State of play: Development of enzyme replacement therapies for Sanfilippo

09 Nov 2021

Sanfilippo is a genetic disease that results in a form of childhood dementia. In Sanfilippo, there is a deficiency of one of four enzymes essential to break down heparan sulfate (HS), a complex sugar. There are currently no approved treatment options for Sanfilippo. Several therapeutic avenues are being explored, including enzyme replacement therapy.

What is enzyme replacement therapy?

Enzyme replacement therapy aims to introduce functional enzymes into the body to replace the enzyme that is missing or faulty. 

In Sanfilippo, enzyme replacement therapy aims to introduce one of the four affected enzymes: sulfamidase (type A), NAGLU (type B), HGSNAT (type C) or GNS (type D). The body uses the functional enzyme to complete the breakdown of HS.

What are the benefits of enzyme replacement therapy?

ERT has the potential to address the enzyme deficiency at the heart of Sanfilippo. By delivering the functional enzyme into the cell to degrade HS, it may be possible to minimise or even halt disease progression. 

ERT has been successfully developed and approved for use in Gaucher disease, a lysosomal storage disorder like Sanfilippo, which also involves the build-up of material due to an enzyme deficiency. The enzymes approved in Australia include: imiglucerase (Cerezyme®), velaglucerase (VPRIV®), and taliglucerase (Elelyso®). However, these three ERTs are unable to treat the neurological symptoms associated with some forms of Gaucher Disease. 

What are the challenges of enzyme replacement therapy?

As there are four separate enzymes involved for the four subtypes of Sanfilippo, ERT would need to be developed for each subtype. However, unlike chaperone therapy, an ERT could potentially be used for all patients with the same subtype, regardless of the type of genetic change that an individual has in that gene. 

For enzyme replacement therapy to be effective, the therapy must first get inside cells. Unfortunately, ERT cannot be taken orally, as the enzymes would get broken down by the digestive system. Instead, it must be injected directly into the bloodstream or into the liquid surrounding the brain or spinal cord (the cerebrospinal fluid, or CSF). To treat the neurological symptoms of Sanfilippo, an injection into the CSF is needed, because the large enzyme molecule does not cross the blood brain barrier. However, research is underway into enzymes that are modified so that they can cross more easily from the bloodstream into the brain tissue. This would mean they could be delivered by an intravenous infusion instead. 

Regular ERT administration is required, usually at intervals of 1-4 weeks. This is frequent compared to gene therapy, which currently is given as a single once-off dose.

While one Sanfilippo type B ERT clinical trial currently underway is showing some promise (see details below), other Sanfilippo ERT clinical trials completed previously have been unable to halt the cognitive decline. One possible explanation for this is that patients may need to start ERT at an earlier age to receive benefits from the therapy. This is supported by a study involving mice: Sanfilippo type A mice treated weekly with ERT from birth performed better in a spatial learning and memory test and had reduced toxic material in cells compared to mice that did not start treatment until 6 weeks of age. More research is needed to understand why earlier administration would lead to better outcomes, and what can be done to identify patients earlier or increase the treatment window.

Another potential challenge with ERT development involves the patient’s immune system. Some Sanfilippo patients may not produce any enzyme as a result of the change within their genes. This means that when ERT is delivered into the body, the immune system thinks it is ‘foreign’ like a bacteria or virus and develops immunity against it. In a clinical trial involving ERT for Sanfilippo type A, there was evidence that some patients’ immune systems were reacting to the ERT, possibly decreasing its effectiveness.

ERT is an expensive therapy to produce compared to other small-molecule therapies like chaperone therapy or substrate reduction therapy. This cost could be up to hundreds of thousands of dollars per year. As ERT technologies improve and become more common, it is hoped that their cost reduces substantially.

One further ERT challenge applies to Sanfilippo type C, as the type C enzyme, HGSNAT, sits in the membrane that encloses the lysosome, rather than floating inside. Because of this, it is harder to create an effective ERT for this subtype, and more work is needed in this area. 

What is the state of play for research into enzyme replacement for Sanfilippo?

There are researchers around the world working to develop and trial potential ERTs for Sanfilippo, including: 

For type A:

There are currently no active ERT clinical trials for Sanfilippo type A, but four trials by two sponsors have been completed or ended early. 

Swedish Orphan Biovitrum (SOBI) conducted an initial trial and an extension study of an ERT product for type A called SOBI003. Six children had weekly injections of ERT in the trial. Reduced heparan sulfate was seen in CSF, blood and urine samples, but the data did not indicate cognitive improvements. In April 2021, SOBI concluded their type A trial. 

Shire (now known as Takeda) also sponsored two type A ERT clinical trials, an initial trial and an extension study. In September 2021, long-term data from these trials was published.  A device implanted into the spinal column of patients was used, allowing the ERT to be injected into the fluid of the spinal canal and reach the brain. The ERT itself was well-tolerated by patients, but some side effects were experienced from the drug delivery device. Despite reduced HS levels in the cerebrospinal fluid, cognitive assessments at 54 months post-initial-treatment showed continued cognitive decline. Because key outcome measures were not met, the trial was discontinued.

For type B: 

The only Sanfilippo ERT trial currently active for type B involves Allievex Corporation’s ??Tralesinidase Alfa (AX 250). There have been 22 individuals treated biweekly with AX 250 to date, and the treatment has been well-tolerated. For 40% of rapidly progressing individuals, Allievex has reported stabilisation or improvement of cognitive development, which has been more pronounced in the patients who were younger at the start of treatment. Data on the cognitive development of attenuated (slowly progressing) type B patients is yet to come. The full clinical trial results have not yet been presented but Allievex has indicated that it is making preparations to seek FDA approval for the treatment. More information about the trial can be found in the clinical trial factsheet for type B here

Previously, Alexion (formerly Synageva) sponsored clinical trials into an ERT product called SBC-103 for Sanfilippo type B. In an initial study, 11 patients between 2-10 years of age were recruited. Patients received escalating doses of the ERT via intravenous infusion for around two years. Although the ERT treatment itself was well-tolerated, there was no clear evidence that the SBC-103 offered clinically meaningful neurocognitive benefits. In February 2017, Alexion decided to discontinue investigations into SBC-103.  

Researchers are continuing to investigate improvements for type B ERT, including the enzyme itself or its administration. In one study, Prof. Patricia Dickson and her team found a single ERT dose in newborn type B mice could provide similar levels of enzyme activity for the first 4 weeks after treatment. In this timeframe, there was no build-up of HS in the Sanfilippo mice treated. 

For type C: 

There are currently no ERT lines of investigation that we are aware of for Sanfilippo type C.

For type D: 

In one proof-of-concept study, a type D ERT was able to reduce the level of toxic build-up in type D cells to normal levels.  When the enzyme was injected directly into the ventricles (fluid-filled cavities in the brain that hold CSF) of newborn mice with Sanfilippo type D,  the HS levels were significantly decreased. Prof. Patricia Dickson and Prof. Tsui-Fen Chou led the study, in a collaboration with Phoenix Nest, Inc. The team is continuing to progress this research towards a clinical trial.


  • Enzyme Replacement Therapy (ERT) is a promising therapeutic avenue for Sanfilippo
  • For Sanfilippo, ERT aims to deliver working copies of the enzyme into the body, so the cells can break down heparan sulfate
  • There are challenges associated with ERT, including the patient’s age at administration, efficient delivery of the ERT to the brain, immunity to the ERT, and the cost of the therapy itself.
  • ERT is currently under investigation for Sanfilippo in clinical trials in Australia and around the world

More information on different therapy avenues currently in, or close to, a clinical trial can be found on our website: