra-peritoneal injections — into the lining of the abdominal cavity — starting at 2 weeks of age.
A decrease in brain heparan sulfate was associated with a 28% improvement in motor activity in male mice.
Investigators observed no injection-related reactions and limited production of anti-cTfRMAb-SGSH antibodies, which is indicative of the protein’s safety.