A new treatment approach effectively carried the enzyme defective in Sanfilippo type A syndrome into the brains of mice in a disease model, researchers report, suggesting the strategy used may be of future importance to patients.
The study, “Reduction in Brain Heparan Sulfate with Systemic Administration of an IgG Trojan Horse-Sulfamindase Fusion Protein in the Mucopolysaccharidosis Type IIIA Mouse,” was published in the journal Molecular Pharmaceutics.
Patients with Sanfilippo Type A syndrome have an abnormal accumulation of heparan sulphate (HS) in their brain cells, affecting the central nervous system. This occurs due to a mutation in the gene which codes for the lysosomal enzyme N- sulfoglucosamine sulfohydrolase (SGSH or sulfamidase), involved in the break down of HS.
Enzyme replacement therapy (ERT) is used to treat several lysosomal storage disorders. It replaces the enzyme that is deficient or absent in the body with a synthetic enzyme given directly to patients’ bloodstream.
But ERT is not an option for Sanfilippo type A patients, because a synthetic SGSH is too large to cross the blood-brain barrier (BBB) — the semipermeable membrane that protects the brain from substances trying to enter.
Researchers at ArmaGen have developed a form of SGSH that is able to cross the BBB and be delivered to its site of action, using a strategy that resembles a “Trojan horse” approach.
The team synthesized a SGSH enzyme coupled to an antibody that recognizes a receptor protein normally present in the blood-brain barrier, known as the transferrin receptor. This fusion was able to “disguise” the enzyme so that it could be transported across the BBB.
Sanfilippo type A mouse models received injections of the new fusion protein threes times a week for six weeks. Post-treatment analyses found these mice had a 70% and 85% reduction in HS levels in their brain and liver, respectively. The mice also showed a 28% improvement in a test of motor activity.
Importantly, fusion protein injections were tolerated and no adverse effects were detected.
Researchers believe these results may be extended to human studies, suggesting that similar fusion protein injections “may treat the brain with non-invasive administration of the enzyme via intravenous infusion.”