Challenges of Enzyme Replacement Therapy for Sanfilippo Syndrome

Emily Malcolm, PhD avatar

by Emily Malcolm, PhD |

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Sanfilippo syndrome is a lysosomal storage disorder. Mutations in one or more of four genes — GNSHGSNATNAGLU, and SGSH — can cause the disease.

These four genes are important for the function of the lysosome, a cellular compartment responsible for breaking down cellular wastes. Without the enzymes that these genes code for, the lysosome can’t work as it should, leading to the build up of damaging waste products inside cells.

Unlike some other lysosomal storage disorders, Sanfilippo syndrome has symptoms that are primarily neurologic — largely affecting the central nervous system (brain and spinal cord) — which makes treatment challenging.

What is enzyme replacement therapy?

Enzyme replacement therapy (ERT) involves treating patients by supplying the enzyme or enzymes that they can’t make themselves. These enzymes are usually recombinant proteins, meaning that they are made artificially (in the laboratory) rather than being isolated, for example, from blood.

ERT and Sanfilippo syndrome

Several challenges must be addressed for ERT to be effective in Sanfilippo syndrome.

First, a Sanfilippo patient could be missing several enzymes. Therefore, doctors must test each patient to be sure which enzymes they aren’t able to make.

Second, recombinant proteins are not available as a pill, tablet or oral liquid that patients can take at home. This is because the digestive system would break down the proteins before they could make it to the bloodstream or the brain.

The third and final challenge is that Sanfilippo syndrome primarily affects the nervous system, so any treatment has to reach the brain. ERT infusions into the bloodstream would not be effective, because of the blood-brain barrier. This barrier consists of endothelial cells in blood vessels of the brain that protect the it by blocking the free movement of blood-borne molecules, cells and the like.

Getting treatments through the blood-brain barrier is difficult. Doctors would need to deliver the therapy either directly into the brain or into the cerebrospinal fluid (CSF, the fluid that surrounds the brain and spinal cord), or modify the treatment so that it could cross the barrier, which is very difficult. Delivery into the brain requires a small surgery, while delivery into the CSF is similar to a spinal tap or lumbar puncture.

At this time, it’s unclear whether a single use this type of therapy would be sufficient, or how often patients would need the treatment if a one-time treatment is unlikely.

Clinical trials for ERT for Sanfilippo syndrome

Two ERTs are being tested in clinical trials for Sanfilippo syndrome. One is tralesinidase alfa (previously BMN-250) being developed by Allievex, and the other is SOBI003 that Sobi (Swedish Orphan Biovitrum AB) is developing.

A Phase 1/2 clinical trial (NCT02754076) is testing the safety and efficacy of tralesinidase alfa in about 20 children, ages 1 to 10, with Sanfilippo syndrome type B. Participants are being given the medication once a week by injection into the CSF. The study’s main goal is safety, with researchers recording adverse events, and efficacy. The study is expected to conclude in July 2020.

The SOBI003 trial (NCT03811028), also a Phase 1/2 clinical trial, is testing this treatment’s safety and efficacy in nine toddlers and children (18 months to 78 months, or 6.5 years) with Sanfilippo syndrome type A. Participants are being given an intravenous infusion (into the bloodstream) once a week for 80 weeks. This experimental therapy has been modified in a way that should make it possible to cross the blood-brain barrier.

As this is an extension of an earlier trial, some children will have been treated with SOBI003 for a total of 104 weeks (two years) when this study concludes, set for December 2021.


Last updated: May 26, 2020


Sanfilippo Syndrome News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.